Improved adhesion between the vitreous humor and the retina.

Abstract

This disclosure relates, in general, to a method for improving adhesion between the vitreous humor and the retina.

Description

[Technical Field]

[0001] Cross-reference of related applications In accordance with 35 U.S. SC § 119(e), this application claims priority to the filing date of U.S. Provisional Patent Application No. 63 / 472,722, filed on 13 June 2023, the respective disclosures of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Retinal detachment (RD) occurs when the sensory retina separates from the retinal pigment epithelium and the choroid, which provides the underlying vascular supply. Rhegmatogenous retinal detachment (RRD) occurs when vitreous fluid leaks through a tear in the retina into the subretinal space. Despite advances in surgical techniques, delayed diagnosis and treatment can lead to permanent vision loss. The overall incidence is 1 in 10,000 people per year, but the incidence can be much higher in individuals with established risk factors such as high myopia, a history of ophthalmic surgery, or a history of retinal tears in the other eye. Patients with retinal lattice degeneration or retinal tears can be prophylactically treated with laser photocoagulation to reduce the risk of RRD, but there is no reliable way to prevent RRD in these high-risk patients.

[0003] Posterior vitreous detachment (PVD) is a condition that can precede recurrent retinal reduction (RRD). PVD occurs when the vitreous gel detaches from the back of the eyeball. PVD allows the vitreous humor to move freely with eye movements, "whipping" the eye. This can generate excessive traction on the remaining anterior vitreous-retinal attachment, potentially tearing the retina and triggering RRD.

[0004] By preventing the detachment of the posterior vitreous humor, it is possible to prevent the generation of excessive traction forces caused by the free movement of the vitreous humor, thereby preventing retinal tears and retinal detachment.

[0005] Currently, there is no treatment or preventive measure for the loss of adhesion between the vitreous humor and the retina that causes PVD. Improving this adhesion and preventing complete PVD would represent an advance in the art. This specification presents, among other things, a solution to this problem. [Overview of the project]

[0006] This disclosure relates, in general, to a method for improving adhesion between the vitreous humor and the retina.

[0007] In one embodiment, the present invention provides a method for improving adhesion between the vitreous humor and the retina of a mammalian eye, comprising administering a photosensitive substance to the mammalian eye, the photosensitive substance accumulating at the vitreoretinal interface (VRI), and irradiating a selected region of the VRI with light of a wavelength that causes crosslinking between the vitreous humor and the retina, thereby improving adhesion between the vitreous humor and the retina in the mammalian eye.

[0008] In one embodiment, the present invention provides a method for improving adhesion between the vitreous humor and the retina of a mammalian eye, comprising administering a photosensitive substance to the mammalian eye, the photosensitive substance accumulating at the vitreoretinal interface (VRI), and irradiating a selected region of the VRI where the photosensitive substance has accumulated with light of a wavelength that causes crosslinking between the vitreous humor and the retina, thereby improving adhesion between the vitreous humor and the retina in the mammalian eye.

[0009] The above summary is illustrative and not intended to limit the scope of this disclosure. In addition to the exemplary embodiments and features described herein, further aspects, embodiments, purposes and features of this disclosure will be fully apparent from the drawings, detailed description and claims.

[0010] The features of this disclosure are described in detail in the appended claims. A better understanding of the features and advantages of this disclosure will be obtained by referring to the following detailed description illustrating exemplary embodiments in which the principles of this disclosure are utilized, and to the appended drawings. [Brief explanation of the drawing]

[0011] [Figure 1] It is a diagram showing a plasmin eye injection strategy.

[0012] [Figure 2] It is a diagram showing the relationship between the average vitrector decompression degree and the maximum mass lifted by suction.

[0013] [Figure 3] It is a diagram showing the influence of the injected plasmin concentration on the average minimum decompression degree required to induce PVD.

[0014] [Figure 4] It is a diagram showing PVD data of eyes treated with plasmin, glutaraldehyde, MetB 1:100 solution, and MetB 1:1000 solution.

[0015] [Figure 5] It is a diagram showing the output of a 660 nm flashlight measured after each condition.

[0016] [Figure 6] It is a diagram showing the funnel-shaped light at the bottom of the beaker.

[0017] [Figure 7] It is a diagram showing the intensity of the laser light with respect to the measured output.

[0018] [Figure 8] It is a diagram showing the average minimum pressure required for PVD induction for each category.

Mode for Carrying Out the Invention

[0019] I. Definitions Unless otherwise defined, all technical terms, notations, and other scientific or technical terms used herein are intended to have meanings that are generally understood by those skilled in the art to which this application pertains. In some cases, terms that have generally understood meanings are defined herein for clarity and / or for ease of reference, and the inclusion of such definitions herein should not necessarily be interpreted as representing a substantial difference from those generally understood in the art. Many of the techniques and procedures described or referenced herein are well understood and commonly adopted by those skilled in the art using prior methodologies.

[0020] The singular forms “a,” “an,” and “the” include multiple references unless the context clearly indicates otherwise. For example, the term “cell” includes one or more cells, including mixtures thereof. “A and / or B” is used herein to include all of the following options: “A,” “B,” “A or B,” and “A and B.”

[0021] Where a numerical range is provided, unless the context clearly indicates otherwise, each intermediate value between the upper and lower limits of that range, up to one-tenth of the lower limit unit, and any other stated or intermediate values ​​within that range are understood to be included in this disclosure. These smaller upper and lower limits may independently be included in smaller ranges and are included in this disclosure, subject to any specifically excluded limits within the described range. If the described range includes one or both limits, the range excluding one or both of those limits is also included in this disclosure.

[0022] In this specification, the term “about” is used before a number to indicate a specific range. The term “about” is used herein to provide literal support for the exact number it precedes, as well as for any number that is close or nearly close to the preceding number. When determining whether a number is close to or approximates a specifically mentioned number, the close or approximate unspecified number may be substantially equivalent to the specifically mentioned number in the context in which it is presented. Where the degree of approximation is not evident from the context, “about” means either within plus or minus 10% of the given value, or, in all cases including the given value, the value rounded to the nearest significant figure. In some embodiments, the term “about” indicates a given value ± up to 10%, up to ± 5%, or up to ± 1%.

[0023] As used herein, photosensitive substances refer to molecules that, when activated by light, promote crosslinking between biological components in the vitreous humor and biological components in the retina. In certain embodiments, crosslinking occurs between glycoproteins (such as glycocollagen) in the vitreous humor and glycoproteins (such as glycocollagen) in the retina. Crosslinking of the cortical vitreous humor to the internal limiting membrane (ILM), which is the inner surface of the retina. In certain embodiments, crosslinking occurs between the glycan portion on glycoproteins (such as glycocollagen) in the vitreous humor and glycochain portion on glycoproteins (such as glycocollagen) in the retina. In certain embodiments, crosslinking occurs between the glycan portion on glycoproteins (such as glycocollagen) in the vitreous humor and glycochain portion on glycoproteins (such as glycocollagen) in the retina. In certain embodiments, crosslinking occurs between the amino acid portion on glycoproteins (such as glycocollagen) in the vitreous humor and amino acid portion on glycoproteins (such as glycocollagen) in the retina. In certain embodiments, crosslinking is crosslinking of the vitreous gel to prevent liquefaction.

[0024] As used herein, adhesion refers not only to covalent interactions but also to non-covalent interactions (hydrogen bonds, van der Waals interactions, ionic bonds, and / or hydrophobic bonds).

[0025] As used herein, crosslinking refers to the process of chemically bonding two or more molecules together by covalent bonds.

[0026] As used herein, the vitreoretinal interface (VRI) refers to the junction between the vitreous humor and the retina. In certain embodiments, the vitreoretinal interface refers to the junction between the cortical vitreous humor and the retina. In certain embodiments, the vitreoretinal interface refers to the junction between the cortical vitreous humor and the internal limiting membrane (ILM) of the retina.

[0027] As used herein, MetB or Met B refers to methylene blue.

[0028] The aspects and embodiments of the disclosure described herein are understood to include aspects and embodiments that “comprising,” “consisting,” and “consisting essentially of.” As used herein, “comprising” is synonymous with “including,” “containing,” or “characterized by,” and is comprehensive or open-ended and does not exclude additional unlisted elements or steps of the method. As used herein, “consisting of” excludes elements, steps, or components not specified in the claimed composition or method. As used herein, “consisting essentially of” does not exclude materials or steps that do not substantially affect the basic and novel features of the claimed composition or method. Any enumeration of the term “comprising” as used herein, particularly in descriptions of the components of a composition or the steps of a method, is understood to encompass compositions and methods that are essentially composed of and consist of the enumerated components or steps.

[0029] All genes, gene names, and gene products disclosed herein are intended to correspond to homologs derived from any species to which the compositions and methods disclosed herein are applicable. Therefore, these terms include, but are not limited to, genes and gene products derived from humans and mice. Where a gene or gene product derived from a particular species is disclosed, it should be understood that this disclosure is illustrative only and should not be construed as limiting unless indicated by the context in which it appears. Therefore, for example, in some embodiments, genes or gene products disclosed herein relating to mammalian nucleic acids and amino acid sequences are intended to include, but are not limited to, homologous genes and / or orthologous genes and gene products from other animals, including other mammals, fish, amphibians, reptiles, and birds. In some embodiments, the genes, nucleic acid sequences, amino acid sequences, peptides, polypeptides, and proteins are of human origin. The term “gene” is also intended to include its variants.

[0030] For clarity, it is understood that certain features of the Disclosure described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features of the Disclosure described in the context of a single embodiment for the sake of brevity may be provided separately or in any suitable partial combination. All combinations of embodiments relating to the Disclosure are specifically encompassed by the Disclosure and are disclosed herein as if each and all combinations were individually and expressly disclosed. Furthermore, all partial combinations of various embodiments and their elements are also specifically encompassed by the Disclosure and are disclosed herein as if each and all such partial combinations were individually and expressly disclosed herein.

[0031] II. Method II.a) Methods to improve adhesion between the vitreous humor and the retina In one embodiment, the present invention provides a method for improving adhesion between the vitreous humor and retina of a mammalian eye, comprising administering a photosensitive substance to the mammalian eye, the photosensitive substance accumulating at the vitreoretinal interface (VRI), and irradiating a selected region of the VRI with light of a wavelength that causes crosslinking between the vitreous humor and retina, thereby improving adhesion between the vitreous humor and retina in the mammalian eye. In one embodiment, the present invention provides a method for improving adhesion between the vitreous humor and retina of a mammalian eye, comprising administering a photosensitive substance to the mammalian eye, the photosensitive substance accumulating at the vitreoretinal interface (VRI), and irradiating a selected region of the VRI where the photosensitive substance has accumulated with light of a wavelength that causes crosslinking between the vitreous humor and retina, thereby improving adhesion between the vitreous humor and retina in the mammalian eye. In an exemplary embodiment, the irradiation is performed with light of a wavelength that induces crosslinking between the vitreous humor and retina of the mammalian eye by the photosensitive substance. In exemplary embodiments, irradiation is performed with light of a wavelength that initiates crosslinking between the vitreous humor and retina of the mammalian eye. In exemplary embodiments, crosslinking occurs between the cortical vitreous humor and the retina. In exemplary embodiments, crosslinking occurs between the cortical vitreous humor and the internal limiting membrane of the retina. In exemplary embodiments, improved adhesion results in increased tensile strength between the vitreous humor and the retina.

[0032] II.b) Methods for improving adhesion between the vitreous humor and the retina In one embodiment, the present invention provides a method for improving adhesion between the vitreous humor and the retina of a mammalian eye, comprising: administering a photosensitive substance to the mammalian eye, allowing the photosensitive substance to accumulate at the vitreoretinal interface (VRI); and irradiating a selected region of the VRI with light of a wavelength that causes crosslinking between the vitreous humor and the retina, thereby improving adhesion between the vitreous humor and the retina in the mammalian eye. In one embodiment, the present invention provides a method for improving adhesion between the vitreous humor and the retina of a mammalian eye, comprising: administering a photosensitive substance to the mammalian eye, allowing the photosensitive substance to accumulate at the vitreoretinal interface (VRI); and irradiating a selected region of the VRI where the photosensitive substance has accumulated with light of a wavelength that causes crosslinking between the vitreous humor and the retina, thereby improving adhesion between the vitreous humor and the retina in the mammalian eye. In an exemplary embodiment, the irradiation is performed with light of a wavelength that induces crosslinking between the vitreous humor and the retina of the mammalian eye by the photosensitive substance. In exemplary embodiments, irradiation is performed with light of a wavelength that causes the photosensitive material to initiate crosslinking between the vitreous humor and retina of the mammalian eye. In exemplary embodiments, crosslinking occurs between the cortical vitreous humor and the retina. In exemplary embodiments, crosslinking occurs between the cortical vitreous humor and the internal limiting membrane of the retina. In exemplary embodiments, improved adhesion results in increased tensile strength between the vitreous humor and the retina.

