Composition for transparent artificial corneal scaffold, and transparent artificial corneal scaffold

Abstract

According to one aspect of the present invention, a composition for an artificial corneal scaffold comprises a 2-hydroxyethyl methacrylate (HEMA) monomer and a methyl methacrylate (MMA) monomer, wherein the molar ratio of the 2-hydroxyethyl methacrylate (HEMA) monomer and the methyl methacrylate (MMA) monomer can be 83:17 to 97:3. In addition, according to one aspect of the present invention, an artificial corneal scaffold and an artificial cornea can be prepared by polymerization of the composition for an artificial corneal scaffold.

Description

Composition for a transparent artificial corneal support and a transparent artificial corneal support

[0001] The present invention relates to a composition for an artificial corneal support, an artificial corneal support, and an artificial cornea comprising the same. More specifically, the invention relates to a composition for an artificial corneal support, an artificial corneal support, and an artificial cornea comprising the same, wherein the physicochemical and mechanical properties of the transparent artificial corneal support are improved while maintaining the biocompatibility of the transparent artificial corneal support.

[0002]

[0003] Artificial corneas and contact lenses show distinct differences in material selection depending on their functional purpose and usage environment. Artificial corneas replace damaged corneal tissue, with biocompatibility and structural stability being key factors, whereas contact lenses focus on temporary vision correction and comfort.

[0004] Unlike contact lenses that are replaced daily or monthly, artificial corneas are permanently implanted; therefore, they must be able to regenerate tissue, allow oxygen permeability at physiological corneal levels, and possess biocompatibility for strong adhesion through fusion with ocular tissue. Additionally, they must be able to suppress immune responses during permanent implantation.

[0005] Meanwhile, unlike contact lenses, artificial corneas are integrally composed of a transparent optical portion and an opaque support portion surrounding the optical portion. In this case, the transparent optical portion plays the primary role of transmitting light, while the opaque support portion plays the primary role of enabling corneal epithelial cells to grow and fuse with ocular tissue to ensure firm adhesion. Generally, they are manufactured using different monomer compositions to optimize the characteristics of the optical portion and the support portion, respectively.

[0006] However, if the supporting portion of the artificial cornea is opaque, it may be visually visible as a white or grayish-white band around the periphery of the cornea, and unlike the uniform transparency of a normal cornea, the contrast between the center and the periphery is pronounced, making it easy to identify the fact of the artificial cornea transplant from the outside.

[0007] Meanwhile, conventionally, polyurethane-based materials, polypropylene-based materials, polyvinyl alcohol hybrid materials, collagen / hydrogel hybrid materials, and polymethyl methacrylate-based materials have been studied as artificial corneal supports.

[0008] Meanwhile, the inventors disclosed in Korean Published Patent Application KR 10-2017-0126329 A a method for manufacturing an artificial cornea using a mold for manufacturing an artificial cornea in which the optical part and the support part of the artificial cornea are integrally formed, and there was a problem that the artificial cornea support part manufactured by copolymerizing 2-hydroxyethyl methacrylate (HEMA) monomer and methyl methacrylate (MMA) monomer was opaque.

[0009] The following prior art documents exist.

[0010] (Patent Document 0001) U.S. Published Patent Application US 20110125260 A1

[0011] (Patent Document 0002) Korean Published Patent Application KR 100305222 B1

[0012] (Patent Document 0003) Korean Published Patent Application KR 10-2017-0126329 A

[0013]

[0014] The present invention aims to provide a composition for an artificial corneal support, an artificial corneal support, and an artificial cornea that minimizes the suspension phenomenon, which causes opacity in the artificial corneal support, thereby ensuring transparency where there is no noticeable contrast between the optical portion of the artificial cornea and its appearance, and significantly improves visible light transmittance.

[0015] In addition, the present invention aims to provide a composition for an artificial corneal support, an artificial corneal support, and an artificial cornea that ensures transparency without significant visual contrast with the optical portion of the artificial cornea, while meeting the corneal epithelial cell growth, strong adhesion to ocular tissue, and stable support characteristics required for an artificial corneal support.

[0016] In addition, the present invention aims to provide a composition for an artificial corneal support, an artificial corneal support, and an artificial cornea in which the physicochemical and mechanical properties of the artificial corneal support are significantly improved.

[0017] In addition, we aim to provide a composition for an artificial corneal support, an artificial corneal support, and an artificial cornea, in which continuous bonding and adhesion with an artificial corneal optical part are significantly improved.

[0018]

[0019] A composition for an artificial corneal support according to one embodiment of the present invention may include a 2-hydroxyethyl methacrylate (HEMA) monomer and a methyl methacrylate (MMA) monomer.

