Crosslinkable liquid composition for use in a method of myopia management in a subject

Abstract

The invention relates to a crosslinkable liquid composition comprising a gelatin or a gelatin-based crosslinkable biomaterial for use in a method of myopia management in a subject, such as for use in a method of one or more of preventing or reducing the progression of myopia or preventing an eye disease associated with myopia progression in a subject. In particular, the method may comprise: applying a crosslinkable liquid composition onto the anterior corneal surface of the eyes of the subject, wherein the method comprises introducing the crosslinkable liquid composition into a mold which is positioned onto the anterior corneal surface of the eyes; crosslinking the crosslinkable liquid composition on the anterior corneal surface of the eyes, thereby obtaining a crosslinked composition on the anterior corneal surface of the eyes; and correcting the curvature of the crosslinked composition to create a peripheral myopic defocus.

Description

[0001] CROSSLINKABLE LIQUID COMPOSITION FOR USE IN A METHOD OF MYOPIA MANAGEMENT IN A

[0002] SUBJECT

[0003] FIELD OF THE INVENTION

[0004] The invention is broadly in the field of medicine, more precisely in the field of ophthalmology. In particular, the invention concerns the use of a crosslinkable liquid composition in a method of myopia management in a subject such as in a method of preventing or reducing the progression of myopia, e.g., juvenile onset myopia, and / or in a method of reducing the risk of eye conditions that occur as myopia worsens.

[0005] BACKGROUND OF THE INVENTION

[0006] Myopia, also known as near-sightedness, is a common vision condition and occurs when the eyeball is longer than usual or when the cornea (i.e., the clear front surface of the eye) has too much curvature. As a result, light entering the eye focuses in front of the retina instead of directly on it. It is one of the most prevalent refractive errors estimated to affect 34% of the human population. By 2050 it has been estimated that myopia will affect 50% of the world population. The cause of myopia remains unclear. While it is known to have a degree of genetic inheritance, also environmental factors such as the number of years in education is known to play a role.

[0007] While there are a number of options to correct myopia - spectacles, contact lenses, laser - the increasing prevalence of myopia is associated with a number of other pathological conditions. In most cases, the myopia is associated with increased growth of the axial length of the eye. These changes are associated with cataract, glaucoma, retinal detachment, and macular damage, all of which can lead to visual loss that cannot be improved with lenses.

[0008] The majority of myopia occurs during childhood while the eye is still developing. This is typically between the age of 8-13 years and is known as juvenile onset myopia. Given the increasing prevalence as well as the health and societal implications, there is a need for treatment strategies that prevent the development of myopia rather than just correct it.

[0009] Myopia management refers to various strategies and treatments aimed at slowing down the elongation of the eyeball (i.e., the axial length) and thus slowing the progression of myopia. Therefore, there is a clear difference between the correction of myopia and its management. The goal of myopia management is to reduce the degree of myopia and the risk of associated eye conditions that can occur as myopia worsens. Currently, there are a number of strategies aimed at slowing myopia progression. First, low-dose atropine eye drops have been shown to slow down the elongation of the eyeball and reduce the progression of myopia. By temporarily relaxing the focusing mechanism of the eye, i.e., the ciliary muscle, atropine reduces the accommodative effort and the associated elongation of the eyeball. Topical atropine has few side effects but can be associated with regression after cessation of the medication.

[0010] Second, optical strategies in myopia progression reduction are based on the concept of peripheral defocus, where the lens corrects the myopia with the central portion but imposes a myopic defocus in the rest of the visual field. Multifocal eyeglasses and contact lenses help to slow myopia progression but have the same disadvantages as for normal glasses and contact lenses, namely the risk of losing them and that the patient has to wear them to have the effect. Additional shortcomings of contact lenses are dry eyes and the risk for infection.

[0011] Thirdly, orthokeratology (Ortho-K) lenses are worn overnight to flatten and temporarily reshape the cornea to correct myopia. The corneal reshaping induced by Ortho-K lenses alters the way light focuses on the retina. This can reduce the stimulus for eye elongation and axial length growth, thus slowing down the progression of myopia. The main drawback of multifocal lenses is that they have a higher risk of sight threatening corneal infections.

[0012] In view thereof, there remains a need in the art for further and / or improved compositions and methods for myopia management such as for preventing or reducing the progression of myopia and associated eye diseases.

[0013] SUMMARY OF THE INVENTION

[0014] The present inventors have found a method of myopia management based on a crosslinkable liquid composition that is placed on the cornea and crosslinked in situ, thereby addressing one or more of the above-mentioned problems in the art.

[0015] The present invention is at least in part based on the inventors' innovative insight and experimental evaluation that myopia progression can be reduced by applying a crosslinkable liquid composition comprising a gelatin or a gelatin-based crosslinkable biomaterial onto the anterior corneal surface of the affected eye as a liquid using a mold, and subsequently crosslinking the composition in situ, thereby obtaining a crosslinked composition onto the anterior corneal surface, also referred to herein as a corneal onlay. It is then possible to correct the curvature of the newly formed corneal onlay, using a technique such as photoablation, without subtracting the stroma volume from the cornea per se. The correction of the curvature of the crosslinked composition allows to create a peripheral myopic defocus, thereby affecting the physiological process of the eyeball development. By slowing down the axial growth of the eye, myopia progression can be prevented, thereby resulting in myopia management. In addition to the peripheral myopic defocus, the curvature of the crosslinked composition may be corrected to create a central correction, thereby treating the myopia at the same time. In general, myopia stabilizes in young adulthood. The corneal onlay advantageously is reversible so that when the eye is stable, the corneal onlay can be removed and the natural layers of the cornea reformed. Alternatively, the peripheral defocus effect can be removed by the laser and a standard myopic correction profile provided on the crosslinked composition so that the patient can remain spectacle free. The advantages of crosslinking in situ are that the crosslinking causes intermolecular crosslinking of the liquid composition and simultaneously results in crosslinking (or connecting) the composition with the cornea thereby ensuring adhesion to the cornea through chemical interaction. In this way, problems which are common with lenses such as infection are avoided. Additionally, as the crosslinkable biomaterial is liquid, it perfectly fits the patient's corneal geometry compared to a prefabricated corneal onlay.

[0016] The method of the present invention provides a long-term but reversible solution for myopia management including preventing or reducing the progression of myopia and eye diseases associated with myopia progression. There is very limited risk of post-procedure complications such as dry eye disease or post operative pain, as the corneal stromal tissue is not affected, neither are the corneal nerves damaged.

[0017] Accordingly, a first aspect of the invention relates to a crosslinkable liquid composition comprising a gelatin or a gelatin-based crosslinkable biomaterial for use in a method of myopia management in a subject, such as for use in a method of one or more of preventing or reducing the progression of myopia or preventing an eye disease associated with myopia progression in a subject.

[0018] In embodiments of the uses or methods as taught herein, the method comprises: applying a crosslinkable liquid composition onto the anterior corneal surface of the eyes of the subject, wherein the method comprises introducing the crosslinkable liquid composition into a mold which is positioned onto the anterior corneal surface of the eyes, crosslinking the crosslinkable liquid composition on the anterior corneal surface of the eyes, thereby obtaining a crosslinked composition on the anterior corneal surface of the eyes, and correcting the curvature of the crosslinked composition to create a peripheral myopic defocus.

[0019] In embodiments of the uses or methods as taught herein, the peripheral myopic defocus may be created by providing zones of positive power in the mid-periphery.

[0020] In embodiments of the uses or methods as taught herein, the myopia may be juvenile onset myopia. In embodiments of the uses or methods as taught herein, the subject may be a child having an age of 6 years to 18 years; preferably the subject is a child having an age of 8 years to 13 years.

[0021] In embodiments of the uses or methods as taught herein, the eye disease associated with myopia progression may be selected from the group consisting of macular degeneration, retinal detachment, cataract, and glaucoma.

[0022] In embodiments of the uses or methods as taught herein, the gelatin-based crosslinkable biomaterial may be selected from the group consisting of a gelatin methacrylate, a gelatin desaminotyrosine, a gelatin desaminotyrosyl tyrosine, a gelatin tyramine, and a thiolated gelatin.

[0023] In embodiments of the uses or methods as taught herein: the crosslinkable liquid composition comprises from about 5.0% to about 40.0% (w / v) of the gelatin or gelatin-based crosslinkable biomaterial; and / or the gelatin-based crosslinkable biomaterial is a functionalized gelatin having a degree of substitution of from about 40% to about 90%.

[0024] In embodiments of the uses or methods as taught herein, the mold may be a corneal vacuum suction device, a corneal bath, or a contact lens.

[0025] In embodiments of the uses or methods as taught herein, the crosslinkable liquid composition may be applied as a single layer.

[0026] In embodiments of the uses or methods as taught herein, the crosslinking may be performed by photocrosslinking, by exposure to O2 or by one or more enzymes; preferably wherein the crosslinking is performed by photocrosslinking such as by UV irradiation or irradiation with visible light.

[0027] In embodiments of the uses or methods as taught herein, the crosslinkable liquid composition may further comprise a photoinitiator and optionally a co-initiator.

[0028] In embodiments of the uses or methods as taught herein, the photoinitiator may be a visible or UV light photoinitiator; preferably the photoinitiator is Irgacure 2959, Lithium phenyl-2,4,6- trimethylbenzoylphosphinate, tris(2,2'-bipyridyl)dichlororuthenium(ll) hexahydrate, or riboflavin, and optionally the co-initiator may be sodium persulphate.

[0029] In embodiments of the uses or methods as taught herein, the crosslinkable liquid composition may further comprise a polyethylene glycol diacrylate (PEGDA); preferably wherein the crosslinkable liquid composition comprises from about 0.5% to about 15.0% (w / v) of the PEGDA and / or wherein the PEGDA may have a molecular mass of about 250 g / mol to about 6000 g / mol; preferably of about 500 g / mol to about 1000 g / mol. In embodiments of the uses or methods as taught herein, the crosslinked composition may have a diameter of from about 6.0 mm to about 10.0 mm and a thickness of from about 10.0 pm to about 400.0 pm, prior to correcting the curvature of the crosslinked composition; and / or wherein the crosslinked composition may be resistant to biodegradation for a period of 6 months to 5 years, preferably for a period of 12 months to 4 years.

[0030] In a further aspect, the invention provides a crosslinkable liquid composition comprising a gelatin or a gelatin-based crosslinkable biomaterial for use in a surgical method of preparing a corneal onlay on the eyes of a subject, wherein the method comprises: applying a crosslinkable liquid composition onto the anterior corneal surface of the eyes of the subject, wherein the method comprises introducing the crosslinkable liquid composition into a mold which is positioned onto the anterior corneal surface of the eyes, crosslinking the crosslinkable liquid composition on the anterior corneal surface of the eyes, thereby obtaining a crosslinked composition on the anterior corneal surface of the eyes, and correcting the curvature of the crosslinked composition to create a peripheral myopic defocus.

[0031] The above and further aspects and preferred embodiments of the invention are described in the following sections and in the appended claims. The subject-matter of appended claims is hereby specifically incorporated in this specification.

[0032] DESCRIPTION OF THE DRAWINGS

[0033] Figure 1: Schematic representation illustrating the different steps of an exemplary method according to an embodiment of the invention for myopia management with and without the use of a mold. In Figure 1A: the biopolymer is applied onto the cornea using a mold, or in Figure IB: the biopolymer is applied directly applying onto the cornea.

[0034] Figure 2A: Schematic representation illustrating the correction of the curvature of the crosslinked composition or corneal onlay to create central correction and peripheral myopic defocus in an exemplary method according to an embodiment of the invention.

[0035] Figure 2B: Schematic representation of an eye in top view (top panel) and cross-sectional view (bottom panel) illustrating the pupil (black), the iris (pattern), the cornea, and the sclera (white). The three right-hand panels illustrate corneal onlays according to embodiments of the invention applied on top of the eye (top view) (dark grey area: defocus zone; light grey area: corrective zone; white area: the sclera).

[0036] Figure 3: Graph illustrating the degradation of crosslinked compositions in function of varying gelatin concentration, namely of crosslinked compositions comprising 15% gelatin (no PEGDA) (black striped line) or 10% gelatin (no PEGDA) (black dotted line). X-axis: time (days); Y-axis: residual weight (%).