[0033] II.c) Method for improving covalent adhesion between the vitreous humor and the retina In one embodiment, the present invention provides a method for improving covalent adhesion between the vitreous humor and retina of a mammalian eye, comprising: administering a photosensitive substance to the mammalian eye, allowing the photosensitive substance to accumulate at the vitreoretinal interface (VRI); and irradiating a selected region of the VRI with light of a wavelength that causes crosslinking between the vitreous humor and retina, thereby improving covalent adhesion between the vitreous humor and retina in the mammalian eye. In one embodiment, the present invention provides a method for improving covalent adhesion between the vitreous humor and retina of a mammalian eye, comprising: administering a photosensitive substance to the mammalian eye, allowing the photosensitive substance to accumulate at the vitreoretinal interface (VRI); and irradiating a selected region of the VRI where the photosensitive substance has accumulated with light of a wavelength that causes crosslinking between the vitreous humor and retina, thereby improving covalent adhesion between the vitreous humor and retina in the mammalian eye. In an exemplary embodiment, the irradiation is performed with light of a wavelength that induces crosslinking between the vitreous humor and retina of the mammalian eye by the photosensitive substance. In exemplary embodiments, irradiation is performed with light of a wavelength that causes the photosensitive material to initiate crosslinking between the vitreous humor and retina of the mammalian eye. In exemplary embodiments, crosslinking occurs between the cortical vitreous humor and the retina. In exemplary embodiments, crosslinking occurs between the cortical vitreous humor and the internal limiting membrane of the retina. In exemplary embodiments, improved covalent adhesion results in increased tensile strength between the vitreous humor and the retina.

[0034] II.d) Method for introducing covalent adhesion between the vitreous humor and the retina In one embodiment, the present invention provides a method for introducing covalent adhesion between the vitreous humor and retina of a mammalian eye, comprising: administering a photosensitive substance to the mammalian eye, allowing the photosensitive substance to accumulate at the vitreoretinal interface (VRI); and irradiating a selected region of the VRI with light of a wavelength that causes crosslinking between the vitreous humor and retina, thereby introducing covalent adhesion between the vitreous humor and retina in the mammalian eye. In one embodiment, the present invention provides a method for introducing covalent adhesion between the vitreous humor and retina of a mammalian eye, comprising: administering a photosensitive substance to the mammalian eye, allowing the photosensitive substance to accumulate at the vitreoretinal interface (VRI); and irradiating a selected region of the VRI where the photosensitive substance has accumulated with light of a wavelength that causes crosslinking between the vitreous humor and retina, thereby introducing covalent adhesion between the vitreous humor and retina in the mammalian eye. In an exemplary embodiment, the irradiation is performed with light of a wavelength that induces crosslinking between the vitreous humor and retina of the mammalian eye by the photosensitive substance. In exemplary embodiments, irradiation is performed with light of a wavelength that initiates crosslinking between the vitreous humor and retina of the mammalian eye. In exemplary embodiments, crosslinking occurs between the cortical vitreous humor and the retina. In exemplary embodiments, crosslinking occurs between the cortical vitreous humor and the internal limiting membrane of the retina. In exemplary embodiments, the introduction of covalent adhesion results in an increase in tensile strength between the vitreous humor and the retina.

[0035] II.e) Method for covalently attaching the vitreous humor to the retina In one embodiment, the present invention provides a method for covalently attaching the vitreous humor and retina of a mammalian eye, comprising administering a photosensitive substance to the mammalian eye, the accumulation of the photosensitive substance at the vitreoretinal interface (VRI), and irradiating a selected region of the VRI with light of a wavelength that causes crosslinking between the vitreous humor and the retina, thereby causing covalent attachment between the vitreous humor and the retina in the mammalian eye. In one embodiment, the present invention provides a method for covalently attaching the vitreous humor and retina of a mammalian eye, comprising administering a photosensitive substance to the mammalian eye, the accumulation of the photosensitive substance at the vitreoretinal interface (VRI), and irradiating a selected region of the VRI where the photosensitive substance has accumulated with light of a wavelength that causes crosslinking between the vitreous humor and the retina, thereby causing covalent attachment between the vitreous humor and the retina in the mammalian eye. In an exemplary embodiment, the irradiation is performed with light of a wavelength that induces crosslinking between the vitreous humor and the retina of the mammalian eye. In exemplary embodiments, irradiation is performed with light of a wavelength that causes the photosensitive material to initiate crosslinking between the vitreous humor and retina of the mammalian eye. In exemplary embodiments, crosslinking occurs between the cortical vitreous humor and the retina. In exemplary embodiments, crosslinking occurs between the cortical vitreous humor and the internal limiting membrane of the retina. In exemplary embodiments, the tensile strength between the vitreous humor and the retina is increased by covalent bonding.

[0036] II.f) Method for covalently attaching vitreous collagen and retinal collagen In one embodiment, the present invention provides a method for covalently attaching vitreous collagen and retinal collagen in the eye of a mammal, comprising administering a photosensitive substance to the eye of a mammal, the accumulation of the photosensitive substance at the vitreoretinal interface (VRI), and irradiating a selected region of the VRI with light of a wavelength that causes crosslinking between vitreous collagen and retinal collagen, thereby causing covalent attachment of vitreous collagen and retinal collagen in the eye of a mammal. In one embodiment, the present invention provides a method for covalently attaching vitreous collagen and retinal collagen in the eye of a mammal, comprising administering a photosensitive substance to the eye of a mammal, the accumulation of the photosensitive substance at the vitreoretinal interface (VRI), and irradiating a selected region of the VRI where the photosensitive substance has accumulated with light of a wavelength that causes crosslinking between vitreous collagen and retinal collagen, thereby causing covalent attachment of vitreous collagen and retinal collagen in the eye of a mammal. In an exemplary embodiment, the irradiation is performed with light of a wavelength that induces crosslinking between vitreous collagen and retinal collagen in the eye of a mammal. In exemplary embodiments, irradiation is performed with light of a wavelength that causes the photosensitive material to initiate crosslinking between vitreous and retinal collagen in the mammalian eye. In exemplary embodiments, crosslinking occurs between the cortical vitreous humor and the retina. In exemplary embodiments, crosslinking occurs between the cortical vitreous humor and the internal limiting membrane of the retina. In exemplary embodiments, the tensile strength between the vitreous humor and the retina is increased by covalent bonding.

[0037] II.g) Method for covalently attaching vitreous glycoprotein and retinal glycoprotein In one aspect, the present invention provides a method for covalently attaching vitreous glycoprotein and retinal glycoprotein in the eye of a mammal, comprising: administering a photosensitive substance to the eye of a mammal, thereby allowing the photosensitive substance to accumulate at the vitreoretinal interface (VRI); and irradiating a selected region of the VRI with light of a wavelength that causes crosslinking between vitreous glycoprotein and retinal glycoprotein, thereby covalently attaching the vitreous glycoprotein and retinal glycoprotein in the eye of the mammal. In one aspect, the present invention provides a method for covalently attaching vitreous glycoprotein and retinal glycoprotein in the eye of a mammal, comprising: administering a photosensitive substance to the eye of a mammal, thereby allowing the photosensitive substance to accumulate at the vitreoretinal interface (VRI); and irradiating a selected region of the VRI where the photosensitive substance has accumulated with light of a wavelength that causes crosslinking between vitreous glycoprotein and retinal glycoprotein, thereby covalently attaching the vitreous glycoprotein and retinal glycoprotein in the eye of the mammal. In exemplary embodiments, irradiation is performed with light of a wavelength that induces crosslinking between the photosensitive material and retinal glycoproteins in the mammalian eye. In exemplary embodiments, irradiation is performed with light of a wavelength that initiates crosslinking between the photosensitive material and retinal glycoproteins in the mammalian eye. In exemplary embodiments, crosslinking occurs between the cortical vitreous humor and the retina. In exemplary embodiments, crosslinking occurs between the cortical vitreous humor and the internal limiting membrane of the retina. In exemplary embodiments, the tensile strength between the vitreous humor and the retina is increased by covalent bonding.

[0038] II.h) Methods for treating lack of adhesion between the vitreous humor and the retina In one embodiment, the present invention provides a method for treating a lack of adhesion between the vitreous humor and retina of a mammalian eye, comprising administering a photosensitive substance to the mammalian eye, allowing the photosensitive substance to accumulate at the vitreoretinal interface (VRI), and irradiating a selected region of the VRI with light of a wavelength that causes crosslinking between the vitreous humor and retina, thereby treating the lack of adhesion between the vitreous humor and retina in the mammalian eye. In one embodiment, the present invention provides a method for treating a lack of adhesion between the vitreous humor and retina of a mammalian eye, comprising administering a photosensitive substance to the mammalian eye, allowing the photosensitive substance to accumulate at the vitreoretinal interface (VRI), and irradiating a selected region of the VRI where the photosensitive substance has accumulated with light of a wavelength that causes crosslinking between the vitreous humor and retina, thereby treating the lack of adhesion between the vitreous humor and retina in the mammalian eye. In an exemplary embodiment, the irradiation is performed with light of a wavelength that induces crosslinking between the vitreous humor and retina of the mammalian eye by the photosensitive substance. In exemplary embodiments, irradiation is performed with light of a wavelength at which a photosensitive material initiates crosslinking between the vitreous humor and retina of a mammalian eye. In exemplary embodiments, crosslinking occurs between the cortical vitreous humor and the retina. In exemplary embodiments, crosslinking occurs between the cortical vitreous humor and the internal limiting membrane of the retina. In exemplary embodiments, the treatment results in an increase in tensile strength between the vitreous humor and the retina. In exemplary embodiments, the method further includes diagnosing a mammal (such as a human) that requires treatment. In exemplary embodiments, the method further includes diagnosing a mammal (such as a human) that has an eye disease treatable by the method. In exemplary embodiments, the method further includes diagnosing a mammal (such as a human) that has an eye disease described herein. In exemplary embodiments, the mammal (such as a human) lacks adhesion between the vitreous humor and the retina in a first eye, and the treatment is directed to the first eye. In exemplary embodiments, the mammal (such as a human) lacks adhesion between the vitreous humor and the retina in both a first and a second eye, and the treatment is directed to the first and / or second eye.

[0039] II.i) Methods for treating decreased adhesion between the vitreous humor and the retina In one embodiment, the present invention provides a method for treating reduced adhesion between the vitreous humor and retina of a mammalian eye, comprising administering a photosensitive substance to the mammalian eye, allowing the photosensitive substance to accumulate at the vitreoretinal interface (VRI), and irradiating a selected region of the VRI with light of a wavelength that causes crosslinking between the vitreous humor and retina, thereby treating the reduced adhesion between the vitreous humor and retina in the mammalian eye. In one embodiment, the present invention provides a method for treating reduced adhesion between the vitreous humor and retina of a mammalian eye, comprising administering a photosensitive substance to the mammalian eye, allowing the photosensitive substance to accumulate at the vitreoretinal interface (VRI), and irradiating a selected region of the VRI where the photosensitive substance has accumulated with light of a wavelength that causes crosslinking between the vitreous humor and retina, thereby treating the reduced adhesion between the vitreous humor and retina in the mammalian eye. In an exemplary embodiment, the irradiation is performed with light of a wavelength that induces crosslinking between the vitreous humor and retina of the mammalian eye by the photosensitive substance. In exemplary embodiments, irradiation is performed with light of a wavelength that causes the photosensitive material to initiate crosslinking between the vitreous humor and retina of the mammalian eye. In exemplary embodiments, crosslinking occurs between the cortical vitreous humor and the retina. In exemplary embodiments, crosslinking occurs between the cortical vitreous humor and the internal limiting membrane of the retina. In exemplary embodiments, the treatment results in an increase in tensile strength between the vitreous humor and the retina. In exemplary embodiments, the method further includes diagnosing a mammal (such as a human) that requires treatment. In exemplary embodiments, the method further includes diagnosing a mammal (such as a human) that has an eye disease treatable by the method. In exemplary embodiments, the method further includes diagnosing a mammal (such as a human) that has an eye disease described herein. In exemplary embodiments, the mammal (such as a human) has reduced adhesion between the vitreous humor and retina in a first eye, and the treatment is directed to the first eye. In exemplary embodiments, the mammal (such as a human) has reduced adhesion between the vitreous humor and retina in both a first and a second eye, and the treatment is directed to the first and / or second eye.

[0040] II.j) Methods to prevent eye diseases In another embodiment, the present invention provides a method for preventing eye disease in a mammalian eye, comprising administering a photosensitive substance to the eye of the mammal, allowing the photosensitive substance to accumulate at the vitreoretinal interface (VRI), and irradiating a selected region of the VRI with light of a wavelength that causes bridging between the vitreous humor and the retina, thereby preventing eye disease in the mammalian eye. In another embodiment, the present invention provides a method for preventing eye disease in a mammalian eye, comprising administering a photosensitive substance to the eye of the mammal, allowing the photosensitive substance to accumulate at the vitreoretinal interface (VRI), and irradiating a selected region of the VRI where the photosensitive substance has accumulated with light of a wavelength that causes bridging between the vitreous humor and the retina, thereby preventing eye disease in the mammalian eye. In exemplary embodiments, the eye disease is posterior vitreous detachment, retinal tear, rhegmatogenous retinal detachment, macular hole, vitreomacular traction, epiretinal membrane, or vitreous floatation. In exemplary embodiments, the eye disease is complete posterior vitreous detachment, retinal tear, rhegmatogenous retinal detachment, macular hole, epiretinal membrane, or vitreous floatation. In exemplary embodiments, the eye disease is reduced adhesion between the vitreous humor and the retina. In exemplary embodiments, the eye disease is decreased adhesion between the vitreous humor and the retina. In exemplary embodiments, the eye disease is a lack of adhesion between the vitreous humor and the retina. In exemplary embodiments, crosslinking occurs between the cortical vitreous humor and the retina. In exemplary embodiments, crosslinking occurs between the cortical vitreous humor and the internal limiting membrane of the retina. In exemplary embodiments, the method further includes diagnosing a mammal (such as a human) that requires prevention. In exemplary embodiments, the method further includes diagnosing a mammal (such as a human) that has an eye disease described herein. In exemplary embodiments, the method further includes diagnosing a mammal (such as a human) that has an eye disease in a first eye that can be prevented by the method in a second eye. In exemplary embodiments, the method further includes diagnosing a mammal (such as a human) with posterior vitreous detachment in the first eye, and preventing a posterior vitreous detachment in the second eye. In exemplary embodiments, the method further includes diagnosing a mammal (such as a human) with a retinal tear in the first eye, and preventing a retinal tear in the second eye.

