Corneal implant

Abstract

The present disclosure provides corneal implants, comprising: a base membrane, a seal ring, and / or a soft edge, that can be used to replace a cornea or sclera of a patient in need thereof and methods of make the same.

Description

CORNEAL IMPLANTCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 671,947, filed July 16, 2024, and U.S. Provisional Application No. 63 / 764,471, filed February 27, 2025, which are hereby incorporated by reference in their entireties for all purposes.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (BILT_002_02WO_SeqList_ST26.xml; Size: 4,506 bytes; and Date of Creation: July 14, 2025) are herein incorporated by reference in its entirety.BACKGROUND

[0003] A cornea serves to refract and focus light onto the retina, while also serving as a protective barrier for the eye. Due to trauma or a keratopathy the light that is transmitted and / or focused by the retina can be limited, and there will be a need to replace the cornea via a keratoplasty.

[0004] Current artificial corneas do not integrate well with the underlying tissue and relatively quickly turn opaque causing a need to further replace the artificial cornea. Therefore, there exists a need for a long-lasting artificial cornea that is able to integrate well with the surrounding tissue.SUMMARY

[0005] In aspects, the present disclosure provides a corneal implant, comprising: a base membrane comprising a first crosslinked polymer comprising poly(2- hydroxyethyl methacrylate) (PHEMA), poly(methyl methacrylate) (PMMA), or a mixture thereof; wherein: i. the posterior surface and the anterior surface of the base membrane are modified with one or more anti-fouling agents, and the perimeter of the base membrane is modified with one or more integration agents; or11. the posterior surface of the base membrane is modified with one or more anti-fouling agents, and the anterior surface and the perimeter of the base membrane are modified with one or more integration agents; and a seal ring attached to the posterior surface of the base membrane; and wherein the seal ring comprises a second crosslinked polymer comprising PHEMA, PMMA, or a mixture thereof.

[0006] In aspects, the present disclosure provides a corneal implant, comprising: a base membrane comprising a first crosslinked polymer comprising PHEMA, PMMA, or a mixture thereof; wherein the posterior and / or anterior surface of the base membrane is modified with one or more anti-fouling agents; a seal ring attached to the anterior surface of the base membrane; and wherein the seal ring comprises a second crosslinked polymer comprising PHEMA, PMMA, or a mixture thereof; and a soft edge attached to the edge of the base membrane and / or seal ring; and wherein the soft edge comprises a third crosslinked polymer comprising PHEMA, PMMA, polyvinylpyrrolidone (PVP), or a mixture thereof; and wherein the soft edge is modified with one or more integration agents.

[0007] In aspects, the present disclosure provides a corneal implant, comprising: a base membrane comprising a first crosslinked polymer comprising poly(2- hydroxyethyl methacrylate) (PHEMA), poly(methyl methacrylate) (PMMA), or a mixture thereof; wherein the posterior surface and / or anterior surface of the base membrane is modified with one or more anti-fouling agents; a seal ring comprising a second crosslinked polymer comprising PHEMA, PMMA, or a mixture thereof; and a soft edge comprising a third crosslinked polymer comprising PHEMA, PMMA, polyvinylpyrrolidone (PVP), or a mixture thereof, wherein the seal ring is embedded in the anterior surface of the soft edge, and the seal ring and / or soft edge is modified with one or more integration agents.