[0020] In one embodiment, the molar ratio of the 2-hydroxyethyl methacrylate (HEMA) monomer and the methyl methacrylate (MMA) monomer may be 83:17 to 97:3.

[0021] In one embodiment, the total weight percentage of the 2-hydroxyethyl methacrylate (HEMA) monomer and methyl methacrylate (MMA) monomer included in the composition for the artificial cornea support may be 25.0% to 46.0% by weight based on the total weight percentage of the composition for the artificial cornea.

[0022] In one embodiment, the composition for the artificial cornea support may further include distilled water.

[0023] In one embodiment, the weight percentage of the distilled water may be 25.0% to 45.0% based on the total weight percentage of the composition for the artificial cornea support.

[0024] In one embodiment, the weight percentage of the distilled water may be 70% to 100% by weight based on the total weight percentage of the 2-hydroxyethyl methacrylate (HEMA) monomer and methyl methacrylate (MMA) monomer included in the composition for the artificial cornea support.

[0025] An artificial corneal support according to one embodiment of the present invention can be manufactured through a polymerization reaction of the composition for the artificial corneal support.

[0026] An artificial corneal support according to one embodiment of the present invention may include a material comprising a copolymer of 2-hydroxyethyl methacrylate (HEMA) monomer and methyl methacrylate (MMA) monomer.

[0027] In one embodiment, the molar ratio of the copolymerized 2-hydroxyethyl methacrylate (HEMA) monomer and methyl methacrylate (MMA) monomer may be 83:17 to 97:3.

[0028] In one embodiment, the material may include a copolymer comprising a unit represented by the following chemical formula 1 and a unit represented by the following chemical formula 2.

[0029] [Chemical Formula 1]

[0030]

[0031] [Chemical Formula 2]

[0032]

[0033] In the above chemical formula 1, x and y are each independently natural numbers greater than or equal to 1.

[0034] In one embodiment, the material may have an average haze (%) value of 0.1% to 10.0% according to the ratio of the transmittance of diffuse light (Dt) and transmitted light (Tt).

[0035] In one embodiment, the material may have a light transmittance of 80% or more at a wavelength of 550 nm as measured by a UV-Vis Spectrometer.

[0036] In one embodiment, the material may have an average tensile strength of 800 KPa to 1200 KPa measured at a tensile speed of 5 mm / sec.

[0037] An artificial cornea according to one embodiment of the present invention can be manufactured by polymerizing the composition for the artificial cornea support.

[0038] An artificial cornea according to one embodiment of the present invention may include the artificial cornea support.

[0039]

[0040] One effect of the present invention is to provide a composition for an artificial corneal support, an artificial corneal support, and an artificial cornea, which minimize the suspension phenomenon that causes opacity in the artificial corneal support, thereby ensuring transparency where there is no noticeable contrast in appearance with the optical part of the artificial cornea, and significantly improved visible light transmittance.

[0041] In addition, the present invention provides a composition for an artificial corneal support, an artificial corneal support, and an artificial cornea that ensures transparency without significant visual contrast with the optical portion of the artificial cornea, while meeting the corneal epithelial cell growth, strong adhesion to ocular tissue, and stable support characteristics required for an artificial corneal support.

[0042] In addition, the present invention provides a composition for an artificial corneal support, an artificial corneal support, and an artificial cornea, wherein the physicochemical and mechanical properties of the artificial corneal support are significantly improved.

[0043] In addition, the present invention provides a composition for an artificial corneal support, an artificial corneal support, and an artificial cornea, wherein the continuous bonding and adhesion with the optical part of the artificial cornea are significantly improved.

[0044]

[0045] Figure 1 is an image of an artificial corneal support composition and a polymer according to one manufacturing example of the present invention.

[0046] Figure 2 is the result of an opacity analysis (Haze meter) of an artificial corneal support according to one manufacturing example of the present invention.

[0047] Figure 3 is the result of a visible light transmittance analysis (UV-Vis spectrometer) of an artificial corneal support according to one manufacturing example of the present invention.

[0048] Figure 4 is the result of the tensile strength analysis (ASTM D882) of an artificial corneal support according to one manufacturing example of the present invention.

[0049] Figure 5 is the polymerization reaction analysis (FT-IR) result of an artificial corneal support according to one manufacturing example of the present invention.

[0050] FIG. 6 is a method for manufacturing an artificial cornea according to one manufacturing example of the present invention.

[0051] Figure 7 is an image of an artificial cornea according to one manufacturing example of the present invention.

[0052] Figures 8 and 9 are the results of a small animal subcutaneous transplantation experiment of an artificial corneal support according to one manufacturing example of the present invention.