[0041] In exemplary embodiments, if the eye disease is posterior vitreous detachment, the VRI selection region includes the nasal region of the optic nerve. In exemplary embodiments, if the eye disease is a retinal tear, the VRI selection region includes the nasal region of the optic nerve. In exemplary embodiments, if the eye disease is rhegmatogenous retinal detachment, the VRI selection region includes the nasal region of the optic nerve. In exemplary embodiments, if the eye disease is a macular hole, the VRI selection region includes the macula. In exemplary embodiments, if the eye disease is vitreomacular traction, the VRI selection region includes the macula. In exemplary embodiments, if the eye disease is an epiretinal membrane, the VRI selection region includes the macula. In exemplary embodiments, if the eye disease is vitreous floatations, the VRI selection region includes the nasal region of the optic nerve. In exemplary embodiments, prevention results in increased tensile strength between the vitreous and the retina.

[0042] In exemplary embodiments, if the eye disease is posterior vitreous detachment, the selective region of VRI where photosensitive material accumulates includes the nasal region of the optic nerve. In exemplary embodiments, if the eye disease is a retinal tear, the selective region of VRI where photosensitive material accumulates includes the nasal region of the optic nerve. In exemplary embodiments, if the eye disease is rhegmatogenous retinal detachment, the selective region of VRI where photosensitive material accumulates includes the nasal region of the optic nerve. In exemplary embodiments, if the eye disease is a macular hole, the selective region of VRI where photosensitive material accumulates includes the macula. In exemplary embodiments, if the eye disease is vitreomacular traction, the selective region of VRI where photosensitive material accumulates includes the macula. In exemplary embodiments, if the eye disease is an epiretinal membrane, the selective region of VRI where photosensitive material accumulates includes the macula. In exemplary embodiments, if the eye disease is vitreous floatations, the selective region of VRI where photosensitive material accumulates includes the nasal region of the optic nerve. In exemplary embodiments, prevention results in increased tensile strength between the vitreous and the retina.

[0043] II.k) Methods for preventing eye diseases through targeted adhesion enhancement In another embodiment, the present invention provides a method for preventing eye disease in the eye of a mammal through the effect of improving targeted adhesion between the vitreous humor and the retina, comprising: administering a photosensitive substance to the eye of a mammal, thereby allowing the photosensitive substance to accumulate at the vitreoretinal interface (VRI); and irradiating a selected region of the VRI with light of a wavelength that causes crosslinking between the vitreous humor and the retina, thereby preventing eye disease by improving adhesion between the vitreous humor and the retina in the eye of a mammal. In another embodiment, the present invention provides a method for preventing eye disease in the eye of a mammal through the effect of improving targeted adhesion between the vitreous humor and the retina, comprising: administering a photosensitive substance to the eye of a mammal, thereby allowing the photosensitive substance to accumulate at the vitreoretinal interface (VRI); and irradiating a selected region of the VRI where the photosensitive substance has accumulated with light of a wavelength that causes crosslinking between the vitreous humor and the retina, thereby preventing eye disease by improving adhesion between the vitreous humor and the retina in the eye of a mammal. In exemplary embodiments, the eye disease is posterior vitreous detachment, retinal tear, rhegmatogenous retinal detachment, macular hole, vitreomacular traction, epiretinal membrane, or vitreous float. In exemplary embodiments, the eye disease is complete posterior vitreous detachment, retinal tear, rhegmatogenous retinal detachment, macular hole, epiretinal membrane, or vitreous float. In exemplary embodiments, crosslinking occurs between the cortical vitreous and the retina. In exemplary embodiments, crosslinking occurs between the cortical vitreous and the internal limiting membrane of the retina. In exemplary embodiments, the method further includes diagnosing a mammal (such as a human) that requires prevention. In exemplary embodiments, the method further includes diagnosing a mammal (such as a human) that has an eye disease described herein. In exemplary embodiments, the method further includes diagnosing a mammal (such as a human) that has an eye disease in a first eye that can be prevented by the method in a second eye. In exemplary embodiments, the method further includes diagnosing posterior vitreous detachment in a mammal (such as a human) in a first eye, and preventing posterior vitreous detachment in a second eye.In exemplary embodiments, the method further includes diagnosing a mammal (such as a human) having a retinal tear in a first eye, and the method prevents a retinal tear in a second eye.

[0044] In exemplary embodiments, if the eye disease is posterior vitreous detachment, the VRI selection region includes the nasal region of the optic nerve. In exemplary embodiments, if the eye disease is a retinal tear, the VRI selection region includes the nasal region of the optic nerve. In exemplary embodiments, if the eye disease is rhegmatogenous retinal detachment, the VRI selection region includes the nasal region of the optic nerve. In exemplary embodiments, if the eye disease is a macular hole, the VRI selection region includes the macula. In exemplary embodiments, if the eye disease is vitreomacular traction, the VRI selection region includes the macula. In exemplary embodiments, if the eye disease is an epiretinal membrane, the VRI selection region includes the macula. In exemplary embodiments, if the eye disease is vitreous floatations, the VRI selection region includes the nasal region of the optic nerve. In exemplary embodiments, prevention results in increased tensile strength between the vitreous and the retina.

[0045] In exemplary embodiments, if the eye disease is posterior vitreous detachment, the selective region of VRI where photosensitive material accumulates includes the nasal region of the optic nerve. In exemplary embodiments, if the eye disease is a retinal tear, the selective region of VRI where photosensitive material accumulates includes the nasal region of the optic nerve. In exemplary embodiments, if the eye disease is rhegmatogenous retinal detachment, the selective region of VRI where photosensitive material accumulates includes the nasal region of the optic nerve. In exemplary embodiments, if the eye disease is a macular hole, the selective region of VRI where photosensitive material accumulates includes the macula. In exemplary embodiments, if the eye disease is vitreomacular traction, the selective region of VRI where photosensitive material accumulates includes the macula. In exemplary embodiments, if the eye disease is an epiretinal membrane, the selective region of VRI where photosensitive material accumulates includes the macula. In exemplary embodiments, if the eye disease is vitreous floatations, the selective region of VRI where photosensitive material accumulates includes the nasal region of the optic nerve. In exemplary embodiments, prevention results in increased tensile strength between the vitreous and the retina.

[0046] II.l) Method for improving adhesion between the vitreous humor and the retina without the use of light and photosensitive materials. In another aspect, the present invention relates to a method for improving adhesion between the vitreous humor and the retina of a mammalian eye, comprising irradiating a selected region of the vitreoretinal interface (VRI) of the mammalian eye with light of wavelengths from about 650 nm and about 670 nm, thereby causing crosslinking between the vitreous humor and the retina, eliminating the presence of photosensitive substances in the mammalian eye, and thereby improving adhesion between the vitreous humor and the retina of the mammalian eye.

[0047] II.m) Test method for improving adhesion between the vitreous humor and the retina In another embodiment, the present invention relates to a method for testing a photosensitive substance that increases adhesion (such as covalent adhesion, including crosslinking) between the vitreous humor and the retina in a mammalian eye, comprising: a) administering a photosensitive substance to a mammalian eye so that the photosensitive substance accumulates at the vitreoretinal interface (VRI); b) preparing a test eye by irradiating a selected area of ​​the VRI with light of a wavelength that causes crosslinking between the vitreous humor and the retina; c) administering a protease to the VRI; d) examining the adhesion between the vitreous humor and the retina; and e) testing for a photosensitive substance that increases adhesion (such as covalent adhesion, including crosslinking) between the vitreous humor and the retina in a mammalian eye by comparing the results of step d) with the results obtained for a second eye. In an exemplary embodiment, the test is ex vivo. In an exemplary embodiment, the eye being tested is ex vivo, and the second eye is ex vivo. In an exemplary embodiment, if adhesion increases in the eye being tested compared to the second eye, the photosensitive substance increases adhesion between the vitreous humor and the retina in a mammalian eye. In exemplary embodiments, the protease is serine protease. In exemplary embodiments, the protease is plasmin. The amount of protease applied to the eye ranges from about 0.5 U to about 5 U. The amount of protease applied to the eye ranges from 2 U to 5 U. In exemplary embodiments, the test includes applying the depressurization described herein. In exemplary embodiments, the test includes determining the mean minimum depressurization required to induce posterior vitreous detachment of the eye. In exemplary embodiments, the result of step d) for the second eye includes determining the mean minimum depressurization required to induce posterior vitreous detachment in the second eye, where the second eye was not administered the photosensitive substance, protease, or light according to step b). In exemplary embodiments, the result of step d) for the second eye includes determining the mean minimum depressurization required to induce posterior vitreous detachment in the second eye, where the second eye was administered the protease, but was not administered the photosensitive substance, or light according to step b).

[0048] III. Systems and / or Kits In another embodiment, the present invention provides a system. In an exemplary embodiment, the system is useful for one or more of the reasons provided herein. In an exemplary embodiment, the system includes a photosensitive material and a light source for activating the photosensitive material. In an exemplary embodiment, the photosensitive material is as described herein, and the light source is as described herein.

[0049] In another embodiment, the present invention provides a kit. In an exemplary embodiment, the kit is useful for one or more of the reasons provided herein. In an exemplary embodiment, the kit includes a photosensitive material, a light source for activating the photosensitive material, and instructions for using the photosensitive material and light source for one or more of the reasons provided herein. In an exemplary embodiment, the photosensitive material is as described herein, and the light source is as described herein.

[0050] IV. Components of methods, systems and / or kits IV.a) Photosensitive materials and light wavelengths In exemplary embodiments, the photosensitive substance is selected from the group consisting of porphyrionoids, phthalocyanines, porphyrins, protoporphyrins, chlorines, bacteriochlorines, texaphyllins, porphycenes, corols, verteporfins, halogenated fluorescein, xanthenes, flavins, rhodamines, anthraquinones, phenothiazines, substituted cyanines, curcuminoids, and halogenated BODIPY. In exemplary embodiments, the photosensitive substance is phenothiazine. In exemplary embodiments, the photosensitive substance is riboflavin-5'-monophosphate, and the wavelength of light is in the range of 355 nm and 375 nm. In exemplary embodiments, the photosensitive substance is riboflavin-5'-monophosphate, and the wavelength of light is in the range of 445 nm and 465 nm. In exemplary embodiments, the photosensitive substance is fluorescein, and the wavelength of light is in the range of 490 nm and 510 nm. In exemplary embodiments, the photosensitive substance is eosin B, and the wavelength of light ranges from 520 nm to 540 nm. In exemplary embodiments, the photosensitive substance is eosin Y, and the wavelength of light ranges from 525 nm to 545 nm. In exemplary embodiments, the photosensitive substance is erythrosine B, and the wavelength of light ranges from 530 nm to 550 nm. In exemplary embodiments, the photosensitive substance is rose bengal, and the wavelength of light ranges from 555 nm to 575 nm. In exemplary embodiments, the photosensitive substance is methylene blue, and the wavelength of light ranges from 650 nm to 670 nm. In exemplary embodiments, the photosensitive substance is aluminum chloride phthalocyanine tetrasulfonate, and the wavelength of light ranges from 680 nm to 700 nm. In exemplary embodiments, the photosensitive substance is verteporfin bisudyne, and the wavelength of light ranges from 680 nm to 700 nm. In exemplary embodiments, the photosensitive material is IR780, and the wavelength of light is in the range of 770 nm to 790 nm. In exemplary embodiments, the photosensitive material is indocyanine green, and the wavelength of light is in the range of 800 nm and 820 nm. In exemplary embodiments, the photosensitive material is IR820, and the wavelength of light is in the range of 810 nm to 830 nm.

[0051] In exemplary embodiments, the photosensitive substance is riboflavin-5'-monophosphate, and the wavelength of light is approximately 365 nm. In exemplary embodiments, the photosensitive substance is riboflavin-5'-monophosphate, and the wavelength of light is approximately 455 nm. In exemplary embodiments, the photosensitive substance is fluorescein, and the wavelength of light is approximately 500 nm. In exemplary embodiments, the photosensitive substance is eosin B, and the wavelength of light is approximately 530 nm. In exemplary embodiments, the photosensitive substance is eosin Y, and the wavelength of light is approximately 535 nm. In exemplary embodiments, the photosensitive substance is erythrosine B, and the wavelength of light is approximately 540 nm. In exemplary embodiments, the photosensitive substance is rose bengal, and the wavelength of light is approximately 565 nm. In exemplary embodiments, the photosensitive substance is methylene blue, and the wavelength of light is approximately 660 nm. In exemplary embodiments, the photosensitive substance is aluminum chloride phthalocyanine tetrasulfonate, and the wavelength of light is approximately 690 nm. In exemplary embodiments, the photosensitive material is verteporfin bisudyne, and the wavelength of light is approximately 690 nm. In exemplary embodiments, the photosensitive material is IR780, and the wavelength of light is approximately 780 nm. In exemplary embodiments, the photosensitive material is indocyanine green, and the wavelength of light is approximately 810 nm. In exemplary embodiments, the photosensitive material is IR820, and the wavelength of light is approximately 820 nm.