[0008] In embodiments, the first crosslinked polymer comprises about 55% to about 90% by weight of PHEMA and about 1% to about 20% by weight of PMMA. In embodiments, the first crosslinked polymer comprises about 55% to about 95% by weight of PHEMA and about 1% to about 20% by weight of PMMA. In embodiments, the second crosslinked polymer comprises about 55% to about 90% by weight of PHEMA and about 1% to about 20% by weight of PMMA. In embodiments, the base membrane and / or seal ring is prepared by solvent casting, photo-crosslinking, electrospinning, or 3D printing. In embodiments, the crosslinked polymer is crosslinked by a crosslinking agent. In embodiments, the crosslinking agent is genipin; glyoxal; glutaraldehyde; EDTA; urea; tripolyphosphate; terephthalaldehyde; epichlorohydrin; camphorquinone; fluorescein; riboflavin; ruthenium; oxidized sucrose; ethylene glycol diglycidyl ether; 4,4’-methylenebis (phenyl isocyanate); pentasodium triphosphate; periodateoxi dized sucrose; an Fe(III) salt; a Cu(II) salt; 2-hydroxy-l-[4-(2-hydroxyethoxy)phenyl]-2- m ethyl- 1 -propanone; 1-hydroxy-cyclohexyl-phenyl-ketone; a, a-dimethoxy-alpha- phenyl acetophenone; 2-benzyl-2-(dimethylamino)-l-[4-(4-morpholinyl) phenyl]-l-butanone; 2-methyl-l-[4-(methylthio)phenyl]-2-(4-morpholinyl)-l-propanone; or a mixture thereof. In embodiments, the crosslinking agent is 2-hydroxy- 1-[4-(2 -hydroxy ethoxy )phenyl]-2-methyl- 1 -propanone. In embodiments, the first crosslinked polymer comprises about 70% by weight of PHEMA, and about 7% by weight of PMMA crosslinked with up to 1% by weight of divinyl benzene, or other crosslinkers. In embodiments, the first crosslinked polymer comprises about 92% by weight of PHEMA, and about 8% by weight of PMMA crosslinked with up to 1% by weight of divinyl benzene, or other crosslinkers. In embodiments, the second crosslinked polymer comprises about 70% by weight of PHEMA, and about 14% by weight of PMMA crosslinked with up to 1% by weight of divinyl benzene, or other crosslinkers. In embodiments, the second crosslinked polymer comprises about 85% by weight of PHEMA, and about 15% by weight of PMMA crosslinked with up to 1% by weight of divinyl benzene, or other crosslinkers. In embodiments, the second crosslinked polymer comprises about 80% by weight of PHEMA, and about 20% by weight of PMMA crosslinked with up to 1% by weight of divinyl benzene, or other crosslinkers.

[0009] In embodiments, the anti-fouling agent is a hydrophilic or zwitterionic molecule. In embodiments, the anti-fouling agent is polyethylene glycol, hyaluronic acid, phosphorylcholine, or a mixture thereof. In embodiments, the posterior surface of the base membrane is modified with the anti-fouling agent by dip-coating, extrusion printing, or ink-jetprinting. In embodiments, the anterior surface of the base membrane is modified with the antifouling agent by dip-coating, extrusion printing, or ink-jet printing.

[0010] In embodiments, the integration agent is hyaluronic acid, peptides, or extracellular matrix materials. In embodiments, the integration agent is collagen, laminin, or an RGD peptide. In embodiments, the perimeter of the base membrane is modified with the integration agent by extrusion, dip-coating, or ink-jet printing. In embodiments, the anterior surface of the base membrane is modified with the integration agent by extrusion, dip-coating, or ink-jet printing. In embodiments, the soft edge is modified with the integration agent by extrusion, dip-coating, or ink-jet printing.

[0011] In embodiments, the corneal implant transmits at least as much visible light as natural cornea (80% of 400 nm light) as determined by spectrophotometry according to ASTM DI 003- 21. In embodiments, the corneal implant transmits at least 85% of 500 nm light as determined by spectrophotometry according to ASTM DI 003 -21. In embodiments, the corneal implant presents a refractive index that approximates natural cornea as determined by ISO 18369-4. In embodiments, the tensile strength of the corneal implant is about 100 to about 3500 kPa as determined by ASTM D638 - 22. In embodiments, the nominal strain at break of the corneal implant is about 50% to about 150% as determined by ASTM D638 - 22. In embodiments, the elastic modulus of the corneal implant is about 100 to about 3500 kPa as determined by ASTM D638 - 22.