[0037] Figure 4: Graph illustrating the degradation of crosslinked compositions in function of PEGDA concentration in a 10% gelatin solution comprising 0% PEGDA (black striped and dotted line), 1% PEGDA (black striped line), 2% PEGDA (black dotted line), or 5% PEGDA (black full line). X-axis: time (days); Y-axis: residual weight (%).

[0038] Figure 5: Graph illustrating the degradation of crosslinked compositions in function of PEGDA concentration in a 15% gelatin solution comprising 0% PEGDA (black striped and dotted line), 1% PEGDA (black dotted line), or 2% PEGDA (black full line). X-axis: time (days); Y-axis: residual weight (%).

[0039] DETAILED DESCRIPTION OF THE INVENTION

[0040] As used herein, the singular forms "a", "an", and "the" include both singular and plural referents unless the context clearly dictates otherwise.

[0041] The terms "comprising", "comprises" and "comprised of" as used herein are synonymous with "including", "includes" or "containing", "contains", and are inclusive or open-ended and do not exclude additional, non-recited members, elements, or method steps. The terms also encompass "consisting of" and "consisting essentially of".

[0042] The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within the respective ranges, as well as the recited endpoints.

[0043] The term "about" as used herein when referring to a measurable value such as a parameter, an amount, a temporal duration, and the like, is meant to encompass variations of and from the specified value, in particular variations of + / -10% or less, preferably + / -5% or less, more preferably + / -1% or less, and still more preferably + / -0.1% or less of and from the specified value, insofar such variations are appropriate to perform in the disclosed invention. It is to be understood that the value to which the modifier "about" refers is itself also specifically, and preferably, disclosed.

[0044] Whereas the term "one or more", such as one or more members of a group of members, is clear per se, by means of further exemplification, the term encompasses inter alia a reference to any one of said members, or to any two or more of said members, such as, e.g., any >3, >4, >5, >6 or >7 etc. of said members, and up to all said members.

[0045] All documents cited in the present specification are hereby incorporated by reference in their entirety. Unless otherwise specified, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, term definitions may be included to better appreciate the teaching of the present invention.

[0046] The present invention is at least in part based on the inventors' realisation that myopia progression can be slowed down by using a crosslinkable liquid composition comprising a gelatin or a gelatinbased crosslinkable biomaterial, in particular by applying the composition onto the anterior corneal surface of the eye as a liquid, subsequently crosslinking the composition in situ and correcting the curvature of the newly formed corneal onlay, without subtracting the stroma of the cornea perse. Unlike glasses or contact lenses, the method of present invention does not obstruct the subject during playing or contact sport, the crosslinked composition on the cornea obtained by the method present invention does not feel uncomfortable for the subject, and once applied, aids in myopia management without risk of dry eyes or severe bacterial eye infections due to poor lens hygiene. Furthermore, the crosslinked composition or corneal onlay can easily be removed once the myopia management is done, for instance by surgery or in vivo biodegradation.

[0047] The present inventors have found that the crosslinkable liquid composition comprising a gelatin or a gelatin-based crosslinkable biomaterial advantageously allows to create a temporary corneal onlay, thereby allowing the procedure to be performed during childhood and adolescence for myopia management. The peripheral myopic defocus of the incoming light advantageously acts on the physiological process of the eyeball development and by slowing down the axial growth of the eye, myopia progression can be prevented. In addition, the corneal onlay can provide - but not necessary provides - a direct effect on vision correction.

[0048] Accordingly, the invention relates to a crosslinkable liquid composition comprising a gelatin or a gelatin-based crosslinkable biomaterial for use in a method of myopia management in an eye of a subject, such as for use in a method of one or more of preventing or reducing the progression of myopia or preventing an eye disease associated with myopia progression in a subject.

[0049] Related aspects provide: a method of myopia management in an eye of a subject in need of such a treatment, such as a method of one or more of preventing or reducing the progression of myopia or preventing an eye disease associated with myopia progression in a subject in need of such a treatment, wherein the method comprises administering a crosslinkable liquid composition comprising a gelatin or a gelatin-based crosslinkable biomaterial to the eye of the subject. the use of a crosslinkable liquid composition comprising a gelatin or a gelatin-based crosslinkable biomaterial for the manufacture of a medicament for myopia management in an eye of a subject, such as for the manufacture of a medicament for one or more of preventing or reducing the progression of myopia or preventing an eye disease associated with myopia progression in a subject. the use of a crosslinkable liquid composition comprising a gelatin or a gelatin-based crosslinkable biomaterial for myopia management in an eye of a subject, such as for one or more of preventing or reducing the progression of myopia or preventing an eye disease associated with myopia progression in a subject.

[0050] In a further aspect, the invention provides a crosslinkable liquid composition comprising a gelatin or a gelatin-based crosslinkable biomaterial for use in a surgical method of preparing a corneal onlay on the eyes of a subject, wherein the method comprises: applying a crosslinkable liquid composition onto the anterior corneal surface of the eyes of the subject, optionally wherein the method comprises introducing the crosslinkable liquid composition into a mold which is positioned onto the anterior corneal surface of the eyes, crosslinking the crosslinkable liquid composition on the anterior corneal surface of the eyes, thereby obtaining a crosslinked composition on the anterior corneal surface of the eyes, and correcting the curvature of the crosslinked composition to create a peripheral myopic defocus.

[0051] In embodiment, the method of myopia management, such as the method of preventing or reducing the progression of myopia or preventing an eye disease associated with myopia progression in a subject, may comprise: applying a crosslinkable liquid composition onto the anterior corneal surface of the eyes of the subject, optionally wherein the method comprises introducing the crosslinkable liquid composition into a mold which is positioned onto the anterior corneal surface of the eyes, crosslinking the crosslinkable liquid composition on the anterior corneal surface of the eyes, thereby obtaining a crosslinked composition on the anterior corneal surface of the eyes, and correcting the curvature of the crosslinked composition to create a peripheral myopic defocus.

[0052] Hence, an aspect relates to a crosslinkable liquid composition comprising a gelatin or a gelatinbased crosslinkable biomaterial for use in a method of myopia management in an eye of a subject, such as for use in a method of one or more of preventing or reducing the progression of myopia or preventing an eye disease associated with myopia progression in an eye of a subject, wherein the method comprises: applying a crosslinkable liquid composition onto the anterior corneal surface of the eyes of the subject, optionally wherein the method comprises introducing the crosslinkable liquid composition into a mold which is positioned onto the anterior corneal surface of the eyes, crosslinking the crosslinkable liquid composition on the anterior corneal surface of the eyes, thereby obtaining a crosslinked composition on the anterior corneal surface of the eyes, and correcting the curvature of the crosslinked composition to create a peripheral myopic defocus.

[0053] The phrases "myopia management" or "preventive or curative treatment of myopia progression" may be used interchangeably herein.

[0054] In embodiments, the myopia management may comprise one or more of preventing or reducing or slowing down the progression of myopia or preventing eye diseases associated with myopia progression. Eye diseases associated with myopia progression include macular degeneration, retinal detachment, cataract, and glaucoma.

[0055] The term "myopia" or "near-sightedness" as used herein has its meaning as generally accepted in the art. In myopia or near-sightedness, light rays are brought to focus in front of the retina. This may occur because the focusing power of the cornea and lens is very high and / or because the eyeball is too long from front to back.

[0056] In embodiments, the myopia is juvenile onset myopia.

[0057] The terms "juvenile onset myopia", "juvenile myopia", "early onset myopia", "youth onset myopia" or "school myopia" refers to myopia occurring in childhood with progression throughout the early teenage years.

[0058] Reference to "therapy" or "treatment" encompasses curative treatments, and the terms may particularly refer to the alleviation or measurable lessening of one or more symptoms or measurable markers of a pathological condition such as a disease or disorder, e.g. myopia progression or one or more eye diseases associated with the progression of myopia in a subject, such as macular degeneration, retinal detachment, cataract, or glaucoma. Measurable lessening includes any statistically significant decline in a measurable marker or symptom. Generally, the terms encompass both curative treatments and treatments directed to reduce symptoms and / or slow progression of the disease.

[0059] The term "myopia progression" or "progression of myopia" as used herein refers to a worsening or aggravation of myopia in a subject over time (e.g., an increase in minus optical power over time, e.g., from -6.0 to -9.0), such as over a time period of at least 6 months or at least 1 year, e.g., over a time period of 6 months, 9 months, or 1 year. For example, myopia progression may comprise myopia which has been aggravated by at least 0.50 dioptre or at least 1.0 dioptre, such as by at least 1.5 dioptres, at least 2.0 dioptres, at least 2.5 dioptres, at least 3.0 dioptres, at least 3.5 dioptres or at least 4.0 dioptres over a time period, such as a time period of at least 6 months or at least 1 year. In embodiments, myopia progression may comprise myopia which has been aggravated by at least 0.50 dioptre or by at least 1.0 dioptre, such as with at least 1.5 dioptres, at least 2.0 dioptres, at least 2.5 dioptres, at least 3.0 dioptres, at least 3.5 dioptres or at least 4.0 dioptres over a time period of at most 1 year.

[0060] The phrases "preventing the progression of myopia" or "preventing myopia progression" as used herein refer to avoiding or stopping a worsening or aggravation of myopia in a subject over time.

[0061] The phrases "reducing the progression of myopia" or "reducing myopia progression" as used herein refer to diminishing or decreasing a worsening or aggravation of myopia in a subject over time.

[0062] In embodiments, the myopia of a subject after treatment as taught herein, e.g., for a defined time period, may be the same as or even improved relative to (i.e., compared with) the myopia of the subject before the treatment as taught herein, thereby advantageously preventing myopia progression. For instance, a subject after treatment as taught herein, e.g., for a defined time period, may require a minus optical power which is the same (e.g., a dioptre of -3.0) or even improved (i.e., decreased) (e.g., a dioptre of -2.0) relative to (i.e., compared with) the minus optical power of the subject before the treatment (e.g., a dioptre of -3.0).

[0063] In embodiments, the myopia of a subject after treatment as taught herein for a defined time period (such as a time period of at least 6 months or at least 1 year) may be improved by at least 0.50 dioptre relative to (i.e., compared with) the myopia of a reference subject after the same time period (such as a time period of at least 6 months or at least 1 year) without the treatment (i.e., untreated subject), thereby advantageously reducing myopia progression. In embodiments, the myopia of a subject after treatment as taught herein for a defined time period may be improved by at least 1.0 dioptre, such as by at least 1.5 dioptres, at least 2.0 dioptres, at least 2.5 dioptres, at least 3.0 dioptres, at least 3.5 dioptres or at least 4.0 dioptres relative to (i.e., compared with) the myopia of a reference subject after the same time period without the treatment (i.e., untreated subject). For instance, a subject after treatment as taught herein for a defined time period may have a minus optical power which is improved (i.e., decreased) (e.g., a dioptre of -4.0) relative to (i.e., compared with) the minus optical power of a reference subject after the same time period without the treatment (e.g., a dioptre of -5.0). The terms "subject", "individual" or "patient" are used interchangeably throughout this specification, and typically and preferably denote humans, but may also encompass reference to non-human animals, preferably warm-blooded animals, even more preferably non-human mammals. Particularly preferred are human subjects including both genders and all age categories thereof. In other embodiments, the subject is an experimental animal or animal substitute as a disease model. The term does not denote a particular age or sex.

[0064] The term "untreated subject" as used herein refers to a subject of the same age (e.g., defined in years) and / or being diagnosed with the same minus optical power as a subject which has been treated as taught herein, except that the untreated subject has not been treated as taught herein, e.g., by applying the crosslinked composition as taught herein and / or performing method as taught herein. The term may be synonymous with "reference subject" or "reference" and may encompass one or more reference subjects, such as a population of reference subjects.

[0065] The term "subject in need of treatment" or similar as used herein refers to subjects diagnosed with or having a disease or disorder as recited herein, in particular myopia such as juvenile onset myopia, or myopia progression.