[0052] In exemplary embodiments, the photosensitive material is methylene blue, and the wavelength of light ranges from 650 nm to 670 nm. In exemplary embodiments, the photosensitive material is methylene blue, and the wavelength of light is approximately 660 nm.

[0053] In exemplary embodiments, the photosensitive substance is sodium porfimer, and the wavelength of light is in the range of 622 nm to 642 nm. In exemplary embodiments, the photosensitive substance is meta-tetra(hydroxyphenyl)chlorin (m-THPC), and the wavelength of light is in the range of 642 nm to 662 nm. In exemplary embodiments, the photosensitive substance is tin ethylethiopurine, and the wavelength of light is in the range of 654 nm to 674 nm. In exemplary embodiments, the photosensitive substance is N-aspartylchlorin e6 (NPe6), and the wavelength of light is in the range of 654 nm to 674 nm. In exemplary embodiments, the photosensitive substance is 2-(1-hexyloxyethyl)-2-devinylpyropheoforbid (HPPH), and the wavelength of light is in the range of 655 nm to 675 nm. In exemplary embodiments, the photosensitive substance is palladium bacteriopheoforbid (WST09), and the wavelength of light is in the range of 753 nm and 773 nm. In exemplary embodiments, the photosensitive material is WST11, and the wavelength of light is in the range of 740 nm and 760 nm. In exemplary embodiments, the photosensitive material is motexafin lutetium (Lu-Tex), and the wavelength of light is in the range of 722 nm and 742 nm. In exemplary embodiments, the photosensitive material is silicon phthalocyanine, and the wavelength of light is in the range of 665 nm to 685 nm. In exemplary embodiments, the photosensitive material is hyperisin, and the wavelength of light is in the range of 580 nm to 600 nm. In exemplary embodiments, the photosensitive material is toluidine blue, and the wavelength of light is in the range of 620 nm and 640 nm. In exemplary embodiments, the photosensitive material is TH9402, and the wavelength of light is in the range of 504 nm to 524 nm. In exemplary embodiments, the photosensitive material is merocyanine 540, and the wavelength of light is in the range of 546 nm to 566 nm. In an exemplary embodiment, the photosensitive substance is curcumin, and the wavelength of light is in the range of 410 nm to 430 nm.

[0054] In exemplary embodiments, the photosensitive substance is sodium porfimer, and the wavelength of light is approximately 632 nm. In exemplary embodiments, the photosensitive substance is meta-tetra(hydroxyphenyl)chlorin (m-THPC), and the wavelength of light is approximately 652 nm. In exemplary embodiments, the photosensitive substance is tin ethylethiopurine, and the wavelength of light is approximately 664 nm. In exemplary embodiments, the photosensitive substance is N-aspartylchlorin e6 (NPe6), and the wavelength of light is approximately 664 nm. In exemplary embodiments, the photosensitive substance is 2-(1-hexyloxyethyl)-2-devinylpyropheoforbid (HPPH), and the wavelength of light is approximately 665 nm. In exemplary embodiments, the photosensitive substance is palladium bacteriopheoforbid (WST09), and the wavelength of light is approximately 763 nm. In exemplary embodiments, the photosensitive substance is WST11, and the wavelength of light is approximately 750 nm. In exemplary embodiments, the photosensitive material is motexafin lutetium (Lu-Tex), and the wavelength of light is approximately 732 nm. In exemplary embodiments, the photosensitive material is silicon phthalocyanine, and the wavelength of light is approximately 675 nm. In exemplary embodiments, the photosensitive material is hyperisin, and the wavelength of light is approximately 590 nm. In exemplary embodiments, the photosensitive material is toluidine blue, and the wavelength of light is approximately 630 nm. In exemplary embodiments, the photosensitive material is TH9402, and the wavelength of light is approximately 514 nm. In exemplary embodiments, the photosensitive material is merocyanine 540, and the wavelength of light is approximately 556 nm. In exemplary embodiments, the photosensitive material is curcumin, and the wavelength of light is approximately 420 nm.

[0055] The photosensitive materials of the present invention may also contain non-natural ratio atomic isotopes in one or more of the atoms constituting such compounds. For example, the photosensitive materials described herein may contain, for example, deuterium ( 2 H), tritium ( 3 H), or carbon-14 ( 14The compounds can be radiolabeled with radioactive isotopes such as C). All isotopic variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention. In exemplary embodiments, the photosensitive substances described herein are deuterated photosensitive substances. In exemplary embodiments, methylene blue is deuterated methylene blue.

[0056] IV.b) Pharmaceutical preparations containing photosensitive substances In exemplary embodiments, the photosensitive substance is administered to a mammal to provide an effective amount to the eye. The term “effective amount” of the photosensitive substance as used herein refers to a non-toxic but sufficient amount of the photosensitive substance to provide the desired effect. The “effective” amount will vary from subject to subject depending on the age and general condition of the individual, and the appropriate “effective” amount in any individual case can be determined by those skilled in the art using routine experiments. In exemplary embodiments, the photosensitive substance is administered to a mammal in amounts starting from about 0.05 cc and about 10 cc. In exemplary embodiments, the photosensitive substance is administered to a mammal in amounts starting from about 0.1 mg / kg and about 10 mg / kg.

[0057] In exemplary embodiments, the photosensitive substance is part of a pharmaceutical formulation. In exemplary embodiments, the pharmaceutical formulation comprises the photosensitive substance and a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” refers to any formulation or carrier medium that provides adequate delivery of an effective amount of the photosensitive substance described herein, does not impede the efficacy of the biological activity of the photosensitive substance, and is sufficiently non-toxic to mammals. Typical carriers include water (such as distilled or deionized water), physiological saline, and equilibrium salt solutions.

[0058] The pharmaceutically acceptable carriers of the present invention may also contain non-natural proportion atomic isotopes in one or more of the atoms constituting such compounds. For example, the pharmaceutically acceptable carriers described herein may contain, for example, deuterium ( 2 H), tritium ( 3 H), or carbon-14 ( 14The carriers may be radiolabeled with radioactive isotopes such as C). All isotopic variants of the pharmaceutically acceptable carriers of the present invention, whether radioactive or not, are intended to be included within the scope of the invention. In exemplary embodiments, the pharmaceutically acceptable carrier described herein is a deuterated pharmaceutically acceptable carrier. In exemplary embodiments, the pharmaceutically acceptable carrier is deuterated water or deuterated saline. Further information relating to the carriers is disclosed in Remington: The Science and Practice of Pharmacy, 23rd Ed., Academic Press (2020), which is incorporated herein by reference.

[0059] IV.c) Route of administration of photosensitive substances In exemplary embodiments, administration is carried out by intravitreous, periocular, sub-Tenon's capsule, oral, or intravenous administration of the photosensitive substance to the mammal. In exemplary embodiments, when administration is carried out by intravitreous administration, the amount of photosensitive substance administered to the mammal ranges from about 0.05 cc to about 0.15 cc. In exemplary embodiments, when administration is carried out by periocular administration, the amount of photosensitive substance administered to the mammal ranges from about 0.1 cc to about 10 cc. In exemplary embodiments, when administration is carried out by sub-Tenon's capsule, the amount of photosensitive substance administered to the mammal ranges from about 0.1 cc to about 5 cc. In exemplary embodiments, when administration is carried out by oral administration, the amount of photosensitive substance administered to the mammal ranges from about 0.1 mg / kg to about 10 mg / kg. In exemplary embodiments, when administration is carried out by intravenous administration, the amount of photosensitive substance administered to the mammal ranges from about 0.1 mg / kg to about 10 mg / kg.

[0060] In exemplary embodiments, when administration is performed intravitreally, the time from administration and irradiation ranges from approximately 1 minute and approximately 60 minutes. In exemplary embodiments, when administration is performed periocularly, the time from administration and irradiation ranges from approximately 1 minute and approximately 280 minutes. In exemplary embodiments, when administration is performed sub-Tenon's capsule, the time from administration and irradiation ranges from approximately 1 minute and approximately 180 minutes. In exemplary embodiments, when administration is performed orally, the time from administration and irradiation ranges from approximately 1 minute and approximately 48 hours. In exemplary embodiments, when administration is performed intravenously, the time from administration and irradiation ranges from approximately 1 minute and approximately 48 hours.

[0061] IV.d) Phototherapy Route In exemplary embodiments, irradiation is performed by methods such as transpupil administration, intraocular administration, or transscleral administration. In exemplary embodiments, the irradiation time ranges from about 1 minute to about 240 minutes. In exemplary embodiments, the irradiation time ranges from about 30 minutes to about 240 minutes. In exemplary embodiments, the irradiation time ranges from about 45 minutes to about 240 minutes. In exemplary embodiments, the irradiation time ranges from about 60 minutes to about 240 minutes. In exemplary embodiments, the irradiation time ranges from about 30 minutes to about 180 minutes. In exemplary embodiments, the irradiation time ranges from about 45 minutes to about 180 minutes. In exemplary embodiments, the irradiation time ranges from about 60 minutes to about 180 minutes. In exemplary embodiments, the irradiation time ranges from about 60 minutes to about 90 minutes. In exemplary embodiments, the irradiation time ranges from about 30 minutes to about 90 minutes. In exemplary embodiments, the irradiation time ranges from about 45 minutes to about 90 minutes. In exemplary embodiments, the irradiation time ranges from about 45 minutes and about 75 minutes. In exemplary embodiments, the irradiation time ranges from about 55 minutes and about 75 minutes. In exemplary embodiments, the irradiation time ranges from about 60 minutes and about 90 minutes. In exemplary embodiments, the irradiation time ranges from about 25 minutes and about 95 minutes. In exemplary embodiments, the irradiation time ranges from about 30 seconds to about 1,000 minutes. In exemplary embodiments, the irradiation time ranges from about 30 seconds to about 60 minutes. In exemplary embodiments, the irradiation time ranges from about 30 seconds to about 30 minutes. In exemplary embodiments, the irradiation time ranges from about 30 seconds to about 20 minutes. In exemplary embodiments, the irradiation time ranges from about 30 seconds to about 10 minutes. In exemplary embodiments, the irradiation time ranges from about 5 minutes to about 45 minutes. In exemplary embodiments, the irradiation time ranges from about 5 minutes to about 25 minutes. In exemplary embodiments, the irradiation time ranges from about 3 minutes to about 13 minutes. In exemplary embodiments, the irradiation time is in the range of approximately 10 minutes to approximately 25 minutes. In exemplary embodiments, the irradiation time is in the range of approximately 15 minutes to approximately 45 minutes.

[0062] In exemplary embodiments, irradiation is performed by transpupil administration. In exemplary embodiments, when irradiation is performed by transpupil administration, the irradiation time ranges from about 1 minute to about 180 minutes, or from about 30 seconds to about 1,000 minutes, or from about 30 seconds to about 60 minutes, or from about 30 seconds to about 30 minutes, or from about 30 seconds to about 20 minutes, or from about 30 seconds to about 10 minutes, or from about 5 minutes to about 45 minutes, or from about 5 minutes to about 25 minutes, or from about 3 minutes to about 13 minutes, or from about 10 minutes to about 25 minutes, or from about 15 minutes to about 45 minutes. In exemplary embodiments, when irradiation is performed by transscleral administration, the irradiation time ranges from about 25 minutes to about 35 minutes. In exemplary embodiments, irradiation is performed by transscleral administration. In exemplary embodiments, when irradiation is performed by transscleral administration, the irradiation time ranges from about 1 minute to about 180 minutes. In exemplary embodiments, irradiation is performed by intraocular administration. In exemplary embodiments, when irradiation is performed by intraocular administration, the irradiation time ranges from approximately 1 minute to approximately 60 minutes. In exemplary embodiments, when irradiation is performed by transscleral administration, the irradiation time ranges from approximately 25 minutes to approximately 35 minutes.

[0063] IV.e) Light source In exemplary embodiments, the light source may depend on the light delivery route. In exemplary embodiments, the light source is outside the eye. In exemplary embodiments, the light source is inside the eye. In exemplary embodiments, when irradiation is via transpupil delivery, the light source is a slit-lamp delivery system. In exemplary embodiments, when irradiation is via transpupil delivery, the light source is an indirect ophthalmoscopic delivery system. In exemplary embodiments, when irradiation is via transpupil delivery, the light source is an LED. In exemplary embodiments, when irradiation is via transpupil delivery, the light source is a laser. In exemplary embodiments, when irradiation is via transpupil delivery, the light source includes multiphoton irradiation. In exemplary embodiments, when irradiation is via transpupil delivery, the light source includes two-photon irradiation. In exemplary embodiments, when irradiation is via transscleral delivery, the light source is a handheld scleral probe. In exemplary embodiments, the light source is about 1 and about 1000 mJ / cm 2 It has irradiance from. In exemplary embodiments, the irradiance is sufficient to achieve crosslinking at the vitreoretinal interface without significantly damaging the underlying retinal tissue.

[0064] For example, irradiation by single-photon excitation, two-photon excitation, or multi-photon excitation is applied to a selected region of the vitreoretinal interface (VRI), thereby increasing the adhesion and / or attachment (such as covalent attachment) of the vitreous humor to the retina.