[0053] Figures 10 and 11 are analysis results according to the monomer mixing weight ratio of a composition for an artificial corneal support according to one manufacturing example of the present invention.

[0054]

[0055] Expressions such as "comprising" as used in this specification should be understood as open-ended terms implying the possibility of including other configurations.

[0056] As used herein, "preferably" and "preferably" refer to embodiments of the present invention that can provide certain advantages under certain conditions. However, it is not intended to exclude other embodiments from the scope of the present invention.

[0057] The numerical ranges used in this specification include lower and upper limits and all values ​​within the range, increments logically derived from the form and width of the defined range, all of which are limited values, and all possible combinations of upper and lower limits of numerical ranges limited in different forms.

[0058] Unless otherwise specifically defined in this specification, values ​​outside the numerical range that may occur due to experimental error or rounding are also included in the defined numerical range.

[0059] The meaning of 'greater than' or 'less than' as used in this specification may be replaced with the meaning of 'greater than' or 'less than'.

[0060] Meanwhile, the technical features described below relate to one embodiment that achieves the intended effect of the present invention described above.

[0061]

[0062] First, the composition for the artificial cornea support of the present invention will be described.

[0063] The artificial cornea of ​​the present invention may include an optical part composed of an optically transparent material and a support part for surrounding and supporting at least a portion of the optical part.

[0064] The optical component of the artificial cornea is responsible for the core function of transmitting and refracting light, and must maintain high transparency to effectively pass light through.

[0065] The artificial corneal support serves to strengthen the bond between the artificial cornea and natural tissue by providing an environment for corneal epithelial cells to grow. Additionally, it stably fixes the artificial cornea to the eyeball and supports it to prevent detachment, enabling long-term use.

[0066] Generally, different monomer compositions are used to manufacture the optical and support parts in order to optimize their characteristics to suit their respective functions. However, when an opaque material is used for the artificial corneal support part, there is an aesthetic problem due to the prominent contrast between the center and the periphery.

[0067] Meanwhile, an artificial cornea according to one embodiment of the present invention may be an artificial cornea mimic type that structurally and functionally imitates an actual human cornea.

[0068] In one embodiment, the artificial cornea of ​​the present invention can reproduce the structure of an actual cornea by including the three cell layers of the cornea—epithelial, stroma, and endothelium—while maintaining transparency, and can maintain the growth and characteristics of corneal epithelial cells, and can inhibit apoptosis of the epithelium and promote epithelialization.

[0069] In one embodiment, the composition for the artificial cornea support may be a thermosetting resin composition. The artificial cornea support of the present invention can be manufactured through a process of polymerizing the composition for the artificial cornea support by heat. In the case of conventional contact lenses, since they consist only of a transparent optical part without the need to form a support, only UV polymerization is required to manufacture them; however, the support constituting the artificial cornea of ​​the present invention can be connected and bonded to the optical part by thermal polymerization.

[0070] A composition for an artificial corneal support according to one embodiment of the present invention may include a 2-hydroxyethyl methacrylate (HEMA) monomer and a methyl methacrylate (MMA) monomer.

[0071] Meanwhile, as a non-limiting embodiment, the composition for the artificial cornea support comprises N-vinylpyrrolidone, silicon-containing monomer, glycidyl methacrylate, glycerol monomethacrylate, diethylene glycol dimethacrylate, diethylene glycol methacrylate, ethylene glycol dimethacrylate, triethylene glycol dimethacrylate, polyethylene glycol diacrylate, trimethylolpropane trimethacrylate, polyethylene glycol, aromatic (meth)acrylate, sodium alginate, cellulose nanofiber, acrylamide, N,N-dimethylacryamide, N-vinyl-N-methylacetamide, N-vinyl-N-ethylacetamide, N-vinyl-N-ethylformamide, N-vinylformamide, N-2-hydroxyethylvinyl carbamate, N-carboxy-β-alanine N-vinyl ester, reactive polyethylene polyol, divinylbenzene, vinyl It may not contain one or more selected from carbamate, hydrophilic oxazolone, hydrophilic oxazolin, styrene, and phosphorylcholine.

[0072] In a non-limiting embodiment, the composition for the artificial cornea support may not include any one or more selected from ethyl acrylate, ethyl methacrylate, butyl acrylate, hydroxyethyl acrylate, hydroxypropyl methacrylate, hydroxybutyl methacrylate, ethyl phenylacrylate, phenylethyl methacrylate, phenoxyethyl acrylate, benzyl ethyl methacrylate, ethoxyethyl methacrylate, ethoxy ethoxyethyl acrylate, and cyanomethacrylate.