[0012] In embodiments, the corneal implant thickness is from about 0.2 mm to about 1 mm. In embodiments, the corneal implant diameter is from about 2 mm to about 10 mm. In embodiments, the radius of curvature of the anterior and posterior surface of the corneal implant is about 6 mm to about 8 mm.

[0013] In embodiments, the corneal implant thickness is about 0.5 mm, the corneal implant diameter is about 10 mm, the radius of curvature of the anterior surface is about 7.8 mm, and the radius of curvature of the posterior surface is about 6.5 mm. In embodiments, the seal ring has an inner lacuna. In embodiments, the seal ring diameter is 6-10 mm. In embodiments, the inner lacuna diameter is 3-7 mm. In embodiments, the seal ring width is between 1-3 mm. In embodiments, the seal ring thickness is 100-200 pm. In embodiments, (a) the first crosslinked polymer comprises 70% PHEMA, 7% PMMA, and 0.1 % divinyl benzene; and (b) the second crosslinked polymer comprises 70% PHEMA, 14% PMMA, and 0.1 % divinyl benzene. Inembodiments, (a) the first crosslinked polymer comprises about 92% PHEMA and about 8% PMMA by weight; and (b) the second crosslinked polymer comprises about 85% PHEMA and about 15% PMMA by weight. In embodiments, (a) the first crosslinked polymer comprises about 92% PHEMA and about 8% PMMA by weight; and (b) the second crosslinked polymer comprises about 80% PHEMA and about 20% PMMA by weight. In embodiments, (a) the first crosslinked polymer comprises about 92% PHEMA, about 8% PMMA, and about 0.1 % to about 0.3% divinyl benzene by weight; and (b) the second crosslinked polymer comprises about 80% PHEMA, about 20% PMMA, and about 0.1 % to about 0.3% divinyl benzene by weight.

[0014] In embodiments, the third crosslinked polymer comprises about 55% to about 90% by weight of PHEMA, about 1% to about 20% by weight of PMMA, and about 1% to about 20% by weight of PVP. In embodiments, the soft edge is prepared by solvent casting, photocrosslinking, electrospinning, or 3D printing. In embodiments, the third crosslinked polymer is crosslinked by a crosslinking agent. In embodiments, the crosslinking agent is genipin; glyoxal; glutaraldehyde; EDTA; urea; tripolyphosphate; terephthalaldehyde; epichlorohydrin; camphorquinone; fluorescein; riboflavin; ruthenium; oxidized sucrose; ethylene glycol diglycidyl ether; 4,4’-methylenebis (phenyl isocyanate); pentasodium triphosphate; periodateoxi dized sucrose; an Fe(III) salt; a Cu(II) salt; 2-hydroxy-l-[4-(2-hydroxyethoxy)phenyl]-2- m ethyl- 1 -propanone; 1-hydroxy-cyclohexyl-phenyl-ketone; a, a-dimethoxy-alpha- phenyl acetophenone; 2-benzyl-2-(dimethylamino)-l-[4-(4-morpholinyl) phenyl]-l-butanone; 2-methyl-l-[4-(methylthio)phenyl]-2-(4-morpholinyl)-l-propanone; or a mixture thereof. In embodiments, the crosslinking agent is 2-hydroxy- 1-[4-(2 -hydroxy ethoxy )phenyl]-2-methyl- 1 -propanone. In embodiments, the third crosslinked polymer comprises about 70% by weight of PHEMA, about 3.5% by weight of PMMA, and about 10% by weight of PVP crosslinked with up to 1% by weight of divinyl benzene, or other crosslinkers. In embodiments, the third crosslinked polymer comprises about 85% by weight of PHEMA, about 10% by weight of PMMA, and about 4% by weight of PVP crosslinked with up to about 1% by weight of divinyl benzene, or other crosslinkers.