[0065] One skilled in the art recognizes that the selection of a photosensitive substance determines the type of light source to be used, and that different photosensitive substances are active at different wavelengths with different efficiencies. In particular, the spatial resolution at which a photosensitive substance can be excited depends on whether the photosensitive substance is excited by single-photon excitation or by multi-photon excitation. The photosensitive substance is water-soluble, inhibited by oxygen, and may preferably be biocompatible. The diffusion of the photosensitive substance into the vitreous body is governed by its size, as well as its hydrophilic and / or hydrophobic interactions with the vitreous body. To minimize the time from administration to irradiation, a desirable diffusion rate needs to be fast. In an exemplary embodiment, the radiation exposure required for the adhesion between the vitreous body and the retina described herein is, for the photosensitive substances described herein, from about 0.01 J / cm 2 and about 60 J / cm 2 In an exemplary embodiment, the radiation exposure required for the covalent attachment between the vitreous body and the retina described herein is, for the photosensitive substances described herein, from about 0.01 J / cm 2 and about 60 J / cm 2 In an exemplary embodiment, the radiation exposure required for the adhesion between the vitreous body and the retina described herein is from about 0.01 J / cm 2 and about 60 J / cm 2 for methylene blue, rose bengal, indocyanine green, riboflavin or verteporfin. In an exemplary embodiment, the radiation exposure required for the covalent attachment between the vitreous body and the retina described herein is from about 0.01 J / cm 2 and about 60 J / cm 2 for methylene blue, rose bengal, indocyanine green, riboflavin or verteporfin. In an exemplary embodiment, the radiation exposure required for the adhesion between the vitreous body and the retina described herein is from about 0.01 J / cm 2 and about 60 J / cm 2 for methylene blue. In an exemplary embodiment, the radiation exposure for the covalent attachment between the vitreous body and the retina described herein is from about 0.01 J / cm 2 and about 60 J / cm 2It is within the range from.

[0066] In certain embodiments, the light source may be defined as single-photon excitation, two-photon excitation, and multi-photon excitation. In certain aspects of the present invention, imaging is used, for example, to characterize and target the VRI for irradiation and treatment (for example, as described in U.S. Patent Application No. 10 / 611,013, which is incorporated entirely herein by reference), and optical coherence tomography (OCT) is used. In further specific embodiments, the light energy comes from any focused light source, including, for example, a laser source. For single-photon excitation, those skilled in the art will recognize that the light does not need to be focused and a broad beam of light irradiating the tissue is sufficient. In further specific embodiments, a selected area for treatment is illuminated in a programmed pattern by one of several techniques well known to those skilled in the art, including, for example, a programmed galvanometer or a DLP micromirror array. In another specific embodiment, the light energy comes from a focused laser source, and the treatment area is controlled by one of various techniques, including, for example, a galvanometer steering optical system.

[0067] OCT can be used for detection in targeted tissues, such as detecting changes in composition (e.g., scattering or labeling by specific agents) or vitreous tissue.

[0068] As used herein, the term “multiphoton excitation” refers to irradiation of light that can activate a photosensitive material by the absorption of two or more photons nearly simultaneously. This can also be said to refer to the excitation of a photosensitive material by the absorption or scattering of several photons simultaneously or nearly simultaneously. In certain embodiments, multiphoton excitation is an intensity and wavelength suitable for bringing the photosensitive material to an activated state. Such multiphoton absorbance can occur by different processes, including a process in which photons activate the absorbing material through nearly simultaneous absorbance, and a process in which multiple photons are absorbed sequentially.

[0069] As used herein, the term “single-photon excitation” refers to irradiation with light that can activate a molecule through the absorption of a single photon. This can also be described as the excitation of an atom or molecule by the absorption or scattering of a single photon.

[0070] As used herein, the term “two-photon excitation” refers to irradiation with light that can activate a molecule by absorbing two photons nearly simultaneously. In other words, it refers to the excitation of atoms or molecules by absorbing or scattering two photons simultaneously or in close proximity in time. Such two-photon absorbances can occur through different processes, including processes in which the photons activate an absorbing material through simultaneous or nearly simultaneous absorbances, and processes in which the two photons are absorbed sequentially.

[0071] IV.f) Location of the vitreoretinal interface (VRI) selection region In exemplary embodiments, the VRI selection region includes the fovea of ​​the mammalian eye. In exemplary embodiments, the VRI selection region includes the macula of the mammalian eye. In exemplary embodiments, the VRI selection region includes the posterior pole of the mammalian eye. In exemplary embodiments, the VRI selection region includes most of the vitreous humor of the mammalian eye. In exemplary embodiments, the VRI selection region includes the optic nerve of the mammalian eye. In exemplary embodiments, the VRI selection region includes the periphery of the optic nerve of the mammalian eye. In exemplary embodiments, the VRI selection region includes the nasal region of the optic nerve of the mammalian eye. In exemplary embodiments, the retina is the internal limiting membrane of the retina. In exemplary embodiments, the retina is the ganglion cell layer of the retina.

[0072] In exemplary embodiments, the selective region of VRI where photosensitive material accumulates includes the fovea of ​​the mammalian eye. In exemplary embodiments, the selective region of VRI where photosensitive material accumulates includes the macula of the mammalian eye. In exemplary embodiments, the selective region of VRI where photosensitive material accumulates includes the posterior pole of the mammalian eye. In exemplary embodiments, the selective region of VRI where photosensitive material accumulates includes most of the vitreous humor of the mammalian eye. In exemplary embodiments, the selective region of VRI where photosensitive material accumulates includes the optic nerve of the mammalian eye. In exemplary embodiments, the selective region of VRI where photosensitive material accumulates includes the peripheral region of the optic nerve of the mammalian eye. In exemplary embodiments, the selective region of VRI where photosensitive material accumulates includes the nasal region of the optic nerve of the mammalian eye. In exemplary embodiments, the retina is the internal limiting membrane of the retina. In exemplary embodiments, the retina is the ganglion cell layer of the retina.

[0073] In an exemplary embodiment, a contact lens is applied to the corneal surface using a coupling agent such as methylcellulose for irradiation with a slit lamp. This lens allows the treating physician to focus the treatment beam on a selected area to improve VRI adhesion.

[0074] In exemplary embodiments, selective targeting of VRIs in specific retinal regions is improved using retinal image-based eye-tracking. In exemplary embodiments, selective targeting of VRIs is performed in a camera-based manner. In exemplary embodiments, selective targeting of VRIs is performed using a laser via a scanning laser ophthalmoscope (SLO). Recent combinations of SLO and adaptive optics (AO) have improved both the speed and resolution of retinal image-based tracking. AO can be combined with OCT as an alternative method for tracking specific retinal regions. Such tracking systems would enable precise localization of VRI bridges.

[0075] IV.g) Mammals In exemplary embodiments, the mammal is a human, a pig, a cat, or a dog. In exemplary embodiments, the mammal is a pig. In exemplary embodiments, the mammal is a human.

[0076] V. More specific embodiments In exemplary embodiments, the present invention provides a method for improving adhesion between the vitreous humor and retina of the human eye, comprising intravenous administration of methylene blue from about 0.1 mg / kg and about 10 mg / kg to a mammal so that a photosensitive substance accumulates at the vitreoretinal interface (VRI), and irradiating the posterior pole of the VRI with light of wavelengths from about 650 nm and about 670 nm for about 25 minutes and about 95 minutes by transpupil administration, thereby increasing adhesion between the vitreous humor and retina in the human eye.

[0077] All publications and patent applications referenced in this disclosure are incorporated herein by reference to the same extent as each individual publication or patent application is specifically and individually incorporated by reference.

[0078] No reference cited herein constitutes prior art. Discussions of references represent the claims of their authors, and the applicant reserves the right to challenge the accuracy and appropriateness of any cited document. While this specification references numerous sources, including scientific journal articles, patent documents, and textbooks, it should be clearly understood that these references do not imply that any of these documents constitute part of the general knowledge in the art.

[0079] The general methods described herein are for illustrative purposes only. Other alternative methods and substitutes will be apparent to those skilled in the art upon consideration of this disclosure and should be included in the spirit and scope of this application.

[0080] Additional embodiments are disclosed in further detail in the following embodiments, which are provided as examples and are not intended in any way to limit the scope of this disclosure or the claims.

[0081] The section headings used herein are for structural purposes only and should not be construed as limiting the subject matter described herein.

[0082] While various features of this disclosure can be described in the context of a single embodiment, features can also be provided individually or in any suitable combination. Conversely, while this disclosure can be described herein in the context of separate embodiments for clarity, this disclosure can also be implemented in a single embodiment. [Examples]

[0083] The implementation of this invention shall, unless otherwise specified, utilize the prior art of ophthalmology and photochemistry well known to those skilled in the art. Further information relating to the eye can be found in Ryan's Retina, 7. th Ed.,Elsevier(2022);Gass's Atlas of Macular Diseases,5 th Ed, Saunders (2012); and Michels, Wilkinson, & Rice, Retinal Detachment, Mosby Inc, (1990), each of which is incorporated herein by reference. Further information on photochemistry is found in Ormond et al., Materials 2013, 6, 817-840; Kamkaew et al., Chem. Soc. Rev., 2013, 42, 77; Atchison et al., Chem. Commun., 2017, 53, 2009; Swamy et al., Coordination Chemistry Reviews, 411 (2020), 213-233, each of which is incorporated herein by reference.

[0084] Additional embodiments are disclosed in further detail in the following embodiments, which are provided as examples and are not intended in any way to limit the scope of this disclosure or the claims. [Examples]

[0085] Crosslinking with photosensitive materials suppresses the formation of posterior vitreous delamination (PVD) in an in vitro model of pigs. Methods: Pig eyes were used in the experiments. These experiments were performed within 24 hours of the pigs' death. As a negative control, 2 U (0.1 cc of sterile water) of human plasmin was intravitreously administered to the pig eyes and incubated at 37°C for 60 minutes. Plasmin was used because it induces PVD. As a positive control, 0.1 cc of 25% glutaraldehyde was intravitreously administered to the pig eyes and incubated at room temperature for 90 minutes. Glutaraldehyde was used as a chemical crosslinking agent.

[0086] Experiment: A 1:100 solution of 0.1 cc of methylene blue was intravitreously administered to the eyes of pigs, followed by a 15-minute rest period, and then the eyes were irradiated with 660 nm light for 30 minutes. Next, 2 U of human plasmin (0.1 cc in sterile water) was intravitreously administered and incubated at 37°C for 60 minutes. Then, to mask the presence of methylene blue, blue food coloring was injected into each pig's eye. Subsequently, masked ophthalmologists dissected the pigs' eyes to assess the state of vitreous adhesion, based on the treatment performed on each eye.

[0087] result: [Table 1]

[0088] These results demonstrate that pretreatment of the porcine vitreoretinal interface with methylene blue and 660 nm irradiation can prevent PVD induction by intravitreous plasmin injection. This method can also be applied to other photoinitiators that are effective collagen crosslinking agents, such as riboflavin / UV or riboflavin / two-photon; eosin Y / visible light; indocyanine green / NIR; and rose bengal / visible light. [Examples]

[0089] Exvivo decompression model method The adhesion of the vitreous humor to the retina was evaluated using a 23-gauge vitrector (Constellation Vision System, Alcon, Fort Worth TX) under various levels of decompression. This vitrector engaged with the vitreous humor on the optic nerve, attempting to mechanically induce vitreous vitreous decompression (PVD). This was performed in an ex vivo pig eye model. The degree of decompression required to induce PVD was evaluated in control eyes injected with equilibrium salt solution (BSS) and in eyes injected with increasing plasmin units. Ten eyes were used for each injected concentration (units) of plasmin.

[0090] Preparation and injection of plasmin BSS (control) or 2U, 3U, or 5U of room-temperature plasmin (human, Sigma-Aldrich, St Louis MO) was injected into the eyes of pigs at a position 0.25 mm posterior to the optic nerve margin (Figure 1). The eyes injected with BSS, 2U, 3U, or 5U of plasmin were placed in a 37°C water bath for 1 hour.

[0091] Induction of posterior vitreous detachment A 23G cannula was positioned 4 mm away from the limbus. BSS injection was attached to the inferior temporal region, and the injection pressure was set to 30 mmHg. The retina was evaluated using wide-field observation, and eyes with pre-existing retinal detachment or PVD were excluded. Core vitrectomy and posterior vitrectomy were performed to allow movement of the mid-vitreous humor. A mixture of diluted triamcinolone and blue dye was dropped into the posterior vitreous humor around the optic nerve to facilitate vitreous visualization. To test the tensile strength of the vitreous connection, a vitrector was used to aspirate the peripapillary vitreous humor at high levels of reduced pressure (starting at 50 mmHg and increasing in 50 mmHg increments). If PVD was induced, it was confirmed by repeated staining of the vitreous humor. If detachment occurred, the solution was aspirated within a few seconds.

[0092] Relationship between the degree of pressure reduction in Vitrector and the tensile strength of vitreous fibers To verify the relationship between decompression and force, the Alcon Constellation System's ability to lift known weights on a test bench was empirically tested. A 23G soft tip was used in the experiment instead of a 23G vitrector because a seal needed to be formed between the handpiece opening and the weight. This relationship was predicted by using two equations: force (F) = mass (m) × acceleration (a) and F = pressure (p) × area (A). Recognizing that A is the acceleration due to gravity (g), the relationship between the degree of decompression (pressure) and mass of the soft tip was:

number

[0093] The Alcon Constellation System consisted of a 23G soft tip. A milligram calibration weight (Taida, China) was used as a known mass. The decompression setting was set to 50 mmHg without a cutter. Starting with a 50 mg weight, the vitretor opening was aligned with the surface of the weight, and the weight was attempted to be lifted. If the weight did not lift, the decompression setting was increased by 50 mmHg until the weight lifted off the table. A positive reaction was defined as the weight being lifted off the table for at least 2 seconds. This process was repeated three times for each weight.