[0073] In one embodiment, the molar ratio of the 2-hydroxyethyl methacrylate (HEMA) monomer and the methyl methacrylate (MMA) monomer may be 83:17 or higher, 85:15 or higher, 87:13 or higher, or 97:3 or lower, 95:5 or lower, or 92:8 or lower.

[0074] To obtain the aforementioned desired effects, the inventors investigated the properties according to various concentration ratios of 2-hydroxyethyl methacrylate (HEMA) and methyl methacrylate (MMA). As a result, it was confirmed that the cell compatibility, physicochemical, and mechanical properties required for artificial corneal supports were significantly improved at the above molar concentration ratios.

[0075] In one embodiment, the total weight percentage of the 2-hydroxyethyl methacrylate (HEMA) monomer and methyl methacrylate (MMA) monomer included in the composition for the artificial cornea support may be 25.0 wt% or more, 30.0 wt% or more, 35.0 wt% or more, 38.0 wt% or more, 39.0 wt% or more, 46.0 wt% or less, 44.0 wt% or less, 43.0 wt% or less, 42.0 wt% or less, or 41 wt% or less, based on the total weight percentage of the composition for the artificial cornea. It was confirmed that within the total weight percentage range of the 2-hydroxyethyl methacrylate (HEMA) monomer and methyl methacrylate (MMA) monomer, transparency and visible light transmittance were significantly improved, while the cell compatibility, physicochemical, and mechanical properties required for the artificial cornea support were also improved.

[0076] In one embodiment, the composition for the artificial cornea support may further include distilled water.

[0077] In one embodiment, the weight percentage of the distilled water may be 25.0 or more, 30.0 or more, 33.0 or more, 45.0 or less, 40.0 or less, or 35.0 or less, based on the total weight percentage of the composition for the artificial cornea support. It was confirmed that within the total weight percentage range of the distilled water, transparency and visible light transmittance were significantly improved, while the cell compatibility, physicochemical, and mechanical properties required for the artificial cornea support were also improved.

[0078] In one embodiment, the weight percentage of the distilled water may be 70% or more, 80% or more, 100% or less, or 90% or less, based on the total weight percentage of the 2-hydroxyethyl methacrylate (HEMA) monomer and methyl methacrylate (MMA) monomer included in the composition for the artificial corneal support. It was confirmed that within the total weight percentage range of the distilled water, transparency and visible light transmittance were significantly improved, while the cell compatibility, physicochemical, and mechanical properties required for the artificial corneal support were also improved.

[0079] In one embodiment, the composition for the artificial cornea support may further include pentaerythritol tetracrylate (PETA). In this case, the weight percentage of the pentaerythritol tetracrylate (PETA) may be 1.00 weight% or more, 1.5 weight% or more, 3.0 weight% or less, or 2.5 weight% or less, based on the total weight percentage of the 2-hydroxyethyl methacrylate (HEMA) monomer and methyl methacrylate (MMA) monomer included in the composition for the artificial cornea support.

[0080] In one embodiment, pentaerythritol tetracrylate (PETA) included in the composition for the artificial cornea support can be used as a crosslinking agent when polymerizing the 2-hydroxyethyl methacrylate (HEMA) monomer and the methyl methacrylate (MMA) monomer.

[0081] In one embodiment, the composition for the artificial cornea support may further include an organic solvent. In this case, the weight percentage of the organic solvent may be 10.0 weight% or more, 12.0 weight% or more, 15.0 weight% or less, or 13.0 weight% or less, based on the total weight percentage of the composition for the artificial cornea support.

[0082] In addition, in this case, the weight % of distilled water included in the composition for the artificial cornea support may be 2.0 to 3.0 times, or 2.5 to 2.8 times, the weight % of the organic solvent.

[0083] Meanwhile, as a non-limiting embodiment, the composition for the artificial cornea support may further include or not include one or more selected from acetones, acetonitriles, alcohols, ketones, ethers, and tetrahydrofuran.

[0084] In one embodiment, the composition for the artificial cornea support may further include a thermal initiator. In this case, the weight ratio of the thermal initiator may be 1.0% to 5.0% by weight based on the total weight percentage of the composition for the artificial cornea support.

[0085] For example, the thermal initiator includes Hydroperoxide, TBHP (t-Butyl Hydroperoxide), BPO (Benzoyl Peroxide), SPS (Sodium Persulfate), KPS (Potassium persulfate), VA-086 (2,2'-Azobis[2-methyl-N-(2-hydroxyethyl)propionamide], V-50 (2,2'-Azobis(2-methylpropionamidine)dihydrochloride), VA-044(2,2'-Azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride), V-501 (4,4'-Azobis(4-cyanovaleric acid)), VA-61 (2,2'-Azobis[2-(2-imidazolin-2-yl)propane]), VA-057 It may be one or more selected from (2,2'-Azobis[N-(2-carboxyethyl)-2-methylpropionamidine]tetrahydrate).