[0015] In aspects, the present disclosure provides a method of making a corneal implant, the method comprising:(a) providing a base membrane comprising a first crosslinked polymer comprising poly(2-hydroxy ethyl methacrylate) (PHEMA), poly(methyl methacrylate) (PMMA), or a mixture thereof;(b) modifying the posterior surface and the anterior surface of the base membrane with one or more anti -fouling agents, and (c) modifying the perimeter of the base membrane with one or more integration agents; or(b) modifying the posterior surface of the base membrane with one or more anti -fouling agents, and (c) modifying the anterior surface and the perimeter of the base membrane with one or more integration agents; and(d) attaching a seal ring comprising a second crosslinked polymer to the posterior surface of the base membrane; wherein the second crosslinked polymer comprises PHEMA, PMMA, or a mixture thereof.

[0016] In aspects, the present disclosure provides a method of making a corneal implant, the method comprising:(a) providing a base membrane comprising a first crosslinked polymer comprising poly(2-hydroxy ethyl methacrylate) (PHEMA), poly(methyl methacrylate) (PMMA), or a mixture thereof;(b) modifying the posterior surface and / or anterior surface of the base membrane with one or more anti-fouling agents;(c) attaching a seal ring comprising a second crosslinked polymer to the anterior surface of the base membrane; wherein the second crosslinked polymer comprises PHEMA, PMMA, or a mixture thereof;(d) attaching a soft edge comprising a third crosslinked polymer to the perimeter of the base membrane; wherein the third crosslinked polymer comprises PHEMA, PMMA, PVP, or a mixture thereof; and(e) modifying the soft edge with one or more integration agents.

[0017] In embodiments, the base membrane, the seal ring, and / or soft edge are prepared by solvent casting. In embodiments, the posterior surface and / or the anterior surface of the basemembrane is modified with the anti-fouling agent by ink-jet, dip-coating, or extrusion printing. In embodiments, the perimeter and / or anterior surface of the base membrane or the perimeter of the soft edge is modified with the integration agent by extrusion or ink-jet printing.

[0018] In aspects, disclosed herein is a method of replacing a cornea or sclera of a patient in need thereof, the method comprising: (a) removing the damaged or diseased portion of the patient’s cornea; and (b) inserting a corneal implant of the present disclosure. In embodiments the corneal implant is inserted by suturing the corneal implant to the patient’s corneal rim.BRIEF DESCRIPTION OF FIGURES

[0019] FIG. 1A- FIG. IB show an artificial cornea of the present disclosure. In FIG. 1A the top arrow points to an optically transparent lens, and the bottom arrow points to the base membrane where integration agents can be added. FIG. IB shows another view of the artificial cornea.

[0020] FIG. 2 shows an example of an artificial cornea of the present disclosure. The artificial cornea includes a base membrane that consists of a crosslinked poly(2-hydroxyelthyl methacrylate) (PHEMA)-poly(methyl methacrylate) (PMMA) membrane (1). Surface modifications are added to the anterior (2) and posterior (3) surfaces of the membrane to maintain optical clarity. A surface modification is added to the edge (4) of the membrane to enable its integration with the adjacent cornea tissue.

[0021] FIG. 3 depicts the suturing of an artificial cornea of the present disclosure.

[0022] FIG. 4A-FIG. 4C depict the mold to create the membrane (FIG. 4A) and a membrane after removal from the mold (FIG. 4B). FIG. 4C depicts a 6.5 mm diameter base membrane cut out of membrane once it was removed from the mold.

[0023] FIG. 5 shows the optical clarity of base membranes comprising different polymer formulations.

[0024] FIG. 6A-FIG. 6B show the mechanical strength of base membranes comprising different polymer formulations. FIG. 6A depicts the stress vs strain curves of the different polymer formulations. FIG. 6B depicts the mechanical testing apparatus.

[0025] FIG. 7 depicts cell growth on base membranes.