[0066] In embodiments, the subject may be a child having an age of 6 years to 18 years, such as an age of

[0067] 7 years to 15 years, 8 years to 14 years, or 9 years to 11 years. Preferably, the subject is a child having an age of 8 years to 13 years, such as an age of 8 years, 9 years, 10 years, 11 years, 12 years, or 13 years. In embodiments, the subject may be a child diagnosed with or having myopia. In embodiments, the subject may be a child diagnosed with or having myopia, such as juvenile myopia, and having an age of 6 years to 18 years, such as an age of 7 years to 15 years, 8 years to 14 years,

[0068] 8 years to 13 years, or 9 years to 11 years. In embodiments, the subject may be a child diagnosed with or having myopia progression. In embodiments, the subject may be a child diagnosed with or having myopia progression, and having an age of 6 years to 18 years, such as an age of 7 years to 15 years, 8 years to 14 years, 8 years to 13 years, or 9 years to 11 years.

[0069] In embodiments, the subject may be a subject diagnosed with or having myopia with (e.g., requiring a correction of) a dioptre of -0.50 to -20.0, such as with a dioptre of -0.75, -1.0 to -20.0, -1.5 to -15.0, -2.0 to -10.0, -2.5 to -10.0, -3.0 to -10.0, -3.5 to -10.0, -4.0 to -10.0, -4.5 to -10.0, -5.0 to -10.0, -5.5 to -10.0, -6.0 to -10.0, -7.0 to -10.0, or -8.0 to -10.0. Preferred patients are those who display a high degree of myopia and / or show fast progression of myopia. Hence, in embodiments, the subject may be a subject diagnosed with or having myopia with a dioptre of more than -8.0, more than -9.0, or more than -10.0 such as from -10.5 to -20.0. In embodiments, the subject may be a subject diagnosed with or having myopia which has aggravated by at least 1.0 dioptre, such as by at least 1.5 dioptres, at least 2.0 dioptres, at least 2.5 dioptres, at least 3.0 dioptres, at least 3.5 dioptres or at least 4.0 dioptres over a time period of at least 6 months or at least 1 year, such as over a time period of 6 months, 9 months, or 1 year. In embodiments, the subject may be a subject diagnosed with or having myopia which has aggravated by at least 1.0 dioptre, such as with at least 1.5 dioptres, at least 2.0 dioptres, at least 2.5 dioptres, at least 3.0 dioptres, at least 3.5 dioptres or at least 4.0 dioptres over a time period of at most 1 year.

[0070] In embodiments, the subject did not receive any invasive treatment for correcting myopia or for preventing or reducing myopia progression in the eye prior to the application of the crosslinkable liquid composition. In more particular embodiments, the subject did not receive refractive laser surgery, such as PRK, LASIK or SMILE, prior to the application of the crosslinkable liquid composition onto the anterior corneal surface of the eye.

[0071] Crosslinking as used herein is the formation of chemical links between molecular chains to form a three-dimensional network of connected molecules. Crosslinks may be formed by chemical reactions that occur spontaneously or are initiated by, for example, one or more enzymes, heat, pressure, change in pH, or irradiation. These chemical reactions may also be initiated by the presence of one or more crosslinking agents such as photoinitiators, which typically comprises multiple functional groups and form radicals upon irradiation, thereby as such starting the crosslinking reaction.

[0072] The "crosslinkable liquid" or "crosslinkable liquid composition" as referred to herein comprises crosslinkable biocompatible material (e.g., biomaterial). The terms "liquid" or "liquid composition" in the context of the present invention encompass both completely liquid and semi-liquid compositions, i.e., include compositions which have a consistency between solid and liquid.

[0073] The crosslinkable liquid composition to be used in the method of present invention comprises a gelatin or gelatin-based crosslinkable biomaterial.

[0074] The term "gelatin" refers to a composition comprising or consisting of proteins and obtained by partial hydrolysis of collagen extracted from the skin, bones, and connective tissues of animals.

[0075] The "gelatin-based crosslinkable biomaterial" refers to a crosslinkable biomaterial based on gelatin. Gelatin-based biomaterials may be GelCORE such as described in 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 such as described in Ghasem Yazdanpanah et al., A light-curable and tunable extracellular matrix hydrogel for in situ suture-free corneal repair, Advanced Functional Materials, 2022.

[0076] In embodiments of the uses or methods as taught herein, the gelatin-based crosslinkable biomaterial may be selected from the group consisting of a gelatin methacrylate, a gelatin desaminotyrosine, a gelatin desaminotyrosyl tyrosine, a gelatin tyramine, and a thiolated gelatin.

[0077] The terms "gelatin methacrylate", "gelatin methacryloyl", "gelatin methacrylamide", "GelMA" or "GelMa" may be used interchangeably herein.

[0078] Suitable examples of gelatin methacrylate include for instance gelatin methacrylate commercially available from Merck KGaA, Darmstadt, Germany under product number 900629 (gel strength 300 g Bloom, 40% degree of substitution), 900622 (gel strength 300 g Bloom, 60% degree of substitution), 900628 (gel strength 90-110 g Bloom, 60% degree of substitution) or 900496 (gel strength 300 g Bloom, 80% degree of substitution).

[0079] The terms "gelatin desaminotyrosine", "gelatin functionalized with desaminotyrosine" or "GelDAT" may be used interchangeably herein.

[0080] Suitable gelatin desaminotyrosine includes X-Pure GelDAT commercially available from Rousselot BV, Ghent, Belgium.

[0081] The term "gelatin desaminotyrosyl tyrosine", "gelatin functionalized with desaminotyrosyl tyrosine" or "GelDATT" may be used interchangeably herein.

[0082] Suitable gelatin desaminotyrosyl tyrosine can be synthesized as described in Roch et al. (2011, Macromol. Symp., 309, 182-189), in particular on p. 184, Materials and Methods, Functionalization of gelatin. For instance, desaminotyrosine or desaminotyrosyl tyrosine (29 mmol) may be activated by reaction with l-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide (EDC) (32 mmol) and N- hydroxysuccinimide (NHS) (43 mmol) in HOmL of dimethyl sulfoxide (DMSO) at 37°C. After 3h, - mercaptoethanol (43 mmol) may be added. A gelatin solution (15 g in 150mL DMSO) may be added, and the mixture stirred at 37°C for 5 h. The functionalized product may be precipitated in ethanol, filtered, washed with ethanol and acetone, and dried under vacuum.

[0083] The terms "gelatin tyramine", "gelatin functionalized with tyramine" or "GTA" may be used interchangeably herein.

[0084] Suitable gelatin tyramine can be synthesized as described in Sakai et al. (2009, Biomaterials, 30, 3371-3377), in particular on p. 3372, Materials and methods, 2.2 Modification of gelatin to incorporate phenol groups, or as described in Li et al. (2015, Acta Biomater., 13, 88-100), in particular in 2. Materials and methods, 2.2 Synthesis of gelatin / tyramine / heparin (G / T / H) conjugates. For instance, gelatin derivatives possessing phenol (Ph) groups may be synthesized by combining gelatin and tyramine hydrochloride via the carbodiimide-mediated condensation of the carboxyl groups of gelatin and the amino groups of tyramine. Gelatin powder may be suspended at 2% (w / v) in a 50 mM morpholinoethanesulfonic acid (MES) aqueous solution and heated to 60 °C. After dissolution of gelatin, the solution may be cooled to 25 °C. To this solution, tyramine hydrochloride, EDC and NHS may be added and the solution may be stirred at 25 °C. After 12 h of stirring, 50 mM sodium phosphate may be added. After a further 30 min of stirring, the resultant polymer solution may be dialyzed against deionized water, using an ultrafiltration membrane (MWCO: 10,000), until an absorbance peak at 275 nm, attributed to the presence of residual tyramine, is undetectable in the filtered solution. The sample may subsequently be lyophilized.

[0085] The terms "thiolated gelatin", "thiol functionalized gelatin", "thiol gelatin", "gelatin thiol" or "Gel- SH" may be used interchangeably herein.

[0086] Suitable thiolated gelatin includes thiol functionalized gelatin commercially available from Merck KGaA, Darmstadt, Germany under product number 904643.

[0087] In embodiments of the uses or methods as taught herein, the gelatin-based crosslinkable biomaterial may be gelatin functionalized with one or more tyrosine-derived or phenol groups. In embodiments, the gelatin functionalized with one or more tyrosine-derived or phenol groups may be selected from the group consisting of a gelatin desaminotyrosine, a gelatin desaminotyrosyl tyrosine, or a gelatin tyramine. Preferably, the gelatin functionalized with one or more tyrosinederived or phenol groups is a gelatin desaminotyrosine. Such gelatin advantageously allows crosslinking with the visible and / or UV light photoinitiator with very fast crosslinking kinetics and provide a crosslinked composition with UV and HEV light blocking properties.

[0088] In embodiments, the crosslinkable liquid composition has a transparency of at least 50%, when measured over the visual spectrum (400-750 nm), when crosslinked.

[0089] In embodiments, the gelatin-based crosslinkable biomaterial may be a functionalized gelatin.

[0090] In embodiments of the uses or methods as taught herein, the gelatin-based crosslinkable biomaterial may be a functionalized gelatin having a degree of substitution of from about 40% to about 90%. For instance, the gelatin-based crosslinkable biomaterial may be a functionalized gelatin having a degree of substitution of from about 50% to about 80%, or from about 60% to about 70%. The "degree of substitution" of a functionalized gelatin refers to the ratio (expressed as a percentage) of the number of modified amino groups to the number of free amino groups of the gelatin. In embodiments, the gelatin-derived crosslinkable biomaterial may be functionalized using methacrylic acid, diacrylate, diacrylamide, desaminotyrosine, desaminotyrosyl tyrosine, tyramine, or thiol (-SH).

[0091] The terms "methacrylic acid", "2-methyl-2-propenoic acid", "a-methacrylic acid", "2-methylacrylic acid", "2-methylpropenoic acid" can be used interchangeably herein. Methacrylic acid has C4H6O2 as chemical formula, 2-methylprop-2-enoic acid as preferred IUPAC name, and 79-41-4 as CAS number.

[0092] The terms "desaminotyrosine", "DAT", "phloretic acid", "phloretate" or "hydro-p-coumaric acid" can be used interchangeably herein. Desaminotyrosine has 3-(4-hydroxyphenyl)propanoic acid as IUPAC name.

[0093] The terms "desaminotyrosyl tyrosine", "desaminotyrosyl-tyrosine" or "DATT" may be used interchangeably. The IUPAC name is (2R,4S)-4-amino-5-(4-hydroxyphenyl)-2-[(4- hydroxyphenyl)methyl]-3-oxopentanoic acid.

[0094] The terms "tyramine" or "4-hydroxyphenethylamine" can be used interchangeably herein. Tyramine has 4-(2-aminoethyl)phenol as the IUPAC name.

[0095] In embodiments of the uses or methods as taught herein, the crosslinkable liquid composition may comprise at least about 1.0% (w / v) of the gelatin or gelatin-based crosslinkable biomaterial. In embodiments, the crosslinkable liquid composition may comprise at least about 5.0% (w / v), at least about 10.0% (w / v), at least about 15.0% (w / v), or at least about 20.0% (w / v) of the gelatin or gelatinbased crosslinkable biomaterial. Such concentrations of the gelatin or gelatin-based crosslinkable biomaterial result in satisfactory crosslinked compositions.

[0096] In embodiments, the crosslinkable liquid composition may comprise from about 1.0% to about 40.0% (w / v), from about 1.0% to about 30.0% (w / v), from about 1.0% to about 20.0% (w / v), from about 1.0% to about 15.0% (w / v), or from about 1.0% to about 10.0% (w / v) of the gelatin or gelatinbased crosslinkable biomaterial. In embodiments of the uses or methods as taught herein, the crosslinkable liquid composition may comprise from about 5.0% to about 40.0% (w / v) of the gelatin or gelatin-based crosslinkable biomaterial. In embodiments, the crosslinkable liquid composition may comprise from about 5.0% to about 30.0% (w / v), from about 5.0% to about 20.0% (w / v), from about 5.0% to about 15.0% (w / v), or from about 10.0% to about 20.0% (w / v) of the gelatin or gelatin-based crosslinkable biomaterial. Such concentrations of the gelatin or gelatin-based crosslinkable biomaterial result in satisfactory crosslinked compositions, while allowing biodegradation of the crosslinked composition after the desired period of myopia management, thereby avoiding surgical removal of the crosslinked composition.