[0086] In one embodiment, the composition for the artificial cornea support may further include a thermal catalyst. In this case, the weight ratio of the thermal catalyst may be 1.0% to 5.0% by weight based on the total weight percentage of the composition for the artificial cornea support.

[0087] For example, the above-mentioned thermal catalyst may be one or more selected from Triethylenetetramine (TETA), Triethanolamine (TEOA), N,N-Dimethylaniline (DMA), and N,N-Dimethyltoluidine (DMT).

[0088]

[0089] Next, the artificial corneal support of the present invention will be described.

[0090] An artificial corneal support according to one embodiment of the present invention can be manufactured through a polymerization reaction of the composition for the artificial corneal support.

[0091] In one embodiment, the polymerization may be thermal polymerization.

[0092] An artificial corneal support according to one embodiment of the present invention may include a material comprising a copolymer of 2-hydroxyethyl methacrylate (HEMA) monomer and methyl methacrylate (MMA) monomer.

[0093] The meaning of the copolymer of the above 2-hydroxyethyl methacrylate (HEMA) monomer and methyl methacrylate (MMA) monomer is a copolymer polymerized from the 2-hydroxyethyl methacrylate (HEMA) monomer and the methyl methacrylate (MMA) monomer.

[0094] In one embodiment, the molar ratio of the copolymerized 2-hydroxyethyl methacrylate (HEMA) monomer and methyl methacrylate (MMA) monomer may be 83:17 or higher, 85:15 or higher, 87:13 or higher, or 97:3 or lower, 95:5 or lower, or 92:8 or lower.

[0095] In one embodiment, the material may include a copolymer comprising a unit represented by the following chemical formula 1.

[0096] [Chemical Formula 1]

[0097]

[0098] In the above chemical formula 1, x and y are each independently natural numbers greater than or equal to 1,000,000,000.

[0099] In one embodiment, the ratio of x and y may be 83:17 or greater, 85:15 or greater, 87:13 or greater, or 97:3 or less, 95:5 or less, or 92:8 or less.

[0100] In one embodiment, the material may include a copolymer comprising a unit represented by the following chemical formula 2.

[0101] [Chemical Formula 2]

[0102]

[0103] In one embodiment, the material may have a haze (%) value according to the ratio of the transmittance of diffuse light (Dt) and transmitted light (Tt) of 0.1% or more, 10.0% or less, 7.5% or less, or 5.0% or less.

[0104] In the present invention, the haze (%) value is a value measured by cutting a specimen with a thickness of 0.5 mm into a sample size of 2 * 2 cm using a haze meter (HM150L2) opacity measuring instrument, and represents the haze (%) value according to the ratio of the transmittance of diffuse light (Dt) and transmitted light (Tt), and the average haze (%) value represents the average of the values ​​measured 5 times.

[0105] In one embodiment, the material may have a light transmittance of 80% or more, or 85% or more, at a wavelength of 550 nm as measured by a UV-Vis Spectrometer.

[0106] In the present invention, light transmittance refers to the light transmittance value measured at 550 nm by cutting a specimen with a thickness of 0.5 mm into a sample size of 1 * 1 cm for a UV-vis spectrometer.

[0107] It can be confirmed that the artificial corneal support of the present invention has no significant difference from the transparency and light transmittance of the optical part, and can be controlled to a value that exhibits similarity to existing tissue when implanted into a human cornea.

[0108] In one embodiment, the material may have a tensile strength of 800 kPa or more, 850 kPa or more, 1200 kPa or less, or 1000 kPa or less, measured at a tensile speed of 5 mm / sec.

[0109] In the present invention, tensile strength refers to a value measured by cutting the specimen to 115 (LO) * 19 (WO) mm, corresponding to the standard tensile strength measurement specification (ASTM D882), applying it to the test, and observing a tensile speed of 5 mm / sec, and the average tensile strength refers to the average of the values ​​measured five times.

[0110] It can be confirmed that the artificial cornea support of the present invention can have its tensile strength controlled to prevent detachment of the artificial cornea and preserve the shape of the device while securing high transparency and light transmittance, in patients with corneal disease who have high intraocular pressure.

[0111]

[0112] Hereinafter, embodiments of the present invention will be described in more detail.