[0094] result The pressure reduction of the Vitrector is directly proportional to the maximum mass that can be lifted. The average depressurization required to lift a standard weight was calculated. The data obtained from this section showed a direct correlation between the Vitrector's depressurization and the maximum mass the system could lift (Figure 2). The data also showed a direct relationship between the weight and the average minimum depressurization required to lift it, with high statistical significance indicated by the squared value of r of the relationship. The slope generated from the data was 1.68 ms. 2 And it was larger than expected. This difference between the slope and the predicted formula value is thought to be due to manufacturing differences in the soft tip, the angle of the opening relative to the weight affecting the seal, and human variability. Since mass is directly related to force, this relationship also extends to the force generated by the adhesion of the vitreous humor. Stronger adhesion results in a higher effective mass, and higher tensile strength is required for separation. Therefore, the higher the degree of depressurization required for removal, the higher the tensile strength between the vitreous humor and the optic nerve head.

[0095] The increase in injected plasmin units was associated with a decrease in the degree of depressurization required to induce PVD. The minimum decompression required to perform PVD near the optic disc was averaged, and the 95% confidence interval (CI) and p-value per plasmin unit were calculated (Figure 3). Statistical significance was set at a p-value of 0.05 or less. The data demonstrated that increasing plasmin led to a decrease in the minimum decompression required to induce PVD. There was no statistically significant difference between 0U and 2U, with the mean minimum decompression required to perform PVD being 395±28 mmHg and 385±58 mmHg, respectively. There were statistically significant differences (p≦0.05) between the minimum decompression required to induce PVD with 2U, 3U, and 5U of plasmin, with mean values ​​of 385±58 mmHg, 265±53 mmHg, and 145±28 mmHg, respectively.

[0096] Conventional experimental methods for evaluating vitreous adhesion ex vivo have relied on incisions, which inevitably influenced the vitreous humor and its relationship to ocular structures. Aras et al. (In vivo generated autologous plasmin assisted vitrectomy in young patients. Int J Retina Vitreous. 2022 Jun 11;8(1):36) recognized this limitation and used the number of attempts required to successfully separate the posterior hyaloid during surgery as a more representative indicator of situ vitreous adhesion. Here, we present a method for quantitatively and clinically appropriate in-situ evaluation of vitreous adhesion, more specifically, the decompression required to induce PVD, using appropriate techniques.

[0097] It is already well known that changes in the concentration of plasmin used affect the quality of exfoliation. (Gandorfer et al. Ultrastructure of the vitreoretinal interface following plasmin-assisted vitrectomy. Br J Ophthalmol. 2001 Jan;85(1):6-10.) Our data demonstrate the expected dose-dependent response curve of intravitreous plasmin at the mean minimum decompression required to induce PVD near the optic disc, reinforcing the validity of our model.

[0098] Previous ex vivo studies in pig eyes compared the effects of 1U and 2U of plasmin on residual vitreous humor adhering to the intraluminal membrane (ILM) after vitrectomy. Ibid. With 2U, no vitreous humor was observed adhering to the ILM by light, scanning, and transmission electron microscopy, while with 1U, plasmin residue remained after treatment. This suggests that higher plasmin concentrations are more likely to induce vitreous detachment. However, these studies typically involved scleral resection for imaging purposes or binary determination of the presence or absence of vitreous detachment. Previous studies did not specify where scleral resection was performed, or where the attempt to induce vitreous detachment was made, as these studies would lead to complete vitrectomy and the collection of tissue samples for histology. (Uemura et al. Effect of plasmin on laminin and fibronectin during plasmin-assisted vitrectomy. Arch Ophthalmol. 2005 Feb;123(2):209-13.)

[0099] While the methods described herein do not assess vitreous residue with the microscale resolution offered by these other techniques, the clinical impact of PVD is adequately captured by this in situ assessment.

[0100] While this data demonstrates statistically significant findings using a novel methodology, the techniques employed in the experiment have limitations. Pig eyes exhibited variability in quality, which was minimized by excluding eyes with a history of ocular rupture, retinal detachment, or pre-existing central PVD. Unfortunately, pre-existing central PVD could not be assessed until the eyes were pre-treated for the experiment, as the tubular needle inserted for vitretor, injection, and illumination punctured multiple holes, leaving an opportunity for vitreous viscosity to be affected by environmental factors. To circumvent this problem, the inventors utilized the fact that 5U of plasmin still requires a pressure exceeding 100mmHg to induce PVD. Therefore, eyes in which PVD was induced at 50mmHg were judged to have pre-existing PVD. A total of 3 eyes with a history of retinal detachment, 17 eyes with a history of ocular rupture, and 12 eyes with a history of vitreous detachment were used. One potential concern was whether the eyes judged to have “pre-existing PVD” were outliers to high doses of plasmin. Of the eyes with a history of vitreous detachment, three did not receive plasmin, and three received 3U of plasmin. This ratio suggests a correlation between the presence of plasmin and a history of vitreous detachment, but none of the eyes that received 5U of plasmin had a history of vitreous detachment. Therefore, the high number of cases with a history of vitreous detachment may be due to variations between eyes. In addition, eyes with ruptured eyeballs or retinal detachment were excluded before injecting plasmin and examining for vitreous detachment, which may also affect the number of cases with a history of vitreous detachment.

[0101] Given the significant impact of the vitreous state on medical and surgical retinal diseases, it is crucial to develop models that evaluate the effects of various interventions on the vitreous. This model offers significant advantages over previous studies by minimizing confounding and quantitatively evaluating vitreous adhesion. [Examples]

[0102] Crosslinking with photosensitive materials prevents the formation of posterior vitreous delamination (PVD) in the ex vivo decompression model. method Adhesion at the vitreoretinal interface was evaluated by mechanically forming a PVD (photorespiratory vitreous dendritic) by pressing the vitreous humor onto the optic nerve using a 23-gauge vitrector (Constellation Vision System, Alcon, Fort Worth TX) with various levels of decompression. This was performed in an ex vivo pig eye model. The control eye was administered balanced saline injection (BSS), glutaraldehyde, or 3U of plasmin.

[0103] Preparation and injection of methylene blue Methylene blue (1% USP grade, 50 mL, Biopharm Inc., Hatfield, AR) was diluted 1:100, 1:1,000, and 1:10,000 times with sterile distilled water. Fat, muscle, and conjunctiva were all removed from the posterior half of each eye. Using a surgical microscope, wide-field lens, and Alcon Constellation light pipe, 0.3 mL of the solution was injected into the eye to visualize the methylene blue being positioned between the macula and the optic nerve. The eye was left standing for 30 minutes with the cornea facing upward and the optic nerve downward to allow most of the solution to accumulate at the back of the eye.

[0104] Activation of methylene blue by an external light source The eye injected with methylene blue was placed cornea-down on the surface. A flashlight with a wavelength of 660 nm (external light source) was placed above so that the light illuminated only the back of the eye (approximately 5.4 cm above the sclera of the posterior pole). The posterior half was covered with glycerin (to dry the sclera and / or improve light transmission). The eye was left under the light for 30 minutes, 1 hour, and 1.5 hours.

[0105] Activation of methylene blue by an internal light source The eye injected with methylene blue was placed with the cornea facing upward. A 5 cm section of fiber optic cable (ThorLabs, Newton, NJ) (internal light source) was stripped to minimize the diameter of the hole. The cable was inserted so that its tip pointed to the methylene blue pool in the eye, approximately 1 cm from the edge of the pool. The intensity was set to 10%, 30%, 50%, and 70% of the maximum value (422.7 ± 4.7 mW). The eye was irradiated for 30 minutes, 1 hour, and 1.5 hours.

[0106] Preparation and injection of glutaraldehyde A 1% solution was injected 0.25 mm from the end of the optic nerve in the pig's eye. The eye was left in a corneal-up position for 30 minutes.

[0107] Preparation and injection of plasmin 3U of plasmin (human, Sigma-Aldrich, St. Louis MO) at room temperature was injected into the eye of a pig 0.25mm posterior to the end of the optic nerve. The eye was then placed in a 37°C water bath for 1 hour.

[0108] Induction of posterior vitreous detachment A 23G cannula was positioned 4 mm away from the limbus. BSS injection was attached to the inferior temporal region, and the injection pressure was set to 30 mmHg. The retina was evaluated using wide-field observation, and eyes with pre-existing retinal detachment or PVD were excluded. Core vitrectomy and posterior vitrectomy were performed to allow movement of the mid-vitreous humor. A mixture of diluted triamcinolone and blue dye was dropped into the posterior vitreous humor around the optic nerve to facilitate vitreous visualization. To test the tensile strength of the vitreous connection, a vitrector was used to aspirate the peripapillary vitreous humor at high levels of depressurization (starting at 50 mmHg and increasing in 50 mmHg increments). If PVD was induced, it was confirmed by repeated staining of the vitreous humor. If detachment occurred, the solution was aspirated within a few seconds. All pressures for each condition were averaged in 95% confidence intervals, and p-values ​​were calculated. A p-value greater than 0.05 was considered statistically significant.

[0109] Relationship between methylene blue dilution and light absorption Methylene blue was diluted with sterile distilled water to 1:10, 1:100, 1:1,000, and 1:1,000, resulting in volumes of 5, 10, and 25 mL, respectively. A power meter (ThorLabs, Newton, NJ) was placed 5.4 cm away from the tip of an external 660 nm flashlight. The output was measured three times. A standard 50 mL beaker was placed on the receiving end of the power meter, and the output was measured three times. Next, the light output was measured three times for each condition: 25 mL of water, 5 mL of 1:10 dilution, 5 mL of 1:100 dilution, 5 mL of 1:1000 dilution, 5 mL of 1:10,000 dilution, 10 mL of 1:10 dilution, 10 mL of 1:100 dilution, 10 mL of 1:1000 dilution, 10 mL of 1:10,000 dilution, 25 mL of 1:10 dilution, 25 mL of 1:100 dilution, 25 mL of 1:1000 dilution, and 25 mL of 1:10,000 dilution. All outputs for each condition were averaged, and the 95% confidence interval and p-value were calculated. A p-value greater than 0.05 was considered statistically significant.

[0110] Relationship between the ratio of the internal 660nm light to the maximum intensity and the output. The fiber optic cable used for internal illumination of the pig's eye was set to 0.1. The power meter was placed 1 cm away from the end of the cable. The output was measured three times. This process was repeated for settings of 0.2, 0.5, and 1. All outputs for each condition were averaged, and the 95% confidence interval and p-value were calculated. A p-value greater than 0.05 was considered statistically significant.

[0111] Results / Discussion The minimum required concentration of methylene blue to induce crosslinking is 1:1000. In a previous study conducted by Dr. Christopher Marotta of the California Institute of Technology, the minimum concentration required to induce crosslinking in a model vitreous humor using type IV collagen was a dilution of 1:1,000.

[0112] Proof-concept experiments were initially conducted using 1:100 and 1:1,000 dilutions. However, the results were either / or, as another method existed to investigate the ease of vitreous detachment by creating an eye cup. One surgeon qualitatively assessed the ease of detachment by manipulating the vitreous humor using a Weck-Cel spear (Figure 4). The data demonstrated that plasmin and glutaraldehyde can induce and prevent PVD, respectively. It was also demonstrated that the 1:1000 dilution may not contain enough methylene blue to consistently crosslink a sufficient amount of vitreous humor to the retina.

[0113] This experiment was extended by relating the degree of dilution to the amount of light absorbed (Figure 5). If the concentration is too low, almost all light passes through the liquid, so the wattmeter will measure the output from the light source at a level close to the baseline. The data showed that the average output at a distance of 5.4 cm from the flashlight was 16.5 ± 0.2 mW. In the case of a beaker (glass), the average output increased to 42.6 ± 0.2 mW. This is thought to be because the bottom of the beaker is not flat, causing the light to bend like a convex lens and focus towards the center of the beaker where the light-receiving end of the wattmeter is located (Figure 6). The average output when the amount of water was varied was 37.9 ± 0.2, 35.9 ± 0.3, and 29.4 ± 0.3 mW for 5 mL, 10 mL, and 25 mL, respectively, indicating that a larger amount of liquid is more effective in transmitting light. This trend is similar even at the highest dilution of 1:10,000. The average power outputs for 5 mL, 10 mL, and 25 mL were 27.6 ± 0.6, 23.5 ± 0.4, and 10.2 ± 0.2 mW, respectively. The average values ​​are lower than for plain water because very dilute methylene blue absorbs some of the transmitted light, reducing the measured power output. The 1:10, 1:100, and 1:1000 dilutions showed the ability to block the transmission of light through the solution, except for 5 mL of the 1:1000 dilution, at 3.0 ± 0.3 mW. All p-values ​​show statistically significant differences between the measured average power outputs. While this data does not precisely replicate the pig model, it demonstrates the need to strike a balance: injecting enough methylene blue into the eye to crosslink the vitreous humor to the retina, while avoiding injecting too much so that light penetrates the solution and does not crosslink most of the methylene blue injected into the eye.

[0114] The minimum required time under an external 660nm flashlight is 1 hour. Eyes were placed 5.4 cm away from ambient light for 30 minutes (7 eyes), 1 hour (14 eyes), and 1.5 hours (7 eyes). The mean pressure required to induce PVD after 30 minutes was 421.4 ± 69.9 mmHg. The mean eye pressure after 1 hour in light was 557.1 ± 123.8 mmHg. The mean eye pressure after 1.5 hours in light was 543.2 ± 130.2 mmHg. Therefore, there was a statistically significant difference between 30 minutes and the other two time intervals (p value 0.004), but no difference between 1 hour and 1.5 hours (p value 0.07). Thus, the minimum time required to induce PVD is 1 hour.