[0097] In embodiments of the uses or methods as taught herein, the gelatin or gelatin-based crosslinkable biomaterial has a molecular mass of about 50000 g / mol (50 kDa) to about 200000 g / mol (200 kDa). For instance, the gelatin or gelatin-based crosslinkable biomaterial has a molecular mass of about 60 kDa to about 190 kDa, about 70 kDa to about 180 kDa, or about 80 kDa to about 170 kDa. Preferably, the gelatin or gelatin-based crosslinkable biomaterial has a molecular mass of about 90 kDa to about 160 kDa. In further embodiments the gelatin functionalized with one or more tyrosinederived or phenol groups has a molecular mass of about 90 kDa and / or about 160 kDa. Such molecular masses of the gelatin or gelatin-based crosslinkable biomaterial result in satisfactory crosslinked compositions.

[0098] In embodiments, the crosslinkable liquid composition as taught herein may further comprise an aqueous solution, in particular a buffer solution, such as phosphate buffered saline (PBS).

[0099] The term "aqueous solution" refers to any solution comprising water or in which the solvent is water. Additionally, "aqueous solution" is used to describe solutions displaying commonalities to water or watery solutions, not limited to characteristics such as appearance, smell, colour, taste, viscosity, pH, absorbance, or physical state under particular temperatures.

[0100] The term "buffer component", "buffer solution", or "buffer" as used interchangeably herein refers to an aqueous solution comprising a mixture of a weak acid and its conjugate base or vice versa. Buffer solutions are characterized by their means to keeping the pH of a solution nearly constant when limited amounts of strong acids or strong bases are added to the solution. The amount of strong acid or strong base that can be added to the buffer solution before a significant pH change occurs is dependent on the specific buffer solution used and is commonly referred to as the buffer capacity. The pH of a buffer solution can be estimated using the Henderson-Hasselbalch equation, which is known to a person skilled in the art.

[0101] In certain embodiments, the crosslinkable liquid composition as taught herein may comprise from about 10% to about 98% by weight of an aqueous solution, in particular a buffer solution such as PBS. In embodiments, the crosslinkable liquid composition as taught herein may comprise from about 20% to about 98%, from about 30% to about 98%, from about 40% to about 98%, from about 50% to about 98%, from about 60% to about 98%, from about 60% to about 95% or from about 60% to about 90% by weight of an aqueous solution, in particular a buffer solution such as PBS. The terms "weight percentage", "mass percentage", "percentage (%) by weight", "weight%" or "wt%" indicate the mass of a substance to the total mass of the formulation (i.e., mass fraction) with a denominator of 100. Unless indicated otherwise, the wt% is provided herein compared to the total weight of the crosslinkable liquid composition.

[0102] In embodiments, the crosslinkable liquid composition as taught herein may not comprise organic solvents. In embodiments, the crosslinkable liquid composition as taught herein may be prepared in an aqueous carrier without the use of organic solvents.

[0103] In embodiments of the uses or methods as taught herein, the crosslinkable liquid composition may further comprise a polyethylene glycol diacrylate (PEGDA).

[0104] The terms "polyethylene glycol diacrylate", "poly(ethylene glycol) diacrylate", "PEG diacrylate" or "PEGDA" can be used interchangeably herein. PEGDA has CaHaC OCHzCHzJnCaHaOj as linear formula and 26570-48-9 as CAS number.

[0105] Suitable poly(ethylene glycol) diacrylate includes for instance poly(ethylene glycol) diacrylate commercially available from Merck KGaA, Darmstadt, Germany under product number 455008 (average Mn 700), 437441 (average Mn 575), or 475629 (average Mn 250). Suitable polyethylene glycol diacrylate includes for instance polyethylene glycol diacrylate commercially available from Polysciences Inc., PA, USA under product number 01871 (average Mn 400 or PEGDA 400) or 25485 (average Mn 1000 or PEGDA 1000). Other suitable PEGDA (more that 80% acrylated) is available from Advanced BioMatrix, Inc. with molecular weights 1000, 3400, 6000, 10000 and 20000.

[0106] In embodiments of the uses or methods as taught herein, the crosslinkable liquid composition comprises from about 0.5% to about 15.0% (w / v) of the PEGDA and / or wherein the PEGDA has a molecular mass of about 250 g / mol to about 6000 g / mol.

[0107] In embodiments of the uses or methods as taught herein, the crosslinkable liquid composition may comprise from about 0.5% to about 15.0% (w / v) of the PEGDA. In embodiments, the crosslinkable liquid composition may comprise from about 0.5% to about 10.0% (w / v), from about 0.5% to about 5.0% (w / v) of the PEGDA, from about 0.5% to about 4.0% (w / v), from about 0.5% to about 3.0% (w / v), or from about 0.5% to about 2.0% (w / v). In embodiments, the crosslinkable liquid composition may comprise from about 1.0% to about 15.0% (w / v), from about 1.0% to about 10.0% (w / v), from about 1.0% to about 5.0% (w / v) of the PEGDA, from about 1.0% to about 4.0% (w / v), from about 1.0% to about 3.0% (w / v), or from about 1.0% to about 2.0% (w / v). Such concentrations of PEGDA result in a crosslinked composition having satisfactory swelling and good resistance to enzymatic degradation, while at the same time allowing biodegradation of the crosslinked composition after the desired period of myopia management, thereby avoiding surgical removal of the crosslinked composition.

[0108] The terms "% \N / \T, "% m / v", "percentage weight per volume" or "percentage mass per volume" may be used interchangeably and refer to the ratio of the mass of a solid (the solute) (in grams) to the volume of the solution (in ml) times 100. For instance, the crosslinkable liquid composition may comprise about 1 g of PEGDA per 100 ml of solution. If lg of PEGDA is used to make up a total volume of 100 ml, then a 1% w / v solution of PEGDA has been made.

[0109] In embodiments of the uses or methods as taught herein, the PEGDA has a molecular mass of about 250 g / mol to about 6000 g / mol. For instance, the PEGDA has a molecular mass of about 300 g / mol to about 5000 g / mol, about 350 g / mol to about 4000 g / mol, about 400 g / mol to about 3000 g / mol, about 450 g / mol to about 2000 g / mol, or about 500 g / mol to about 1000 g / mol. In embodiments, the PEGDA has a molecular mass of about 3000 g / mol to about 5000 g / mol or about 3500 g / mol to about 4500 g / mol Preferably, the PEGDA has a molecular mass of about 500 g / mol to about 1000 g / mol, such as about 600 g / mol to about 900 g / mol, or about 700 g / mol to about 800 g / mol. When reference is made to the molecular mass of PEGDA, this refers to the molecular mass of the PEG component of PEGDA. Such molecular masses of PEGDA result in a crosslinked composition having satisfactory swelling and good resistance to enzymatic degradation.

[0110] The crosslinkable liquid composition may further also comprise one or more crosslinking agents and / or one or more photoinitiators, that participate in the crosslinking reaction.

[0111] In embodiments of the uses or methods as taught herein, the crosslinking may be performed by photocrosslinking, by exposure to O2 or by one or more enzymes; preferably the crosslinking is performed by photocrosslinking such as by UV irradiation or irradiation with visible light.

[0112] In embodiments, the crosslinkable liquid composition may be capable of crosslinking by photocrosslinking such as UV irradiation, by exposure to O2 or by one or more enzymes. In preferred embodiments, the crosslinkable liquid composition is capable of crosslinking by photocrosslinking or enzymatic crosslinking. Therefore, the crosslinkable liquid composition possesses reactive functionalities that form short oligomer / polymer chains between the macromolecule chains.

[0113] In embodiments of the uses or methods as taught herein, the crosslinkable liquid composition may further comprise a photoinitiator and optionally a co-initiator. In embodiments, the crosslinkable liquid composition may further comprise a photoinitiator. In embodiments, the crosslinkable liquid composition may further comprise a photoinitiator and a co-initiator. Photoinitiators are compounds that upon radiation of light decompose into reactive species that activate polymerization of specific functional groups on the crosslinkable biomaterial. Accordingly, photoinitiators are typically used herein when the crosslinkable liquid composition is capable of being crosslinked by photocrosslinking. The type of photoinitiator as well as the concentration thereof can be varied in the crosslinkable liquid composition as intended herein. Each specific photoinitiator is typically linked to an excitation wavelength spectrum, of which the peak of the spectrum is the most optimal wavelength to create radicals upon excitation. Non-limiting examples of photoinitiators that may be used in the uses or methods as taught herein include riboflavin, indocyanine green, Janus green, rose Bengal, methylene blue, sodium persulphate, ruthenium, 2,4,6-trimethylbenzoyl)-phosphine oxide (TPO), Irgacure 2959, Lithium phenyl-2,4,6- trimethylbenzoylphosphinate (LAP), or a combination thereof.

[0114] In embodiments of the uses or methods as taught herein, the photoinitiator is a visible or UV light photoinitiator; preferably wherein the photoinitiator may be selected from the group consisting of Irgacure 2959, Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (lithium aryl phosphinate or LAP), tris(2,2'-bipyridyl)dichlororuthenium(ll) hexahydrate, riboflavin, or camphorquinone, and optionally the co-initiator is sodium persulphate.

[0115] In embodiments, the photoinitiator may be a photoinitiator that can be excited with visible light. Non-limiting examples of photoinitiators that can be excited with visible light include 2,4,6- trimethylbenzoyl)-phosphine oxide (TPO), Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), flavins such as riboflavin, rose bengal or a sulfinate or sulfonate such as sodium persulphate. In embodiments, the photoinitiator may be a photoinitiator that can be excited in the UV spectrum, hence, at a wavelength of from 250 to 450 nm, which may also be referred to as "blue light". Nonlimiting examples of photoinitiators that can be excited with UV irradiation are Irgacure 2959, Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP).

[0116] In embodiments, the one or more photoinitiators are water-soluble photoinitiators. Non-limiting examples are photoinitiators comprising tris(2,2'-bipyridine)ruthenium(ll) such as tris(2,2'- bipyridyl)dichlororuthenium(ll) hexahydrate, or other photoinitiators such as Lithium phenyl-2,4,6- trimethylbenzoylphosphinate (LAP), 2,4,6-trimethylbenzoyl)-phosphine oxide (TPO), and other members of the Irgacure photoinitiator family.

[0117] The terms "tris(2,2'-bipyridyl)dichlororuthenium(ll) hexahydrate", "tris(2,2- bipyridyl)dichlororuthenium(ll) hexahydrate", "Ru(BPY)3", "ruthenium-tris(2,2'-bipyridyl) dichloride", "tris(2,2'-bipyridyl)ruthenium(ll) chloride hexahydrate" may be used interchangeably herein. The CAS number is 50525-27-4. The IUPAC name is 2-pyridin-2- ylpyridine;ruthenium(2+);dichloride;hexahydrate (as computed by Lexichem TK 2.7.0, PubChem release 2021.05.07).

[0118] Flavins, such as riboflavin and flavin are naturally occurring yellow pigments which are photoreducible, have high water solubility and are biocompatible. Riboflavin has an absorption peak of 440 nm and 371 nm.

[0119] In embodiments, the crosslinkable composition comprises from 0.05 to 2.0% (w / v), particularly from 0.5 to 20% such as from 1.0 to 2.0% (w / v), of one or more photoinitiators.

[0120] Suitable co-initiators for the photo-initiators described herein are known in the art. Examples include a sulfinate or sulfonate such as sodium persulphate, amines such as L-arginine.

[0121] In particular embodiments a concentration of between 0.5 and 2 mM of photoinitiator is used with a concentration of 5-20 mM co-initiator, such as ImM photoinitiator with 10 mM co-initiator.

[0122] In embodiments, the co-initiator may be a sulfinate or sulfonate such as sodium persulphate.

[0123] In embodiments of the uses or methods as taught herein, the crosslinkable liquid composition comprises a gelatin methacrylate, a polyethylene glycol diacrylate, and a photoinitiator, such as wherein the photoinitiator is Irgacure 2959 or Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP).