[0026] FIG. 8A-FIG. 8D. show SEM images of a PHEMA / PMMA membrane that was modified with collagen type-1. FIG. 8A and FIG. 8B show an unmodified PHEMA / PMMA membrane at a 20-micron field view and a 100-micron field view, respectively. FIG. 8C andFIG. 8D show a collagen -type 1 modified PHEMA / PMMA membrane with a 5 -micron and 1- micron field view, respectively.

[0027] FIG. 9A-FIG. 9C show the XPS analysis of peptides bound to PHEMA / PMMA membranes. FIG. 9A depicts an unmodified PHEMA / PMMA membrane, FIG. 9B shows an RGD-modified PHEMA / PMMA membrane, and FIG. 9C shows a collagen type 1 -modified PHEMA / PMMA membrane.

[0028] FIG. 10A-FIG. 10D show the Cis and Nls spectrum of either an RGD-modified or a collagen type-1 modified PHEMA / PMMA membrane. FIG.10A and FIG. 10B show the Cis and the Nls spectrum of the RGD-modified PHEMA / PMMA membrane, respectively. FIG.10C and FIG. 10D show the Cis and the Nls spectrum of the collagen type-1 modified PHEMA / PMMA membrane, respectively.

[0029] FIG. 11A-FIG. 11B show the seal ring attached to the base membrane. FIG. HA shows the posterior view of the base membrane and possible dimensions for the seal ring. FIG. 11B shows the side view of the base membrane with the seal ring attached to the posterior side of the base membrane.

[0030] FIG. 12A-FIG. 12B show the seal ring and soft edge attached to the base membrane. FIG. 12A shows the anterior view of the base membrane surrounded by the seal ring, which is surrounded by the soft edge. The seal ring comprises holes to guide the needle for suturing. FIG. 12B shows the side view of the base membrane with the seal ring and soft edges attached to the base membrane.

[0031] FIG. 13A-FIG.13C show the seal ring (SIR) and soft edge (outer skirt) attached to the base membrane. FIG. 13A shows the anterior view (left) and cross-sectional view (right) of the base membrane surrounded by the seal ring (SIR), which is surrounded by the soft edge (outer skirt). The seal ring comprises inner lacuna to guide the needle for suturing. FIG. 13B and FIG. 13C show the cross-sectional view of the seal rings with exemplary inner lacuna configurations, as described in Example 4.DETAILED DESCRIPTIONDefinitions:

[0032] The terms used in this specification generally have their ordinary meaning in the art, within the context of this disclosure and in the specific context where each term is used. Certain terms are discussed below or elsewhere in the specification, to provide additional guidance to the practitioner in describing the compositions and methods of the disclosure and how to makeand use them. The scope and meaning of any use of a term will be apparent from the specific context in which the term is used. As such, the definitions set forth herein are intended to provide illustrative guidance in ascertaining particular embodiments of the disclosure, without limitation to particular compositions or biological systems. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety for all purposes.

[0033] The term “about” when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value). For example, “about 50” can mean 45 to 55, “about 25,000” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example, in a list of numerical values such as “about 49, about 50, about 55, ...”, “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 52.5. Furthermore, the phrases “less than about” a value or “greater than about” a value should be understood in view of the definition of the term “about” provided herein. Similarly, the term “about” when preceding a series of numerical values or a range of values (e.g., “about 10, 20, 30” or “about 10-30”) refers, respectively to all values in the series, or the endpoints of the range.Corneal Implant

[0034] The present disclosure provides cornea implants. In embodiments, the cornea implants disclosed herein are used to replace natural corneas that become ineffective, or whose effectiveness has become compromised. The corneal implants of the present disclosure include a seal ring and a base membrane. The seal ring is both transparent and harder to pierce (e.g., with a suturing needle) than the base membrane. Thus, the seal ring can guide the needle into the patient’s skin to assist in suturing. The corneal implants of the present disclosure further include a soft edge that provides a seal between the implant and the adjacent host cornea tissue.