[0115] For an external 660nm flashlight, the minimum required distance is 5.4cm. The effect of distance on the cross-linking effect was evaluated by positioning eyes at distances of 8 cm (8 eyes) and 5.4 cm (14 eyes) from an external light source. The average pressure required to induce PVD at 8 cm was 381.3 ± 110.0 mmHg. The average pressure for eyes at 5.4 cm was 557.1 ± 123.8 mmHg. There was a statistically significant difference between these two values ​​(p-value 0.003). In the experimental setup, the distance of 5.4 cm was close enough to allow light from a flashlight to cover most of the posterior part of the eye with minimal stray light. Therefore, it was found that the effect of methylene blue was maximized at a distance of 5.4 cm from the light source.

[0116] Increasing the intensity of internal irradiation is ineffective. The output from the fiber optic cable was measured at various intensities (Figure 7). The data shows the difference in average output measured between the lowest setting, which showed an output of 12.4 ± 0.4 mW, and the highest measurement, which showed an output of 422.7 ± 4.7 mW. The p-value indicates a statistically significant difference in the measured average output. Therefore, there should be better irradiation at increased intensity.

[0117] However, data on the mean minimum pressure inducing PVD indicates that light intensity does not affect the mean minimum pressure inducing PVD. The mean pressure with methylene blue and plasmin in 10% internal 660nm light (5 eyes) was 360±65.2 mmHg, 20% (4 eyes) was 375±86.6 mmHg, and 50% (4 eyes) was 362.5±47.9 mmHg. 100% was tested but was not used because the light at that intensity would damage the retina, and therefore it is not used in vivo or clinical trials. As expected, the p-values ​​did not show statistical significance between intensities. However, the mean pressure required with external light was 557.1±123.8 mmHg, which was statistically significantly higher than with internal light (p-values ​​of 0.0005, 0.01, and 0.0003 for 10%, 20%, and 50%, respectively). This suggests that either the light does not activate the methylene blue to the same extent as ambient light, or the light does not adequately crosslink the methylene blue because it first illuminates the methylene blue furthest from the back of the eye, preventing the methylene blue closest to the vitreoretinal interface from being illuminated.

[0118] Inactivated methylene blue yields similar results to those without it. Data were measured to compare the effects of plasmin, methylene blue, ambient light, and glutaraldehyde on the mean minimum pressure required to induce PVD (Figure 8). The data showed that plasmin alone (10 eyes) resulted in a mean pressure of 195.0 ± 65.2 mmHg, while methylene blue and plasmin together resulted in a mean pressure of 215.0 ± 47.4 mmHg. This indicates that injecting methylene blue alone (10 eyes) without additional photoactivation did not affect the mean pressure. The p-value was 0.37, indicating no statistically significant difference. Therefore, methylene blue alone does not affect the vitreoretinal interface.

[0119] Irradiation alone does not explain the effect of activated methylene blue. The data in the figure also compares the effect of 660nm illumination on the vitreoretinal interface. The mean minimum pressure in normal eyes (10 eyes) injected with BSS alone was 395.0 ± 22.4 mmHg, while in eyes injected with plasmin alone (10 eyes) it was 195.0 ± 65.2 mmHg. However, in eyes treated with both light and plasmin (10 eyes), the mean was 355.0 ± 36.9 mmHg. The attractive force required to induce PVD with light in plasmin-treated eyes was plasmin alone (p value 1.8 × 10⁻⁶). -7 The attractive force was statistically significantly different from that of the treated eye (p-value 0.01) and the control eye. However, this was significantly below the required pressure in eyes treated with both methylene blue and ambient light.

[0120] Crosslinking with methylene blue is almost as strong as crosslinking with glutaraldehyde. The data in the figure also compares the effects of activated methylene blue and glutaraldehyde, a known crosslinking agent. The mean minimum pressure for inducing PVD in activated methylene blue (14 eyes) was 557.1 ± 123.8 mmHg, while for glutaraldehyde (10 eyes) it was 630 ± 25.8 mmHg. The standard deviation and 95% confidence interval bars overlap, but the p-value was 0.04995, rounded up to 0.05. Therefore, there is a statistically significant difference, albeit slight, between the effects of the two reagents. This indicates that activated methylene blue improves adhesion to almost the same extent as glutaraldehyde.

[0121] Notwithstanding the attached claims, this disclosure is also defined by the following clauses:

[0122] 1. A method for preventing eye disease in mammals by targeting and strengthening adhesion between the corticovitreous humor and the retina, comprising: administering a photosensitive substance to the eye of a mammal, thereby causing the photosensitive substance to accumulate at the vitreoretinal interface (VRI); and irradiating a selected region of the VRI with light of a wavelength that causes crosslinking between the corticovitreous humor and the retina, thereby preventing eye disease by applying targeted strengthening adhesion between the corticovitreous humor and the retina in the eye of a mammal.

[0123] 2. The method according to Clause 1, wherein the eye disease is complete posterior vitreous detachment, retinal tear, rhegmatogenous retinal detachment, macular hole, epiretinal membrane, or vitreous floatation.

[0124] 3. The method according to Clause 1, wherein if the eye disease is posterior vitreous detachment, the selection area of ​​the VRI includes the area nasal to the optic nerve; if the eye disease is a retinal tear, the selection area of ​​the VRI includes the area nasal to the optic nerve; if the eye disease is rhegmatogenous retinal detachment, the selection area of ​​the VRI includes the area nasal to the optic nerve; if the eye disease is a macular hole, the selection area of ​​the VRI includes the macula or perimacular area; if the eye disease is an epiretinal membrane, the selection area of ​​the VRI includes the macula or perimacular area; or if the eye disease is vitreous opacity, the selection area of ​​the VRI includes the area nasal to the optic nerve or the area around the optic nerve.

[0125] 4. A method for improving adhesion between the vitreous humor and the retina of a mammalian eye, comprising: administering a photosensitive substance to the mammalian eye so that the photosensitive substance accumulates at the vitreoretinal interface (VRI); and irradiating a selected region of the VRI with light of a wavelength that causes crosslinking between the vitreous humor and the retina, thereby improving adhesion between the vitreous humor and the retina in the mammalian eye.

[0126] 5. The method according to one of the items in paragraphs 1 to 4, wherein the irradiation is light of a wavelength that induces the photosensitive material to crosslink between the vitreous humor and the retina.

[0127] 6. The method according to any of the items in paragraphs 1 to 5, wherein administration is carried out by intravitreous, periocular, sub-Tenon's capsule, oral, or intravenous administration of a photosensitive substance to a mammal.

[0128] 7. The method according to one of the clauses 1 to 6, wherein the administration is carried out by intravitreal administration, the amount of the photosensitive substance is in the range of about 0.05 cc and about 0.15 cc; if the administration is carried out by periocular administration, the amount of the photosensitive substance is in the range of about 0.1 cc and about 10 cc; if the administration is carried out by sub-Tenon's capsule administration, the amount of the photosensitive substance is in the range of about 0.1 cc and about 5 cc; if the administration is carried out by oral administration, the amount of the photosensitive substance is in the range of about 0.1 mg / kg and about 10 mg / kg; or if the administration is carried out by intravenous administration, the amount of the photosensitive substance is in the range of about 0.1 mg / kg and about 10 mg / kg.

[0129] 8. The method according to one of the clauses 1 to 7, wherein when administration is performed intravitreally, the time from administration to irradiation is in the range of approximately 1 minute and approximately 60 minutes; for periocular administration, the time from administration to irradiation is in the range of approximately 1 minute and approximately 280 minutes; for sub-Tenon's capsule administration, the time from administration to irradiation is in the range of approximately 1 minute and approximately 180 minutes; for oral administration, the time from administration to irradiation is in the range of approximately 1 minute and approximately 48 hours; and for intravenous administration, the time from administration to irradiation is in the range of approximately 1 minute and approximately 48 hours.

[0130] 9. The method described in any of the paragraphs 1 to 8, wherein the irradiation is performed by transscleral, transpupil, or intraocular administration of light.

[0131] 10. The method according to one of the items in paragraphs 1 to 9, wherein when irradiation is performed by transscleral administration, the irradiation time is in the range of approximately 1 minute and approximately 180 minutes; when it is performed by transpupil administration, the irradiation time is in the range of approximately 1 minute and approximately 180 minutes; or when it is performed by intraocular administration, the irradiation time is in the range of approximately 1 minute and approximately 60 minutes.

[0132] 11. The method according to Clause 10, wherein the irradiation is performed by transscleral administration, and the irradiation time is in the range of approximately 25 minutes and approximately 35 minutes.

[0133] 12. The method according to one of the clauses 1 to 11, wherein the selected region of the VRI includes the fovea of ​​the mammalian eye.

[0134] 13. The method according to one of the claims 1 to 12, wherein the selected region of the VRI includes the macula of the mammalian eye.

[0135] 14. The method described in any of the clauses 1 to 13, wherein the selected region of the VRI includes the posterior pole of the mammalian eye.

[0136] 15. The method according to one of the clauses 1 to 14, wherein the selected region of the VRI includes a large portion of the vitreous humor of a mammalian eye.

[0137] 16. The method according to any of the clauses 1 to 15, wherein the selected region of the VRI includes the optic nerve of the mammalian eye, or the nasal region of the optic nerve.

[0138] 17. The method according to one of the provisions of paragraphs 1 to 16, wherein the retina is the internal limiting membrane of the retina.

[0139] 18. The method according to one of the clauses 1 to 17, wherein the retina is the ganglion cell layer of the retina.

[0140] 19. The method according to any of the claims 1 to 18, wherein the photosensitive substance is selected from the group consisting of porphyrionoids, phthalocyanines, porphyrins, protoporphyrins, chlorines, bacteriochlorines, texaphyllins, porphycenes, corols, verteporfins, halogenated fluoresceins, xanthenes, flavins, rhodamines, anthraquinones, phenothiazines, substituted cyanines, curcuminoids, and halogenated BODIPY.

[0141] 20. The method according to one of the claims 1 to 19, wherein the photosensitive substance is a phenothiazine.

[0142] 21. The photosensitive substance is riboflavin-5'-monophosphate, and the wavelength of light is in the range of 355 nm and 375 nm; the photosensitive substance is riboflavin-5'-monophosphate, and the wavelength of light is in the range of 445 nm and 465 nm; the photosensitive substance is fluorescein, and the wavelength of light is in the range of 490 nm and 510 nm; the photosensitive substance is eosin B, and the wavelength of light is in the range of 520 nm and 540 nm; the photosensitive substance is cosine Y, and the wavelength of light is in the range of 525 nm and 545 nm; the photosensitive substance is erythrosine B, and the wavelength of light is in the range of 530 nm and 550 nm; the photosensitive substance is rose bengal, and the wavelength of light is in the range of 555 nm and 575 nm. The method according to one of the clauses 1 to 20, wherein the photosensitive substance is methylene blue and the wavelength of light is in the range of 650 nm and 670 nm, the photosensitive substance is aluminum chloride phthalocyanine tetrasulfonate and the wavelength of light is in the range of 680 nm and 700 nm, the photosensitive substance is verteporfin bisudyne and the wavelength of light is in the range of 680 nm and 700 nm, the photosensitive substance is IR780 and the wavelength of light is in the range of 770 nm and 790 nm, the photosensitive substance is indocyanine green and the wavelength of light is in the range of 800 nm and 820 nm, and the photosensitive substance is IR820 and the wavelength of light is in the range of 810 nm and 830 nm.

[0143] 22. The photosensitive substance is riboflavin-5'-monophosphate with a wavelength of light of approximately 365 nm, the photosensitive substance is riboflavin-5'-monophosphate with a wavelength of light of approximately 455 nm, the photosensitive substance is fluorescein with a wavelength of light of approximately 500 nm, the photosensitive substance is eosin B with a wavelength of light of approximately 530 nm, the photosensitive substance is eosin Y with a wavelength of light of approximately 535 nm, the photosensitive substance is erythrosine B with a wavelength of light of approximately 540 nm, and the photosensitive substance is rose bengal with a wavelength of light of approximately 565 nm. The method according to one of the clauses 1 to 21, wherein the photosensitive substance is methylene blue with a wavelength of light of approximately 660 nm, the photosensitive substance is aluminum chloride phthalocyanine tetrasulfonate with a wavelength of light of approximately 690 nm, the photosensitive substance is verteporfin bisudyne with a wavelength of light of approximately 690 nm, the photosensitive substance is IR780 with a wavelength of light of approximately 780 nm, the photosensitive substance is indocyanine green with a wavelength of light of approximately 810 nm, and the photosensitive substance is IR820 with a wavelength of light of approximately 820 nm.

[0144] 23. The method according to one of the claims 1 to 22, wherein the photosensitive substance is methylene blue and the wavelength of light is in the range of 650 nm and 670 nm.

[0145] 24. The method according to one of the claims 1 to 23, wherein the photosensitive substance is methylene blue and the wavelength of light is approximately 660 nm.

[0146] 25. The method described in any of the paragraphs 1 to 24, wherein the mammal is a human or a pig.