[0124] In embodiments of the uses or methods as taught herein, the crosslinkable liquid composition comprises a gelatin desaminotyrosine, a polyethylene glycol diacrylate, a photoinitiator, and optionally a co-initiator; such as wherein the photoinitiator comprises tris(2,2'- bipyridine)ruthenium(ll) or riboflavin (e.g., for crosslinking the GelDAT) and Irgacure 2595 or LAP (e.g., for crosslinking the PEGDA), and the co-initiator is sodium persulphate. In embodiments of the uses or methods as taught herein, the crosslinkable liquid composition comprises a gelatin desaminotyrosine, a polyethylene glycol diacrylate, tris(2,2'-bipyridyl)dichlororuthenium(ll) hexahydrate, Irgacure 2595, and sodium persulphate.

[0125] In embodiments of the uses or methods as taught herein, the crosslinkable liquid composition comprises a gelatin desaminotyrosine, a photoinitiator, and optionally a co-initiator; such as wherein the photoinitiator comprises tris(2,2'-bipyridine)ruthenium(ll) or riboflavin, and the coinitiator is sodium persulphate. In embodiments of the uses or methods as taught herein, the crosslinkable liquid composition comprises a gelatin desaminotyrosine, tris(2,2'- bipyridyl)dichlororuthenium(ll) hexahydrate, and sodium persulphate. In embodiments, the crosslinkable liquid composition comprises a gelatin desaminotyrosine, riboflavin, and sodium persulphate. In embodiments, the crosslinkable liquid composition may further comprise one or more therapeutic agents (e.g., an analgesic, an anti-inflammatory agent, an antibiotic, a growth factor to stimulate epithelialization, or a steroid), and / or other agents such as colorants.

[0126] Once the crosslinkable liquid composition has been crosslinked, the crosslinked composition preferably does not interfere with the normal functionality of the eye and provides sufficient nutrient and gas exchange to maintain a viable corneal epithelium and stroma. Accordingly, in embodiments, the crosslinked composition is permeable to water, nutrients, oxygen, therapeutic agents (e.g., an analgesic, an anti-inflammatory agent, an antibiotic, a growth factor to stimulate epithelialization, or a steroid), and / or growth factors (e.g., exogenous or endogenous growth factors, such as nerve growth factor (NGF)).

[0127] Preferably, the crosslinked composition is compatible with clinical imaging techniques, such as clinical corneal investigation using a refractometer, optical coherence tomography, Scheimpflug tomography, Placido based tomography device or in vivo confocal imaging.

[0128] Accordingly, in embodiments, the crosslinkable liquid composition and / or crosslinked composition has a transparency of at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90%, when measured using light with a wavelength spectrum that is representative of the visual spectrum (400-750 nm), when crosslinked. The transparency may be determined by any means in the art, such as by a microplate reader or spectrophotometer such as described by Rizwan et al. (Biomaterials, 2017, 120:139-154) or by Van Hoorick et al. (Adv. Healthcare Materials, 2020, 9(6):2000760).

[0129] In embodiments, the crosslinkable liquid composition and / or crosslinked composition has a refractive index similar to that of the native corneal stroma. The refractive index may be measured by any means in the art, such as by use of a refractometer.

[0130] Upon crosslinking of the crosslinkable liquid composition, the crosslinked composition will hold water within its three-dimensional network of polymers, resulting in the formation of a hydrogel.

[0131] The term "hydrogel" as used herein has its meaning as known in the art and refers to a biphasic material, a mixture of porous, permeable solids and at least 10% by weight or volume of interstitial fluid composed completely or mainly by water. In hydrogels the porous permeable solid is a water insoluble three-dimensional network of polymers and a fluid, having absorbed a large amount of water or biological fluids. The term "hydrogel" may be used interchangeably herein with the term "crosslinked composition". In embodiments, the crosslinked composition may be stable at body temperature, such 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.

[0132] In embodiments, the methods as taught herein comprise the step of applying the crosslinkable liquid composition onto the anterior corneal surface of the eyes of the subject.

[0133] In embodiments, the methods as taught herein comprise the step of applying the crosslinkable liquid composition onto the anterior corneal surface of the eyes of the subject, wherein the method comprises introducing the crosslinkable liquid composition into a mold which is positioned onto the anterior corneal surface of the eyes.

[0134] By applying the crosslinkable liquid composition to the anterior corneal surface of the eye using a mold, the crosslinkable liquid composition and final crosslinked composition, can be precisely placed onto the anterior corneal surface of the eye while avoiding spilling of the crosslinkable liquid composition over the entire anterior eye surface and / or under the eyelids before crosslinking. Furthermore, the mold may already give a primary shape, diameter and / or preliminary curvature to the final corneal onlay that will be formed by the crosslinked composition. By creating the corneal onlay in situ, it perfectly fits the patient's corneal geometry, compared to a corneal onlay created separately.

[0135] In embodiments of the uses or methods as taught herein, the mold may be a corneal vacuum suction device, a corneal bath, or a contact lens. In embodiments, the mold is a corneal vacuum suction device. In 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, more preferably a scleral contact lens, that does not adhere to the biomaterial either in uncrosslinked or crosslinked state. In embodiments, the mold is a silicone hydrogel contact lens. A contact lens with a converging meniscus-shape allows shaping the crosslinked composition (i.e., biomaterial) into a lens-shape having a lens body (or lens (optical) zone) and a lens edge at the periphery of the lens body (or peripheral zone). Accordingly, the shaped crosslinked composition would use such a contact lens as a mold that is thinner towards its peripheral edges, and hence, typically having a peripherical edge which is less thick than when use is made of a corneal bath. As a result, less biomaterial will need to be removed upon correcting the curvature of the crosslinked composition, thereby making the uses or methods as taught herein more efficient and attractive.

[0136] In embodiments, the mold may be a standard contact lens which may generate a corneal onlay for which the periphery is thicker than the centre. This advantageously aids in the corrective treatment of myopia, for which the crosslinkable liquid composition is added predominantly peripherally of the cornea.

[0137] The shape of the mold may take into account the swelling of the crosslinkable liquid composition that may occur upon crosslinking and uptake of water by the biomaterial. For example, if a crosslinkable biomaterial is known to swell to twice its size upon crosslinking, and if a thickness of about 50.0 pm of the crosslinked composition (prior to eventual correcting the curvature) would be desired, the mold may be designed to only allow applying a layer of crosslinkable liquid composition with a thickness of about 25.0 pm.

[0138] In embodiments, the curvature of the contact lens may have a back central zone radius of from 8.0 to 15.0 mm, from 8.0 to 14.0 mm, from 8.0 to 13.0 mm, from 8.0 to 12.0 mm, from 8.0 to 11.0 mm, or from 8.0 to 10.0 mm.

[0139] Preferably, the curvature of the contact lens is so that it allows forming a void space or lens shaped cavity between the anterior surface of the cornea of the subject to be treated and the back surface of the central (optical) zone of the contact lens, while the back surface of the peripheral zone closely aligns with the peripheral zone of the cornea or sclera. This void space or lens shaped cavity can be filled with the crosslinkable liquid composition as described herein.

[0140] In embodiments, the shape of the mold is so that it allows the generation of a crosslinked composition or the subsequent shaping the crosslinked composition as to have an average thickness of from about 10.0 pm to about 400.0 pm, such as from about 20.0 pm to about 400.0 pm, from about 25.0 pm to about 400.0 pm, from about 50.0 pm to about 400.0 pm, from about 100.0 pm to about 400.0 pm, from about 200.0 pm to about 400.0 pm, or from about 100.0 pm to about 300.0 pm, prior to eventual correcting the curvature of the crosslinked composition.

[0141] In embodiments, the mold may cover at least 80%, at least 85%, at least 90%, or at least 95%, such as at least 95%; at least 96%, at least 97%, at least 98%, at least 99% or 100%, of the anterior corneal surface of the eye. In embodiments, the mold may completely cover the anterior corneal surface of the eye.

[0142] In embodiments, the shape of the mold may be such that it allows shaping the crosslinked composition as to have a diameter of from about 6.0 mm to about 10.0 mm, such as from about 7.0 mm to about 10.0 mm, from about 6.0 mm to about 9.0 mm, from about 6.0 mm to about 8.0 mm, or from about 7.0 mm to about 9.0 mm. Present inventors realized that a wider diameter could risk covering the limbal epithelial cells, which differentiate and migrate to become corneal epithelial cells. Therefore, physically covering the limbus forms a risk of corneal epithelial cell ingrowth or impedes limbal stem cell differentiation, which is preferably avoided.

[0143] In embodiments, the mold, preferably the contact lens, has a total diameter (including the diameter of the central zone as well as peripheral zone of the mold) of from about 5.0 mm to about 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.

[0144] In embodiments, if UV irradiation or visible light is used to crosslink the crosslinkable liquid composition, the mold is capable of allowing the UV or visible light to reach the crosslinkable liquid composition. For example, if the mold is a contact lens, the contact lens allows passage of UV or visible light.

[0145] In embodiments, the method may comprise applying or positioning said mold onto the anterior corneal surface of the eye either before or after applying said crosslinkable liquid composition into said mold. In embodiments of the uses or methods as taught herein, the mold may be a corneal vacuum suction device, a corneal bath, or a contact lens and the method comprises applying or positioning said mold onto the anterior corneal surface of the eye either before or after applying said crosslinkable liquid composition into said mold.

[0146] In embodiments, the mold such as a contact lens may be filled with the crosslinkable liquid composition prior to applying the mold and crosslinkable liquid composition to the anterior corneal surface of the eye, as illustrated in Figure 1A. In embodiments, the mold such as an O-ring shaped corneal bath (also referred to as an O-ring) may be applied to the anterior corneal surface of the eye prior to filling the mold with the crosslinkable liquid composition.

[0147] As illustrated in Figure 1A, in embodiments, the uses or methods as taught herein may comprise the steps of: filling a mold such as a contact lens with the crosslinkable liquid composition; applying the mold onto the anterior corneal surface of the eye; irradiating the mold comprising the crosslinkable liquid composition with UV or visible light to crosslink the crosslinkable liquid composition, thereby obtaining the crosslinked composition onto the anterior corneal surface of the eye; taking the mold from the eye; and performing photoablation of the crosslinked composition such as with a laser to obtain a crosslinked composition with myopic defocus zones and optionally corrective zones, thereby allowing myopia management and optionally myopia correction.

[0148] A vacuum suction device acts similarly as an O-ring except that the suction device can be secured on the cornea and consists in different diameters. In practice, a vacuum suction device (either a dedicated vacuum suction ring or a vacuum suction device from which the blade has been removed) may be vacuum locked on top of the eye, then the crosslinkable liquid composition as taught herein may be added and irradiated with UV or visible light. Then the vacuum suction device is taken off the eye. A vacuum suction device is for instance illustrated in Fig IB of Kim et al. (J. Vet Sci, 2015, 16, 349-356).

[0149] In embodiments, the crosslinkable liquid composition may be applied onto the anterior corneal surface of the eye in a volume of from 10.0 to 200.0 pl, from 25.0 to 100.0 pl, preferably from 50.0 to 100.0 pl, such as about 50.0 pl. The combination of the mold and the limited amount of volume being used further allows avoiding spilling of the crosslinkable liquid composition over the entire anterior eye surface and / or under the eyelids before crosslinking.

[0150] In embodiments, the method may comprise maintaining the mold in place on the anterior corneal surface of the eye for the entire period of crosslinking the crosslinkable liquid composition.

[0151] In embodiments, if the mold is a contact lens, the centre of the contact lens is placed onto the centre of the anterior surface of the cornea.

[0152] In embodiments of the uses or methods as taught herein, the method may comprise removing the mold after crosslinking the crosslinkable liquid composition. In embodiments of the methods which involve a correction step, the method may comprise removing the mold after crosslinking the crosslinkable composition and prior to correcting the curvature of the crosslinked composition.

[0153] In embodiments of the uses or methods as taught herein, the crosslinkable liquid composition may be applied as a single layer. In embodiments, the crosslinkable liquid composition may be provided as a single layer onto the anterior corneal surface of the eye. In line therewith, in embodiments, the crosslinked composition on the anterior corneal surface of the eye consists of a single layer of biomaterial.