[0113]

[0114] Analysis results according to the mixed weight ratio of 2-hydroxyethyl methacrylate (HEMA) and methyl methacrylate (MMA)

[0115] <Preparation Example 1>

[0116] A solution was prepared by mixing 30 wt% of a monomer mixture of 2-hydroxyethyl methacrylate (HEMA) and methyl methacrylate (MMA) mixed in weight ratios of 95:5 (Preparation Example 1-1), 90:10 (Preparation Example 1-2), 85:15 (Preparation Example 1-3), and 80:20 (Preparation Example 1-4), DW : ethyl acetate = 80 : 20 (w / w), 2.8 mol% of pentaerythritol tetraacrylate, 3.0 mol% of TBHP (t-Butyl Hydroperoxide), and 3.0 mol% of N,N-dimethyltoluidine (DMT). Subsequently, the homogeneous solution prepared above was poured into a Petri dish (90x15mm, SPL Life Science) and polymerized at 37°C for 1 hour. After the polymerization was completed, the unreacted solution was removed by washing twice with ethanol and purified water.

[0117]

[0118] <Experimental Example 1-1>

[0119] First, SEM images of Preparation Examples 1-1 to 1-4 are shown in FIG. 9. FIG. 9(a) relates to Preparation Example 1-1, FIG. 9(b) to Preparation Example 1-2, FIG. 9(c) to Preparation Example 1-3, and FIG. 9(d) to Preparation Example 1-4.

[0120] In Preparation Examples 1-1 and 1-2, the aggregated polymer chains are connected, but in Preparation Examples 1-3 and 1-4, as the amount of MMA increases, phase separation occurs due to hydrophilicity and hydrophobicity, and it was confirmed that the spacing between aggregated particles widens and the size of the aggregated particles becomes irregular.

[0121]

[0122] <Experimental Example 1-2>

[0123] Next, SEM images regarding the HDF cell adhesion and morphology of Preparation Examples 1-1 to 1-4 are shown in FIG. 10. FIG. 10(a) relates to Preparation Example 1-1, FIG. 10(b) to Preparation Example 1-2, FIG. 10(c) to Preparation Example 1-3, and FIG. 10(d) to Preparation Example 1-4.

[0124] Fetal human skin fibroblasts (HDF) were washed with PBS and then treated with a mixture of 50 μL of EZ-Cytox solution and 500 μL of DMEM in a cell culture incubator according to the manufacturer's instructions. Cells were cultured in each sample for one day, then immediately fixed and dehydrated. Prior to observation, the HDF cells attached to each sample were freeze-dried and then imaged with a 750x SEM to analyze the cell attachment morphology.

[0125] Analysis results confirmed that, in particular, in Preparation Examples 1-1 and 1-2, a biocompatible structure for cell adhesion and proliferation was provided.

[0126]

[0127] Analysis results based on the weight ratio of monomer mixture and distilled water

[0128] <Preparation Example 2>

[0129] Considering the cell compatibility, physicochemical properties, and mechanical properties of the artificial corneal support, a monomer mixture of 2-hydroxyethyl methacrylate (HEMA) and methyl methacrylate (MMA) mixed in a weight ratio of 9:1 was used.

[0130] The weight ratio of the monomer mixture and the weight ratio of distilled water relative to the total solution were adjusted and mixed according to Table 1 below.

[0131] In addition, 2.5 wt% of TBHP (t-Butyl Hydroperoxide) and 1.25 wt% of N,N-Dimethyltoluidine (DMT, N,N-Dimethyltoluidine) (or other units) were mixed relative to the total solution.

[0132] In addition, the ratio of distilled water to ethyl acetate was adjusted to a weight ratio of 2.69:1 and mixed.

[0133] In addition, pentaerythritol tetraacrylate was mixed at 2.00 wt% relative to the monomer mixture.

[0134] Next, the above solution was thermally polymerized at 37°C for 1 hour.

[0135] After the polymerization was completed, the polymerized artificial corneal support was washed with 10% ethanol and 100% purified water, and then a polymerized specimen with a thickness of 0.5 mm was prepared.

[0136]

[0137] [Table 1]

[0138]

[0139]

[0140] <Experimental Example 2-1>

[0141] Images of the solutions and specimens according to the above Preparation Examples 2-1 to 2-9 are shown in FIG. 1.

[0142] As a result of visually inspecting the transparency of the solutions and specimens according to the above Preparation Examples 2-1 to 2-9, it was confirmed that the transparency was higher in Preparation Examples 2-5 to 2-7, and in particular, the transparency was highest in Preparation Example 2-6.