[0147] 26. A method for improving adhesion between the vitreous humor and retina of the human eye, comprising: intravenous administration of approximately 0.1 mg / kg and approximately 10 mg / kg of methylene blue to a mammal so that the photosensitive substance accumulates at the vitreoretinal interface (VRI); and irradiating the posterior pole of the VRI with light of a wavelength of approximately 660 nm for approximately 25 minutes and approximately 95 minutes by transpupil administration, thereby increasing adhesion between the vitreous humor and retina in the human eye.

[0148] In at least some of the embodiments described above, one or more elements used in one embodiment may be interchangeably used in another embodiment, provided that such substitution is not technically impractical. Those skilled in the art will understand that various other omissions, additions, and modifications can be made to the above methods and structures without departing from the scope of the claimed subject matter. All such modifications and changes are intended to fall within the scope of the subject matter, as defined by the appended claims.

[0149] In general, the terms used herein, and in particular in the appended claims (e.g., the body of the appended claims), will be understood by those skilled in the art as being intended as "open" terms (for example, the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” and the term “includes” should be interpreted as “includes but not limited to,” and so on). Where a certain number of introduced claims are intended, such intention will be explicitly stated in the claims, and where such statement is absent, such intention will not be present, will be understood by those skilled in the art. For example, for the sake of understanding, the following appended claims may include the use of the introductory phrases “at least one” and “one or more” to introduce the claims. However, the use of such phrases should not be interpreted as meaning that the introduction of a claim with the indefinite article "a" or "an" limits a particular claim containing such introduced claims to embodiments containing only one such claim; rather, "a" and / or "an" should be interpreted as meaning "at least one" and "one or more." In addition, even if a particular number of introduced claims is explicitly stated, a person skilled in the art would recognize that such a statement should be interpreted as meaning at least the number stated (for example, the statement "two recitations" alone, without other modifiers, means at least two recitations or two or more recitations).Furthermore, when idiomatic expressions similar to "at least one of A, B, and C" are used, such configurations are generally intended to be understood by those skilled in the art (for example, "a system having at least one of A, B, and C" includes, but is not limited to, systems having A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together). When idiomatic expressions similar to "at least one of A, B, or C" are used, such configurations are generally intended to be understood by those skilled in the art (for example, "a system having at least one of A, B, or C" includes, but is not limited to, systems having A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together). Those skilled in the art will further understand that substantially any conjunctional word and / or phrase presenting two or more alternative terms in this specification, claims, or drawings should be understood as presuming the possibility of including either term, either term, or both terms. For example, the expression "A or B" should be understood as including the possibility of "A" or "B," or "A and B."

[0150] Furthermore, if any feature or aspect of the present disclosure is described in relation to the Markush group, a person skilled in the art will recognize that the present disclosure also describes any individual member or subgroup of a member of the Markush group.

[0151] As will be understood by those skilled in the art, all scopes disclosed herein also encompass all possible sub-scopes and combinations thereof for any purpose, including providing written descriptions. Any enumerated scope can be readily recognized as sufficiently describing and enabling the division of the same scope into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each scope described herein can be readily divided into lower thirds, middle thirds, upper thirds, etc. Also, as will be understood by those skilled in the art, all language such as “maximum,” “at least,” “greater than,” and “less than” includes the enumerated numbers and refers to scopes that can be later divided into sub-scopes as described above. Finally, as will be understood by those skilled in the art, scopes include individual components. Thus, for example, a group having one to three items means a group having one, two, or three items. Similarly, a group having one to five items means a group having one, two, three, four, or five items, and so on.

[0152] Although the aforementioned invention has been described in some detail by examples and embodiments for the purpose of clarity of understanding, it will be readily apparent to those skilled in the art in light of the teachings of the present invention that certain changes and modifications can be made without departing from the spirit or scope of the appended claims.

[0153] Therefore, the foregoing merely describes the principles of the present invention. Those skilled in the art will understand that various configurations embodying the principles of the present invention and falling within its spirit and scope can be devised, although these are not expressly described or shown herein. Furthermore, all examples and conditional statements described herein are primarily intended to help the reader understand the principles of the present invention and the concepts to which the inventors have contributed to further developing the art, and are not limited to such specifically described examples and conditions. Moreover, all descriptions herein listing the principles, aspects, and embodiments of the present invention, as well as specific examples thereof, are intended to encompass both their structural and functional equivalents. Furthermore, such equivalents are intended to include both currently known equivalents and those to be developed in the future, i.e., any developed elements that perform the same function regardless of their structure. Furthermore, nothing disclosed herein is intended to be made available to the public, whether such disclosure is expressly described in the claims or not.

[0154] Accordingly, the scope of the present invention is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of the present invention are embodied in the appended claims. In the claims, 35 U.S.C. §112(f) or 35 U.S.C. §112(6) is expressly defined to be invoked only if the exact words “means for” or “step for” are found at the beginning of the limitation of the claim, and if the exact words are not used in the limitation of the claim, 35 U.S.C. §112(f) or 35 U.S.C. §112(6) is not invoked.

Claims

1. A method for preventing eye diseases in mammals by targeting and strengthening the adhesion between the cortical vitreous humor and the retina, the following: The process involves administering a photosensitive substance to the eye of the mammal, wherein the photosensitive substance accumulates at the vitreoretinal interface (VRI), The selected region of the VRI is irradiated with light of a wavelength that causes a crosslink between the cortical vitreous humor and the retina, A method comprising preventing eye diseases by thereby applying targeted reinforcement adhesion between the cortical vitreous humor and the retina in the eye of the mammal.

2. The method according to claim 1, wherein the eye disease is complete posterior vitreous detachment, retinal tear, rhegmatogenous retinal detachment, macular hole, epiretinal membrane, or vitreous floatation.

3. When the eye disease is posterior vitreous detachment, the selected region of the VRI includes a region nasal to the optic nerve. If the eye disease is a retinal tear, the selected region of the VRI includes the nasal region of the optic nerve. If the eye disease is rhegmatogenous retinal detachment, the selected region of the VRI includes the nasal region of the optic nerve. If the eye disease is a macular hole, the selected region of the VRI includes the macula or the region surrounding the macula. If the eye disease is an epiretinal membrane, the selected region of the VRI includes the macula or the region surrounding the macula, If the eye disease is vitreous opacity, the selected region of the VRI includes the nasal region of the optic nerve or the region surrounding the optic nerve. The method according to claim 1.

4. A method for improving adhesion between the vitreous humor and retina of a mammalian eye, comprising administering a photosensitive substance to the mammalian eye, The accumulation of photosensitive substances at the vitreoretinal interface (VRI), By irradiating a selected area of ​​the VRI with light of a wavelength that causes crosslinking between the vitreous humor and the retina, A method comprising improving the adhesion between the vitreous humor and the retina in the eye of a mammal.

5. The method according to claim 4, wherein the irradiation is light of a wavelength that induces the photosensitive material to crosslink between the vitreous humor and the retina.

6. The method according to claim 4 or 5, wherein the administration is carried out by intravitreous administration, periocular administration, sub-Tenon's capsule administration, oral administration, or intravenous administration of the photosensitive substance to the mammal.

7. When the administration is performed by intravitreous administration, the amount of the photosensitive substance is in the range of approximately 0.05 cc and approximately 0.15 cc. When administered by periocular administration, the amount of the photosensitive substance is approximately 0.1 cc and approximately 10 cc. When administered subtenonally, the amount of the photosensitive substance is approximately 0.1 cc and approximately 5 cc. When administered orally, the amount of the photosensitive substance is approximately 0.1 mg / kg and approximately 10 mg / kg, or When administered intravenously, the amount of the photosensitive substance ranges from approximately 0.1 mg / kg to approximately 10 mg / kg. The method according to any one of claims 4 to 6.

8. When the administration is performed by intravitreal administration, the time from administration to irradiation is in the range of approximately 1 minute and approximately 60 minutes. In periocular administration, the time from administration to irradiation is in the range of approximately 1 minute and approximately 280 minutes. In sub-Tenon's capsule administration, the time from administration to irradiation ranges from approximately 1 minute to approximately 180 minutes. In oral administration, the time from administration to irradiation ranges from approximately 1 minute to approximately 48 hours. In intravenous administration, the time from administration to irradiation ranges from approximately 1 minute to approximately 48 hours. The method according to any one of claims 4 to 7.

9. The method according to any one of claims 4 to 8, wherein the irradiation is performed by transscleral administration, transpupil administration, or intraocular administration of the light.

10. When the irradiation is performed by transscleral administration, the irradiation time ranges from approximately 1 minute to approximately 180 minutes. When administered via transpupil, the irradiation time is in the range of approximately 1 minute and approximately 180 minutes, or When administered intraocularly, the irradiation time ranges from approximately 1 minute to approximately 60 minutes. The method according to any one of claims 4 to 9.

11. The method according to claim 10, wherein, when the irradiation is performed by transscleral administration, the irradiation time is in the range of approximately 25 minutes and approximately 35 minutes.

12. The method according to any one of claims 4 to 11, wherein the selected region of the VRI includes the fovea of ​​the eye of the mammal.

13. The method according to any one of claims 4 to 11, wherein the selected region of the VRI includes the macula of the eye of the mammal.

14. The method according to any one of claims 4 to 11, wherein the selected region of the VRI includes the posterior pole of the eye of the mammal.

15. The method according to any one of claims 4 to 11, wherein the selected region of the VRI includes a large portion of the vitreous humor of the eye of the mammal.

16. The method according to any one of claims 4 to 11, wherein the selected region of the VRI includes the optic nerve of the eye of the mammal, or the nasal region of the optic nerve.

17. The method according to any one of claims 4 to 11, wherein the retina is the internal limiting membrane of the retina.

18. The method according to any one of claims 4 to 11, wherein the retina is the ganglion cell layer of the retina.

19. The method according to any one of claims 4 to 18, wherein the photosensitive substance is selected from the group consisting of porphyrionoids, phthalocyanines, porphyrins, protoporphyrins, chlorines, bacteriochlorines, texaphyllins, porphycenes, corols, verteporfins, halogenated fluorescein, xanthenes, flavins, rhodamines, anthraquinones, phenothiazines, substituted cyanines, curcuminoids, and halogenated BODIPY.

20. The method according to any one of claims 4 to 18, wherein the photosensitive substance is phenothiazine.

21. The photosensitive substance is riboflavin-5'-monophosphate and the wavelength of light is in the range of 355 nm and 375 nm; the photosensitive substance is riboflavin-5'-monophosphate and the wavelength of light is in the range of 445 nm and 465 nm; the photosensitive substance is fluorescein and the wavelength of light is in the range of 490 nm and 510 nm; the photosensitive substance is eosin B and the wavelength of light is in the range of 520 nm and 540 nm; the photosensitive substance is eosin Y and the wavelength of light is in the range of 525 nm and 545 nm; the photosensitive substance is erythrosine B and the wavelength of light is in the range of 530 nm and 550 nm; the photosensitive substance is rose bengal and the wavelength of light is in the range of 555 nm and 575 nm The method according to any one of claims 4 to 18, wherein the photosensitive substance is methylene blue and the wavelength of light is in the range of 650 nm and 670 nm, the photosensitive substance is aluminum chloride phthalocyanine tetrasulfonate and the wavelength of light is in the range of 680 nm and 700 nm, the photosensitive substance is verteporfin bisudyne and the wavelength of light is in the range of 680 nm and 700 nm, the photosensitive substance is IR780 and the wavelength of light is in the range of 770 nm and 790 nm, the photosensitive substance is indocyanine green and the wavelength of light is in the range of 800 nm and 820 nm, and the photosensitive substance is IR820 and the wavelength of light is in the range of 810 nm and 830 nm.

22. The photosensitive substance is riboflavin-5'-monophosphate with a wavelength of light of approximately 365 nm, the photosensitive substance is riboflavin-5'-monophosphate with a wavelength of light of approximately 455 nm, the photosensitive substance is fluorescein with a wavelength of light of approximately 500 nm, the photosensitive substance is eosin B with a wavelength of light of approximately 530 nm, the photosensitive substance is eosin Y with a wavelength of light of approximately 535 nm, the photosensitive substance is erythrosine B with a wavelength of light of approximately 540 nm, the photosensitive substance is rose bengal with a wavelength of light of approximately 565 nm, The method according to any one of claims 4 to 18, wherein the photosensitive substance is methylene blue with a wavelength of light of approximately 660 nm, the photosensitive substance is aluminum chloride phthalocyanine tetrasulfonate with a wavelength of light of approximately 690 nm, the photosensitive substance is verteporfin bisudyne with a wavelength of light of approximately 690 nm, the photosensitive substance is IR780 with a wavelength of light of approximately 780 nm, the photosensitive substance is indocyanine green with a wavelength of light of approximately 810 nm, and the photosensitive substance is IR820 with a wavelength of light of approximately 820 nm.

23. The method according to any one of claims 4 to 18, wherein the photosensitive substance is methylene blue and the wavelength of light is in the range of 650 nm and 670 nm.

24. The method according to any one of claims 4 to 18, wherein the photosensitive substance is methylene blue and the wavelength of light is about 660 nm.

25. The method according to any one of claims 4 to 24, wherein the mammal is a human or a pig.

26. A method for improving the adhesion between the vitreous humor and retina of the human eye, as follows: A method comprising intravenously administering approximately 0.1 mg / kg and approximately 10 mg / kg of methylene blue to a mammal, thereby causing the photosensitive substance to accumulate at the vitreoretinal interface (VRI), and irradiating the posterior pole of the VRI with light of a wavelength starting from approximately 660 nm for approximately 25 minutes and approximately 95 minutes by transpupil administration, thereby increasing the adhesion between the vitreous humor and the retina in the human eye.

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