[0154] In the methods envisaged herein, optionally, prior to applying the mold and the crosslinkable liquid composition onto the anterior corneal surface of the eye, the epithelial cells are removed from the cornea to expose the corneal stromal bed for grafting the corneal onlay thereon. The anterior corneal surface may be debrided of corneal epithelial cells by any means known in the art, such as by use of alcohol delamination, a blunt blade, a diamond burr, a cotton sponge or an Amoils brush. Alternatively, the surgeon can opt to remove the epithelium after placing the mold (to only remove the epithelial cells in that area) but before applying the crosslinkable liquid composition onto the anterior corneal surface of the eye. In embodiments, the methods as taught herein comprise the step of applying the crosslinkable liquid composition directly onto the anterior corneal surface of the eyes of the subject, such as without the use of a mold, as illustrated in Figure IB.

[0155] As illustrated in Figure IB, in embodiments, the uses or methods as taught herein may comprise the steps of: applying a crosslinkable liquid composition directly onto the anterior corneal surface of the eye; irradiating the crosslinkable liquid composition with UV or visible light, thereby obtaining the crosslinked composition onto the anterior corneal surface of the eye; and performing photoablation of the crosslinked composition such as with a laser to obtain a crosslinked composition with myopic defocus zones and optionally corrective zones, thereby allowing myopia management and optionally myopia correction.

[0156] In embodiments, the uses and methods as taught herein may not comprise removal or damaging of the Bowman's layer, the corneal stroma, or a combination thereof prior to applying the crosslinkable liquid composition onto the anterior corneal surface of the eye.

[0157] In embodiments, the methods as taught herein comprise the step of crosslinking the crosslinkable liquid composition on the anterior corneal surface of the eyes, thereby obtaining a crosslinked composition on the anterior corneal surface of the eyes.

[0158] In embodiments, the crosslinking may be performed by photocrosslinking, by exposure to O2 or by one or more enzymes such as transglutaminases, transferases, tyrosinases and peroxidases. In case of enzymatic crosslinking, the enzyme and crosslinkable polymer can be mixed upon application in so-called dual barrel syringes which accommodate direct mixing in pre-defined ratios. In preferred embodiments, the crosslinking is performed by photocrosslinking, such as by use of UV light or visible light, more preferably by UV irradiation.

[0159] The terms "photocrosslinking" or "photo-crosslinking" as used herein refers to the process of using electromagnetic radiation, such as visible light or UV radiation, to crosslink compounds such as to crosslink the polymers of the crosslinkable liquid composition and / or to crosslink the polymers of the crosslinkable liquid composition with the anterior corneal surface. The electromagnetic radiation may be generated by a laser such as a pulsed laser.

[0160] In embodiments, photo-crosslinking may be performed by using a lamp. In embodiments, photocrosslinking may be laser-assisted photo-crosslinking (e.g., laser lithography).

[0161] The terms "radiation" and "electromagnetic radiation" may be used interchangeably herein.

[0162] In embodiments, the electromagnetic radiation is ultraviolet radiation or visible light. 1

[0163] The UV spectrum typically spreads from 250 to 450 nm. Preferably, UV irradiation has a wavelength of from 250 to 450 nm, from 300 to 450 nm or from 300 to 400 nm, such as about 365 nm.

[0164] In embodiments, the crosslinkable liquid composition is allowed to crosslink until at least 80.0% of the crosslinkable liquid composition is crosslinked, preferably until at least 90.0%, such as until 99.9% or 100.0% of the crosslinkable liquid composition is crosslinked.

[0165] In embodiments, the crosslinkable liquid composition may be crosslinked using visible or UV light for a period of at least 5 seconds, at least 6 seconds, at least 7 seconds, at least 8 seconds, at least 9 seconds, at least 10 seconds, at least 20 seconds, at least 30 seconds, at least 40 seconds, at least 50 seconds, or at least 60 seconds (1 minute). In embodiments, the crosslinkable liquid composition may be crosslinked using visible or UV light for a period of at least 2 minutes, at least 5 minutes, at least 10 minutes, at least 20 minutes, at least 30 minutes, or at least 40 minutes, preferably at least 30 minutes. In embodiments, the crosslinkable liquid composition may be crosslinked using visible or UV light for a period of at most 5 minutes, at most 4 minutes, at most 3 minutes, at most 2 minutes or at most 1 minute. In embodiments, the crosslinkable liquid composition may be crosslinked using visible light for a period of 5 second to 5 minutes, such as for a period of 5 seconds to 4 minutes, 5 seconds to 4 minutes, 5 seconds to 3 minutes, 5 seconds to 2 minutes, or 5 seconds to 1 minute, preferably for a period of 5 seconds to 30 seconds. In embodiments, the UV light is administered with a UV lamp using a dosage of between lmW / cm2 and 20mW / cm2, such as 18mW / cm2depending on the nature of the lamp. Examples of suitable UV light sources include the Schwind CXL-365 vario system, OmniCure®1500 and AnalytikJena UV crosslinker. In embodiments, the total dose of UV may be at least 0.7 Joule (J) / cm2, such as at least 0.8, at least 0.9, at least 1.0, at least 2.0, at least 3.0, at least 4.0 or at least 5.0 J / cm2, preferably at least 1.0 J / cm2or at least 5 J / cm2, such as about 5.4 J / cm2. In embodiments, the total dose of UV light may be between 3 and 7 J / cm2, such as about 5 J / cm2. In particular embodiments the visible light (around 450 nm) is administered with a strength of between 800-1500 mw / cm2.

[0166] In the uses or methods as taught herein, the crosslinking is performed in situ, onto the anterior corneal surface of the eye. Hence, in the uses or methods as taught herein, the crosslinked composition is a corneal onlay. In embodiments, the crosslinking is performed at body temperature, such as at a temperature of from 35.0°C to 40.0°C or from 36.0°C to 38.0°C.

[0167] The term "corneal onlay" generally refers to an optical device positioned between the epithelium and the stroma of the cornea to correct vision. A corneal onlay generally has a circular shape. The term "corneal onlay" as used herein refers to the crosslinked composition on the anterior corneal surface of the eye either before or after the curvature of the crosslinked composition has been corrected. In particular embodiments, the "corneal onlay" as used herein refers to the crosslinked composition on the anterior corneal surface of the eye after the curvature of the crosslinked composition has been corrected, i.e., the final corneal onlay.

[0168] The use or method as taught herein provides a reversible crosslinked composition that is placed over the Bowman's membrane of a subject such as a child. Once the material attaches to the cornea, the anterior surface of the onlay is reshaped using a refractive laser thereby creating a peripheral defocus, and optionally a central correction of the myopia.

[0169] In embodiments of the uses or methods as taught herein, the crosslinked composition or corneal onlay may be resistant to biodegradation for a period of 6 months to 5 years, such as for a period of 9 months to 4 years, preferably for a period of 12 months to 4 years or 12 months to 3 years. In embodiments, the crosslinked composition or corneal onlay may be resistant to degradation for a period of 6 months to 5 years, such as for a period of 9 months to 4 years, preferably for a period of 12 months to 4 years or 12 months to 3 years. In embodiments, the crosslinked composition or corneal onlay may be resistant to enzymatic degradation for a period of 6 months to 5 years, such as for a period of 9 months to 4 years, preferably for a period of 12 months to 4 years or 12 months to 3 years. Such periods advantageously allow controlled absorption of the crosslinked composition or corneal onlay by the body which is interesting because the crosslinked composition or corneal onlay will automatically disappear without additional intervention. In order to achieve a controlled absorption of the crosslinked composition or corneal onlay by the body, the concentration of PEGDA may be reduced or PEGDA may be omitted and / or the concentration of gelatin or gelatinbased crosslinkable biomaterial may be reduced.

[0170] In embodiments of the uses or methods as taught herein, the crosslinked composition or corneal onlay may be resistant to biodegradation for a period of at least 6 months, preferably at least 12 months. In embodiments, the crosslinked composition or corneal onlay may be resistant to degradation for a period of at least 6 months, preferably at least 12 months. In embodiments, the crosslinked composition or corneal onlay may be resistant to enzymatic degradation for a period of at least 6 months, preferably at least 12 months.

[0171] In embodiments of the uses or methods as taught herein, the crosslinked composition or corneal onlay may be resistant to biodegradation for a period of about 6 years, such as about 5.5 years, about 5 years, about 4.5 years, about 4 years, about 3.5 years, about 3 years, about 2.5 years, about 2 years, about 1.5 year, about 1 year (12 months) or about 6 months. In embodiments, the crosslinked composition or corneal onlay may be resistant to degradation for a period of about 6 years, such as about 5.5 years, about 5 years, about 4.5 years, about 4 years, about 3.5 years, about 3 years, about 2.5 years, about 2 years, about 1.5 year, about 1 year (12 months) or about 6 months. In embodiments, the crosslinked composition or corneal onlay may be resistant to enzymatic degradation for a period of about 6 years, such as about 5.5 years, about 5 years, about 4.5 years, about 4 years, about 3.5 years, about 3 years, about 2.5 years, about 2 years, about 1.5 year, about 1 year (12 months) or about 6 months. Such periods advantageously allow controlled absorption of the crosslinked composition or corneal onlay by the body which is interesting because the crosslinked composition or corneal onlay will disintegrate without the need for surgical removal.

[0172] Crosslinking of the crosslinkable liquid composition onto the anterior corneal surface of the eye leads to adherence between the crosslinked composition or corneal onlay and the anterior corneal surface of the eye through the formation of covalent bonds with the amino acids in the corneal collagen. In 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, and preferably with an adhesion strength from 10.0 to 100.0 kPa. The adhesion strength may be determined by any methods known in the art, such as by a lap shear test with a universal testing machine according to the ASTM F2255 using gelatin-coated glass slides.

[0173] In embodiments, the posterior surface of the crosslinked composition contacts the Bowman's membrane of the eye.

[0174] In embodiments, the crosslinked composition is flexible. The flexibility of the crosslinked composition may be altered by changing the concentration of the gelatin or gelatin-based crosslinkable biomaterial in the crosslinkable liquid composition, its degree of substitution, or its molecular weight. Preferably, the flexibility of the crosslinked composition is similar to native cornea.

[0175] In embodiments of the uses or methods as taught herein, the crosslinked composition or corneal onlay may have a diameter of from about 6.0 mm to about 10.0 mm from about 7.0 mm to about 10.0 mm, from about 6.0 mm to about 9.0 mm, and a thickness of from about 10.0 pm to about 400.0 pm prior to correcting the curvature of the crosslinked composition. For instance, the crosslinked composition may have a diameter of from about 6.0 mm to about 8.0 mm and a thickness of from about 10.0 pm to about 400.0 pm prior to correcting the curvature of the crosslinked composition, or the crosslinked composition may have a diameter of from about 7.0 mm to about 9.0 mm and a thickness of from about 10.0 pm to about 400.0 pm prior to correcting the curvature of the crosslinked composition.

[0176] In embodiments, the crosslinked composition may have a diameter of from about 6.0 mm to about 10.0 mm, such as from about 7.0 mm to about 10.0 mm, from about 6.0 mm to about 9.0 mm, from about 6.0 mm to about 8.0 mm, or from about 7.0 mm to about 9.0 mm, prior to correcting the curvature of the crosslinked composition.

[0177] In embodiments, the crosslinked composition may have a thickness of from about 10.0 pm to about 400.0 pm, such as from about 20.0 pm to about 400.0 pm, from about 25.0 pm to about 400.0 pm, from about 50.0 pm to about 400.0 pm, from about 100.0 pm to about 400.0 pm, from about 200.0 pm to about 400.0 pm, or from about 100.0 pm to about 300.0 pm, prior to correcting the curvature of the crosslinked composition.

[0178] In embodiments, the methods as taught herein comprise the step of correcting the curvature of the crosslinked composition such as the corneal onlay to create a peripheral myopic defocus.

[0179] Reshaping of the crosslinked composition changes the refractive properties of the so-treated eye in a desired manner for myopia management. By creating a peripheral myopic defocus of the incoming light, the physiological process of eyeball development is influenced and the axial growth of the eye slows down, thereby preventing or reducing myopia progression.