[0143]

[0144] <Experimental Example 2-2>

[0145] For the specimens prepared according to Manufacturing Examples 2-1, 2-2, 2-6, and 2-8 above, the specimens were cut to a size of 2 * 2 cm using a Haze meter (HM150L2) to measure the haze (%) value according to the ratio of the transmittance of diffused light (Dt) and transmitted light (Tt), and the same specimens were repeated 5 times to calculate the average value, which is shown in FIG. 2 and Table 2 below.

[0146]

[0147] [Table 2]

[0148]

[0149]

[0150] <Experimental Example 2-3>

[0151] For the specimens prepared according to Manufacturing Examples 2-1, 2-2, 2-6, and 2-8 above, the sample size was cut to 1 * 1 cm for a UV-Vis Spectrometer, and the light transmittance was measured in the wavelength range of 300-1000 nm using a UV-Vis Spectrometer and is shown in Fig. 3, and the light transmittance at a wavelength of 500 nm is shown in Table 3 below.

[0152]

[0153] [Table 3]

[0154]

[0155]

[0156] <Experimental Example 2-4>

[0157] For the specimens prepared according to the above Preparation Examples 2-1, 2-2, 2-6, and 2-8, the Stress-Strain curve and tensile strength were checked.

[0158] Specifically, to measure tensile strength, specimens according to the above preparation examples 2-1, 2-2, 2-6, and 2-8 were cut to 115 (LO) * 19 (WO) mm, corresponding to the standard specification for tensile strength measurement (ASTM D882), and measured at a tensile speed of 5 mm / sec, as shown in FIG. 4. The average value of the tensile strength, repeated 5 times for the same specimen, was calculated and is shown in Table 4 below.

[0159]

[0160] [Table 4]

[0161]

[0162]

[0163] <Experimental Example 2-5>

[0164] To measure specific functional groups constituting the specimens according to Preparation Examples 2-1, 2-2, 2-6, and 2-8 and to confirm the polymerization reactivity of the material, the values ​​measured from infrared spectroscopy were checked by inserting them into an ATR FT-IR module.

[0165] As shown in FIG. 5, the FT-IR peak values ​​measured in the specimens according to each Preparation Example 2-1, 2-2, 2-6, and 2-8 were 3463 cm⁻¹, respectively. -1 , 2944 cm -1 , 1734 cm -1 , 1475 cm -1 , 1166 cm -1 was, and the corresponding interval was -OH, C=O, -COO sym , -COO asym It was confirmed that peaks corresponding to the polymerization functional groups appeared.

[0166] In addition, the C=C region of the raw material's molecular structure, 1634–1636 cm -1 By confirming that no peak was observed in the range, it was confirmed that the polymerization reaction of the artificial corneal support specimens according to the solvent weight ratio was successfully and consistently carried out.

[0167]

[0168] Artificial cornea manufacturing

[0169] <Preparation Example 3>

[0170] An artificial cornea was manufactured using a mold dedicated to manufacturing an artificial cornea according to Korean Patent Publication KR 10-2017-0126329 A (see FIG. 6).

[0171] First, to manufacture the optical part of an artificial cornea, a monomer mixture of 2-hydroxyethyl methacrylate (HEMA) and methyl methacrylate (MMA) in a weight ratio of 9:1 was dissolved in a mixture of ethanol and distilled water to prepare a solution for manufacturing the optical part.

[0172] The weight ratio of 2-hydroxyethyl methacrylate (HEMA) and methyl methacrylate (MMA) to the total solution was adjusted to 80%. In addition, the weight ratio of distilled water and ethanol was adjusted to 85 wt% and 15 wt%, respectively.

[0173] 2-Hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiophenone (Irgacure 2959) and ethylene glycol dimethacrylate (EGDMA) were added to the above solution, and photopolymerization and curing were performed for 1 hour under a UV lamp (365 nm) and 10 W conditions in an artificial cornea manufacturing mold.

[0174] Next, to manufacture an artificial corneal support, the solution according to Preparation Example 2-6 was fully polymerized for 1 hour at a temperature of 37°C, and the polymerized artificial cornea was washed with 10% ethanol and 100% purified water.

[0175] The artificial cornea, after the above washing was completed, was washed in 100% purified water for 24 hours, and then the upper and lower parts of the mold were separated to manufacture the artificial cornea.

[0176] As shown in Fig. 7, it was confirmed that the artificial cornea according to Manufacturing Example 3 has no difference in transparency between the optical part and the support part, and that the optical part and the support part are connected and bonded.

[0177]

[0178] <Experimental Example 3-1>

[0179] The characteristics of the artificial cornea according to the above Manufacturing Example 3 are shown in Table 5 below.