[0180] In embodiments, the periphery of the corneal onlay provides peripheral myopic defocus for preventing myopia progression or reducing the progression of myopia. In embodiments, the peripheral myopic defocus may be created by zones of the mid-peripheral region of the onlay, which provides a positive (plus) power for peripheral light rays passing through it. The higher positive (plus) power provided in zones of the mid-peripheral region of the corneal onlay results in an overall increase in peripheral myopic stimulus, which has the effect of preventing eye growth or at least slowing the progression of eye growth.

[0181] The term "on-axis" as used herein is intended to refer to locations that are along the longitudinal, visual axis of the eyeball. The term "off-axis" as used herein, is intended to refer to locations that are not along the longitudinal, visual axis of the eyeball.

[0182] The term "myopic defocus" as used herein refers to any refractive state where the image of a distant object is formed in front of the retina.

[0183] The terms "peripheral myopic defocus" or "off-axis myopic defocus" refer to myopic defocus provided by an optical system such as an onlay as taught herein that is not on the longitudinal, visual axis of the eyeball.

[0184] The terms "power", "optical power", "dioptre", "dioptric power", "refractive power", "focusing power", or "convergence power" may be used interchangeably herein and refer to the degree to which an onlay, lens, or other optical system converges or diverges light. It is equal to the reciprocal of the focal length of the device: P = 1 / f. The SI unit for optical power is the inverse metre (m1)7which is commonly called the dioptre (symbol: dpt).

[0185] In embodiments, the peripheral myopic defocus may be created by providing zones of positive (plus) power in the mid-periphery of the crosslinked composition or corneal onlay. In embodiments, the peripheral myopic defocus may be created by providing zones of positive (plus) power in the mid-periphery of the crosslinked composition or corneal onlay, while providing negative (minus) power in the surrounding zones. In embodiments, the peripheral myopic defocus may be created by providing zones of positive (plus) power by inducing steepening in the mid-periphery of the crosslinked composition, for instance with an excimer laser or femtosecond laser. In embodiments, the peripheral myopic defocus may be created by steepening the curvature of the crosslinked composition in zones of the mid-peripheral zone. The steepening may be created by indentations or bulges. For instance, a laser pattern can be applied by software to the crosslinked composition. The different regions of the laser pattern can by themselves display a positive power relative to the surrounding zone such as the corrective zone.

[0186] In embodiments, the crosslinked composition or corneal onlay may provide visual correction of the myopia. In embodiments, the visual correction of myopia may be created by providing a negative (minus) power for light passing through it. In embodiments, the crosslinked composition or corneal onlay may provide visual correction of the myopia over the surface of the crosslinked composition or corneal onlay except for the zones providing peripheral myopic defocus. In embodiments, the crosslinked composition or corneal onlay may provide visual correction of the myopia over the surface of the crosslinked composition or corneal onlay except for the zones of positive (plus) power in the mid-periphery of the crosslinked composition or corneal onlay.

[0187] The terms "periphery", "mid-periphery", "peripheral region" or "midperipheral region" as used herein refer to an annular region of the crosslinked composition or corneal onlay located between a circle of about 4 mm (e.g., 3.5 mm to 4.5 mm, such as 3.5 mm, 3.6 mm, 3.7 mm, 3.8 mm, 3.9 mm, 4.0 mm, 4.1 mm, 4.2 mm, 4.3 mm, 4.4 mm, or 4.5 mm) in diameter around the central point of the crosslinked composition or corneal onlay (e.g., when present on the eye corresponding to the fixation point of the eye, i.e., the point at which one's gaze is directed) and the outer diameter of the crosslinked composition or corneal onlay, as illustrated in Figure 2. For example, if the corneal onlay has a diameter of about 9.0 mm, the periphery may refer to the annular region of the corneal onlay located between a circle of about 4 mm (e.g., 3.5 mm to 4.5 mm) in diameter around the central point of the corneal onlay and a circle of about 9.0 mm in diameter. If the corneal onlay has a diameter of about 10.0 mm, the periphery may refer to the annular region of the corneal onlay located between a circle of about 4 mm (e.g., 3.5 mm to 4.5 mm) in diameter around the central point of the corneal onlay and a circle of about 10.0 mm in diameter.

[0188] Hence, in embodiments, if the corneal onlay has a diameter of about 6.0 mm to about 10.0 mm, the periphery may refer to the annular region of the corneal onlay located between a circle of about 4 mm (e.g., 3.5 mm to 4.5 mm, such as 3.5 mm, 3.6 mm, 3.7 mm, 3.8 mm, 3.9 mm, 4.0 mm, 4.1 mm, 4.2 mm, 4.3 mm, 4.4 mm, or 4.5 mm) in diameter around the central point of the corneal onlay and a circle of about 6.0 mm to about 10.0 mm in diameter. In embodiments, if the corneal onlay has a diameter of about 7.0 mm to about 10.0 mm or about 6.0 mm to about 9.0 mm, the periphery may refer to the annular region of the corneal onlay located between a circle of about 4 mm (e.g., 3.5 mm to 4.5 mm, such as 3.5 mm, 3.6 mm, 3.7 mm, 3.8 mm, 3.9 mm, 4.0 mm, 4.1 mm, 4.2 mm, 4.3 mm, 4.4 mm, or 4.5 mm) in diameter around the central point of the corneal onlay and a circle of about 7.0 mm to about 10.0 mm or about 6.0 mm to about 9.0 mm in diameter.

[0189] In embodiments, peripheral myopic defocus may be provided by providing concentric rings of myopic defocus, by providing multiple segments (or lenslets) of myopic defocus, or by providing a gradient of myopic defocus, such as by providing a gradient of radially outwardly increasing myopic defocus.

[0190] In embodiments, the zones of positive (plus) power in the mid-periphery of the crosslinked composition or corneal onlay may be concentric rings, multiple segments (or lenslets), or a gradient.

[0191] In embodiments, the concentric rings of myopic defocus may be concentric rings of constant myopic defocus. In embodiments, the concentric rings of myopic defocus may alternate with concentric rings providing visual correction of the myopia. In embodiments, the concentric rings of constant myopic defocus may alternate with concentric rings providing visual correction of the myopia, as illustrated in Figure 2B ("defocus concentric rings"). For instance, the concentric rings in the midperipheral region may have a dioptre (e.g., from the inner diameter of the periphery of the corneal onlay to the outer diameter of the corneal onlay) of +3, -2, +3, and -2. In embodiments, the concentric rings of myopic defocus may be concentric rings of radially outward increasing myopic defocus. In embodiments, the concentric rings of radially outward increasing myopic defocus may alternate with concentric rings providing visual correction of the myopia. For instance, the concentric rings in the mid-peripheral region may have a dioptre (e.g., from the inner diameter of the periphery of the corneal onlay to the outer diameter of the corneal onlay) of +2.0, -2.0, +3.0, - 2.0, +4.0, and -2.0. The most outward ring of the mid-peripheral zone may be a ring of myopic defocus. The most outward ring of the mid-peripheral zone is preferably a ring providing visual correction of the myopia. The concentric rings providing visual correction of the myopia preferably have a constant dioptre.

[0192] In embodiments, the concentric rings may have a width of about 0.1 mm to 2.5 mm, such as a width of about 0.5 mm to 2.5 mm, about 0.5 mm to 2.0 mm, or 1.0 mm to 1.5 mm. In embodiments, the concentric rings may have a constant or varying width.

[0193] In embodiments, the lenslets or multiple segments of myopic defocus may be lenslets of constant myopic defocus, as illustrated in Figure 2B ("defocus lenslets"), e.g., lenslets having a dioptre of up to +3.0. The lenslets of myopic defocus may be lenslets of radially outward increasing myopic defocus, e.g., lenslets having radially outward dioptre of +1.0 +2.0, +3.0, +4.0. The lenslets of myopic defocus may be evenly distributed in the whole of the mid-peripheral region, as illustrated in Figure 2B ("defocus lenslets"). The lenslets of myopic defocus may be evenly distributed in an annular part of the mid-peripheral region, such as an inner annular part of the mid-peripheral zone. The outward annular part of the mid-peripheral zone is preferably a zone providing visual correction of the myopia.

[0194] In embodiment, the lenslets may have a circular shape, as illustrated in Figure 2B ("defocus lenslets"). In embodiments, the lenslets may have a diameter of about 10 pm to about 1.0 mm, such as a diameter of about 100 pm to about 750 pm or about 200 pm to about 500 pm. In embodiments, the lenslets may have a constant or varying diameter.

[0195] In embodiments, the peripheral myopic defocus may be provided by a radially outward increase or decrease of the myopic defocus in the mid-peripheral region of the corneal onlay. Preferably, the peripheral myopic defocus may be provided by a radially outward increase of the myopic defocus in the mid-peripheral region of the corneal onlay. In embodiments, the gradient of radially outwardly increasing myopic defocus may be provided by a radially outward increase of the dioptre in the mid-periphery of the corneal onlay. In embodiments, the dioptre may increase radially outwardly from a circle of about 4 mm (e.g., 3.5 mm to 4.5 mm, such as 3.5 mm, 3.6 mm, 3.7 mm, 3.8 mm, 3.9 mm, 4.0 mm, 4.1 mm, 4.2 mm, 4.3 mm, 4.4 mm, or 4.5 mm) in diameter around the central point of the corneal onlay to the outer diameter of the corneal onlay. For instance, the dioptre may be +1.0 at the circle of about 4 mm in diameter and increase radially outwardly to a dioptre of +4.0 at the outer diameter of the corneal onlay. In embodiments, the gradient of radially outwardly increasing myopic defocus may be continuous, as illustrated in Figure 2B ("defocus gradient"). In embodiments, the gradient of radially outwardly increasing myopic defocus may be discontinuous such as in concentric rings (or annular zones). For example, the concentric rings (or annular zones) in the mid-periphery may have a dioptre (e.g., from the inner diameter of the periphery of the corneal onlay to the outer diameter of the corneal onlay) of +0.75, +1.0, +1.25, +1.5, +1.75, +2.0, +2.25, +2.5, +2.75, and +3.0.

[0196] In embodiments, the zones of myopic defocus are created on the onlay by photoablation such as with a laser. In embodiments, the zones of visual correction or negative power are created on the onlay by photoablation such as with a laser.

[0197] In order to generate a peripheral myopic defocus on the corneal onlay, crosslinked biomaterial is deposited onto the anterior corneal surface that has been debrided from epithelial cells and the laser may shape the onlay according to a pattern that enables alternating regions of vision correction and myopic defocus. Thereby, the laser allows to create zones of positive (plus) power in the mid-periphery of the crosslinked composition according to the pattern applied, e.g., concentric circles, a gradient or lenslets.

[0198] In embodiments, the crosslinked composition or corneal onlay may be photoablated to obtain a visual or refractive correction for the myopia in the range of from -20 dioptres to -0.50 dioptres or from -20 dioptres to -0.75 dioptres and to obtain a peripheral myopic defocus. In embodiments, the crosslinked composition may be photoablated such that the crosslinked composition has an optical power within a range from -20 dioptres to about -0.75 dioptres, preferably from -10 dioptres to about -1.0 dioptres. In particular embodiments, the visual correction may also be obtained by shaping the curvature of the crosslinked material with a blade.

[0199] In embodiments, the upper surface of the crosslinked biomaterial may be photoablated to shape the upper surface.

[0200] Furthermore, the person skilled in the art will also understand that the possible deswelling of the crosslinked composition upon overgrowth of the epithelial cells should be taken into account when determining the amount of crosslinked composition that will be removed from the eye to create the peripheral myopic defocus and optionally correct vision.

[0201] Photoablation may be performed using a laser, such as an excimer laser.

[0202] In embodiments, the correcting of the curvature of the crosslinked composition may not comprise removing corneal tissue, such as corneal stromal tissue, such as by photoablation.

[0203] In embodiments, the method as taught herein is reversible, meaning that the crosslinked composition may be completely removed from the anterior corneal surface of the eye, if needed, such as by photoablation, hydrodissection, microkeratome or manual dissection.

[0204] After correcting the curvature of the crosslinked composition, the corneal epithelium may spontaneously reform originating from the corneal limbus, the corneal scleral transition zone. Overgrow of the crosslinked composition by the corneal epithelium typically occurs within 1 to 2 weeks after correcting the curvature of the crosslinked composition. In embodiments, one or more therapeutic agents, such as NGF, may be administered to the eye to improve regrowth of the corneal epithelium.

[0205] The subject may post-operatively be treated with therapeutic agents that reduce pain and / or inflammation, such as corticosteroids and / or antibiotics.

[0206] While the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art in light of the foregoing description. Accordingly, it is intended to embrace all such alternatives, modifications, and variations as follows in the spirit and scope of the appended claims.

[0207] The herein disclosed aspects and embodiments of the invention are further supported by the following non-limiting examples.

[0208] EXAMPLES

[0209] Example 1: Resistance to enzymatic degradation of crosslinked compositions according to embodiments of the invention and comparative crosslinked compositions

[0210] Materials and methods

[0211] The materials used were as follows: Eppendorf tubes amber colored (VWR, 525-1223); Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (Merck, 900889-1G); Gelatin methacrylate DS75-85 (PB Leiner, Claro, BG800 freeze-dried form); Collagenase (Merck, C9891-500MG); Phosphate buffered saline IX (Thermo Fisher, 14200083); CCL-365 UV lamp (Vario) UV crosslinker CL-3000 (AnalytikJena).

[0212] First, crosslinkable liquid compositions were prepared in Eppendorf tubes according to the desired concentrations of functionalized gelatin, photoinitiator, and PEGDA. The crosslinkable biomaterial was completely dissolved by mixing and vortexing. Droplets of 50 pL of crosslinkable liquid composition were pipetted onto parafilm and these were irradiated with CCL-365 UV lamp for 5 minutes at 18 mW / cm2or with a UV crosslinker (AnalytikJena) at 1 mW / cm2to obtain an accumulated UV dosage of 5.4 J / cm2.

[0213] The crosslinked compositions were then incubated in PBS until they reach final thickness (>24 hours) and weigh the hydrogels (W0).

[0214] The crosslinked compositions were then placed in collagenase solution (0.1U) and weighed at regular time intervals (Wt). Before weighing, surface water was removed with a tissue. The collagenase solution was refreshed after every measurement with a freshly made collagenase solution.

[0215] Enzymatic degradation was determined by calculating the residual weight according to the following equation: residual weight = (Wt / W0)*100.

[0216] Results

[0217] Crosslinkable liquid solutions were fabricated and crosslinked according to the protocol above and degradation was followed over time. All samples were composed of 10% and 15% gelatin with no additional PEGDA. Crosslinked compositions containing 10% gelatin degraded completely after 7 days, while the other samples remained stable and were only fully degraded after 30 days (Figure 3). This demonstrates that varying the concentration of gelatin allows to control the resistance to enzymatic degradation. Hence, by varying the concentration of the gelatin, crosslinked compositions can be prepared with a resistance of the crosslinked composition to biodegradation for a period of 6 months to 5 years. Depending on the age of the child the period of resistance to biodegradation can be chosen so that after the desired period of myopia management the crosslinked composition has been degraded and no surgery is required to remove the corneal onlay. This is an important advantage since, like for glasses or lenses, no surgery is needed but in addition it overcomes the need to wear glasses or lenses which is sometimes difficult for children as it obstructs them in playing or sporting.

[0218] Example 2: Resistance to enzymatic degradation of crosslinked compositions according to embodiments of the invention comprising 10% gelatin and varying concentrations of PEGDA and comparative crosslinked compositions

[0219] Materials and methods

[0220] The materials used were as follows: Eppendorf tubes amber colored (VWR, 525-1223); Poly ethylene glycol diacrylate (Merck, 455008-100ML); Lithium phenyl-2,4,6- trimethylbenzoylphosphinate (Merck, 900889-1G); Gelatin methacrylate DS75-85 (PB Leiner, Claro, BG800 freeze-dried form); Collagenase (Merck, C9891-500MG); Phosphate buffered saline IX (Thermo Fisher, 14200083); CCL-365 UV lamp (Vario) UV crosslinker CL-3000 (AnalytikJena).

[0221] First, crosslinkable liquid compositions were prepared in Eppendorf tubes according to the desired concentrations of functionalized gelatin, photoinitiator, and PEGDA. The crosslinkable biomaterial was completely dissolved by mixing and vortexing. Droplets of 50 pL of crosslinkable liquid composition were pipetted onto parafilm and these were irradiated with CCL-365 UV lamp for 5 minutes at 18 mW / cm2or with a UV crosslinker (AnalytikJena) at 1 mW / cm2to obtain an accumulated UV dosage of 5.4 J / cm2.

[0222] The crosslinked compositions were then incubated in PBS until they reach final thickness (>24 hours) and weigh the hydrogels (WO).

[0223] The crosslinked compositions were then placed in collagenase solution (0.1U) and weighed at regular time intervals (Wt). Before weighing, surface water was removed with a tissue. The collagenase solution was refreshed after every measurement with a freshly made collagenase solution.

[0224] Enzymatic degradation was determined by calculating the residual weight according to the following equation: residual weight = (Wt / W0)*100.

[0225] Results

[0226] Crosslinkable liquid solutions were fabricated and crosslinked according to the protocol above and degradation was followed over time. All samples were composed of 10% gelatin but with varying concentrations of PEGDA. Crosslinked compositions containing no PEGDA degraded completely after 7 days, while the other samples remained stable (100%) for a period of at least 70 days (Figure 4), implying control over resistance to enzymatic degradation when increasing the PEGDA concentration. This demonstrates that varying the concentration of PEGDA allows to control the resistance to enzymatic degradation. Hence, by varying the concentration of the PEGDA (and optionally the gelatin, e.g., see Examples 1 and 3), crosslinked compositions can be prepared with a resistance of the crosslinked composition to biodegradation for a period of 6 months to 5 years. Depending on the age of the child the period of resistance to biodegradation can be chosen so that after the desired period of myopia management the crosslinked composition has been degraded and no surgery is required to remove the corneal onlay. This is an important advantage since, like for glasses or lenses, no surgery is needed but in addition it overcomes the need to wear glasses or lenses which is sometimes difficult for children as it obstructs them in playing or sporting.

[0227] Example 3: Resistance to enzymatic degradation of crosslinked compositions according to embodiments of the invention comprising 15% gelatin and varying concentrations of PEGDA and comparative crosslinked compositions

[0228] Materials and methods

[0229] The materials and methods used were the same as described above in Example 2. Results

[0230] Crosslinkable liquid solutions were fabricated and crosslinked according to the protocol above and degradation was followed over time. All samples were composed of 15% gelatin but with varying concentrations of PEGDA. Crosslinked compositions containing no PEGDA degraded completely after 28 days, while the other samples remained stable (100%) for a period of at least 70 days (Figure 5), implying control over resistance to enzymatic degradation when increasing the PEGDA concentration. The results of Examples 2 and 3 demonstrate that varying the concentration of gelatin and PEGDA allows to control the resistance to enzymatic degradation. Hence, by varying the concentration of the gelatin and PEGDA, crosslinked compositions can be prepared with a resistance of the crosslinked composition to biodegradation for a period of 6 months to 5 years.

[0231] Depending on the age of the child the period of resistance to biodegradation can be chosen so that after the desired period of myopia management the crosslinked composition has been degraded and no surgery is required to remove the corneal onlay. This is an important advantage since, like for glasses or lenses, no surgery is needed but in addition the crosslinked compositions illustrating the invention overcome the need to wear glasses or lenses which is sometimes difficult for children as it obstructs them in playing or sporting.

Claims

CLAIMS1. A crosslinkable liquid composition comprising a gelatin or a gelatin-based crosslinkable biomaterial for use in a method of one or more of preventing or reducing the progression of myopia or preventing an eye disease associated with myopia progression in a subject.

2. The crosslinkable liquid composition for use according to claim 1, wherein the method comprises: applying a crosslinkable liquid composition onto the anterior corneal surface of the eyes of the subject, wherein the method comprises introducing the crosslinkable liquid composition into a mold which is positioned onto the anterior corneal surface of the eyes, crosslinking the crosslinkable liquid composition on the anterior corneal surface of the eyes, thereby obtaining a crosslinked composition on the anterior corneal surface of the eyes, and correcting the curvature of the crosslinked composition to create a peripheral myopic defocus.

3. The crosslinkable liquid composition for use according to claim 1 or 2, wherein the peripheral myopic defocus is created by providing zones of positive power in the mid-periphery.

4. The crosslinkable liquid composition for use according to claim 1 to 3, wherein the myopia is juvenile onset myopia and / or wherein the subject is a child having an age of 6 years to 18 years; preferably wherein the subject is a child having an age of 8 years to 13 years.

5. The crosslinkable liquid composition for use according to any one of claims 1 to 4, wherein the eye disease associated with myopia progression is selected from the group consisting of macular degeneration, retinal detachment, cataract, and glaucoma.

6. The crosslinkable liquid composition for use according to any one of claims 1 to 5, wherein the gelatin-based crosslinkable biomaterial is selected from the group consisting of a gelatin methacrylate, a gelatin desaminotyrosine, a gelatin desaminotyrosyl tyrosine, a gelatin tyramine, and a thiolated gelatin.

7. The crosslinkable liquid composition for use according to any one of claims 1 to 6, wherein: the crosslinkable liquid composition comprises from about 5.0% to about 40.0% (w / v) of the gelatin or gelatin-based crosslinkable biomaterial; and / or the gelatin-based crosslinkable biomaterial is a functionalized gelatin having a degree of substitution of from about 40% to about 90%.

8. The crosslinkable liquid composition for use according to any one of claims 1 to 7 , wherein the mold is a corneal vacuum suction device, a corneal bath, or a contact lens.

9. The crosslinkable liquid composition for use according to any one of claims 1 to 8, wherein the crosslinkable liquid composition is applied as a single layer.

10. The crosslinkable liquid composition for use according to any one of claims 1 to 9, wherein the crosslinking is performed by photocrosslinking, by exposure to O2 or by one or more enzymes; preferably wherein the crosslinking is performed by photocrosslinking such as by UV irradiation or irradiation with visible light.

11. The crosslinkable liquid composition for use according to any one of claims 1 to 10, wherein the crosslinkable liquid composition further comprises a photoinitiator and optionally a coinitiator.

12. The crosslinkable liquid composition for use according to any one of claims 1 to 11, wherein the photoinitiator is a visible or UV light photoinitiator; preferably wherein the photoinitiator is Irgacure 2959, Lithium phenyl-2,4,6-trimethylbenzoylphosphinate, tris(2,2'- bipyridyl)dichlororuthenium(ll) hexahydrate, or riboflavin, and optionally the co-initiator is sodium persulphate.

13. The crosslinkable liquid composition for use according to any one of claims 1 to 12, wherein the crosslinkable liquid composition further comprises a polyethylene glycol diacrylate (PEGDA); preferably wherein the crosslinkable liquid composition comprises from about 0.5% to about 15.0% (w / v) of the PEGDA and / or wherein the PEGDA has a molecular mass of about 250 g / mol to about 6000 g / mol; preferably of about 500 g / mol to about 1000 g / mol.

14. The crosslinkable liquid composition for use according to any one of claims 1 to 13, wherein the crosslinked composition has a diameter of from about 6.0 mm to about 10.0 mm and a thickness of from about 10.0 pm to about 400.0 pm, prior to correcting the curvature of the crosslinked composition; and / or wherein the crosslinked composition is resistant to biodegradation for a period of 6 months to 5 years, preferably for a period of 12 months to 4 years.

15. A crosslinkable liquid composition comprising a gelatin or a gelatin-based crosslinkable biomaterial for use in a surgical method of preparing a corneal onlay on the eyes of a subject, wherein the method comprises:applying a crosslinkable liquid composition onto the anterior corneal surface of the eyes of the subject, wherein the method comprises introducing the crosslinkable liquid composition into a mold which is positioned onto the anterior corneal surface of the eyes, crosslinking the crosslinkable liquid composition on the anterior corneal surface of the eyes, thereby obtaining a crosslinked composition on the anterior corneal surface of the eyes, and correcting the curvature of the crosslinked composition to create a peripheral myopic defocus.

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