[0180]

[0181] [Table 5]

[0182]

[0183]

[0184] <Experimental Example 3-2>

[0185] To evaluate the in vitro cell proliferation effect of the artificial cornea according to Preparation Example 3 above, human fibroblasts and the artificial cornea according to Preparation Example 3 above were co-cultured and observed for 1, 3, and 7 days. In addition, the AO / PI staining of the cultured human fibroblasts was used to observe the degree of cell proliferation depending on the presence or absence of the artificial cornea support.

[0186] As a result, it was confirmed that cells penetrated into the artificial corneal clearing support and exhibited excellent biocompatibility and cell proliferation.

[0187]

[0188] <Experimental Example 3-3>

[0189] To evaluate the in vivo compatibility and degradability of the artificial cornea according to Preparation Example 3 above, the artificial cornea according to Preparation Example 3 above was implanted subcutaneously in small animals, specifically mice (SD rats), and gross and histological analyses were performed after 3 and 6 weeks.

[0190] Specifically, a total of four subcutaneous pockets were created by non-incisional dissection following a skin incision along the spine of one SD rat, and artificial corneal samples were inserted and transplanted. Then, at 3 and 6 weeks post-transplant, the eight transplanted sites were visually evaluated, and their organization and degradability were observed through H&E staining.

[0191] As shown in Figures 8 and 9, no specific abnormalities were observed in the area where the artificial cornea according to Preparation Example 3 was implanted. As a result of measuring body weight at 3 and 6 weeks after the application of the experimental substance, no weight loss of more than 10% or specific symptoms were found in any of the subjects during the implantation period.

[0192] In addition, at 3 weeks after the artificial cornea was transplanted, fibroblast tissue bands and cell infiltration within the support area were observed in the periphery of the artificial cornea clearing support area, and at 6 weeks after transplantation, the formation of fibroblast tissue bands and cell infiltration were also observed in the artificial cornea clearing support area.

[0193] In addition, it was confirmed that the artificial cornea containing the artificial cornea clearing support possesses biocompatibility and non-degradability characteristics, as evidenced by the fact that the implanted device did not degrade at 6 weeks post-implantation.

Claims

It comprises 1,2-hydroxyethyl methacrylate (HEMA) monomer and methyl methacrylate (MMA) monomer, and The molar ratio of the above 2-hydroxyethyl methacrylate (HEMA) monomer and methyl methacrylate (MMA) monomer is included in a range of 83:17 to 97:3, Composition for artificial corneal support.

2. In Paragraph 1, The total weight percentage of the 2-hydroxyethyl methacrylate (HEMA) monomer and methyl methacrylate (MMA) monomer included in the above composition for the artificial cornea support is 25.0% to 46.0% by weight based on the total weight percentage of the above composition for the artificial cornea, Composition for artificial corneal support.

3. In Paragraph 1, The above composition for an artificial corneal support further comprises distilled water, and The weight percentage of the distilled water is 25.0% to 45.0% by weight based on the total weight percentage of the composition for the artificial cornea support, Composition for artificial corneal support.

4. In Paragraph 3, The weight percentage of the distilled water is 70% to 100% by weight based on the total weight percentage of the 2-hydroxyethyl methacrylate (HEMA) monomer and methyl methacrylate (MMA) monomer included in the composition for the artificial cornea support, Composition for artificial corneal support.

5. A composition for an artificial corneal support prepared through a polymerization reaction according to Claim 1, Artificial corneal support. A material comprising a copolymer of 6,2-hydroxyethyl methacrylate (HEMA) monomer and methyl methacrylate (MMA) monomer, and The molar ratio of the copolymerized 2-hydroxyethyl methacrylate (HEMA) monomer and methyl methacrylate (MMA) monomer is 83:17 to 97:3, Artificial corneal support.

7. In Paragraph 6, The above material comprises a copolymer comprising a unit represented by the following chemical formula 1 and a unit represented by the following chemical formula 2, Artificial corneal support: [Chemical Formula 1] [Chemical Formula 2] In the above chemical formula 1, x and y are each independently natural numbers greater than or equal to 1.

8. In Paragraph 6, The above material has an average haze (%) value of 0.1% to 10.0% according to the transmittance ratio of diffuse light (Dt) and transmitted light (Tt), Artificial corneal support.

9. In Paragraph 6, The above material has a light transmittance of 80% or more at a wavelength of 550 nm as measured by a UV-Vis Spectrometer, Artificial corneal support.

10. In Paragraph 6, The above material has an average tensile strength of 800KPa to 1200KPa measured at a tensile speed of 5mm / sec, Artificial corneal support.

11. Comprising the artificial corneal support of claim 6, Artificial cornea.

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