[0035] In aspects, the corneal implants of the present disclosure comprise a base membrane that is a first crosslinked polymer comprising: poly(2-hydroxyethyl methacrylate) (PHEMA), poly(methyl methacrylate) (PMMA), or mixture thereof, and a crosslinking agent; where the posterior surface and / or anterior surface of the base membrane is modified with one or more anti-fouling agents; wherein the anterior surface and / or the perimeter of the base membrane is modified with one or more integration agents; and wherein the corneal implant further comprises a seal ring that comprises a second crosslinked polymer comprising: poly (2- hydroxyethyl methacrylate) (PHEMA), poly(methyl methacrylate) (PMMA), or mixturethereof and a crosslinking agent. In embodiments, the corneal implant is hydrolytically stable. In embodiments, the corneal implant is not immunoreactive. In embodiments, the corneal implant further comprises a soft edge comprising a third crosslinked polymer that comprises: poly(2-hydroxyethyl methacrylate) (PHEMA), poly(methyl methacrylate) (PMMA), PVP or mixture thereof and a crosslinking agent.

[0036] In embodiments, the present disclosure provides a corneal implant comprising a base membrane, a seal ring, and a soft edge. In embodiments, the base membrane of the corneal implant comprises a first crosslinked polymer comprising poly(2-hydroxyethyl methacrylate) (PHEMA), poly(methyl methacrylate) (PMMA), or a mixture thereof. In embodiments, the seal ring of the corneal implant comprises a second crosslinked polymer comprising PHEMA, PMMA, or a mixture thereof, and is attached to the anterior surface of the base membrane. In embodiments, the seal ring of the corneal implant is embedded in the anterior surface of the base membrane. In embodiments, the soft edge of the corneal implant comprises a third crosslinked polymer comprising PHEMA, PMMA, polyvinylpyrrolidone (PVP), or a mixture thereof.

[0037] In embodiments, the posterior surface of the base membrane is modified with one or more anti-fouling agents. In embodiments, the anterior surface of the base membrane is modified with one or more anti-fouling agents. In embodiments, the posterior and anterior surfaces of the base membrane are modified with one or more anti-fouling agents. In embodiments, the seal ring is attached to the anterior surface or posterior surface of the base membrane and is modified with one or more anti-fouling agents or integration agents. In embodiments, the soft edge is modified with one or more integration agents.

[0038] In embodiment, the seal ring is attached to the anterior surface of the soft edge. In embodiment, the seal ring is embedded within the anterior surface of the soft edge. In embodiments, the seal ring comprises one or more lacuna (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more). In embodiments, the seal ring is embedded in or attached to the anterior surface of the soft edge, and the lacuna (also referred to as “suture hole”) is configured to penetrate the full thickness of the corneal implant. In embodiments, the seal ring is embedded in or attached to the anterior surface of the soft edge, and the lacuna is configured to penetrate a partial thickness of the corneal implant.

[0039] In embodiments, the corneal implant thickness is from about 0.2 mm to about 1 mm. In embodiments, the corneal implant thickness is from about 0.1 mm to about 1 mm, includingabout 0.1 mm, about 0.15 mm, about 0.2 mm, about 0.25 mm, about 0.3 mm, about 0.35 mm, about 0.4 mm, about 0.45 mm, about 0.5 mm, about 0.55 mm, about 0.6 mm, about 0.65 mm, about 0.7 mm, about 0.75 mm, about 0.8 mm, about 0.85 mm, about 0.9 mm, about 0.95 mm, or about 1 mm, including all values and ranges therebetween. In embodiments, the corneal implant thickness is about 0.5 mm to about 1 mm. In embodiments, the corneal implant thickness is about 0.3 mm.

[0040] In embodiments, the corneal implant diameter is from about 2 mm to about 10 mm. In embodiments, the corneal implant diameter is from about 1 mm to about 10 mm, including about 1 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3 mm, about 3.5 mm, about 4 mm, about 4.5 mm, about 5mm, about 5.5 mm, about 6 mm, about 6.5 mm, about 7 mm, about 7.5 mm, about 8 mm, about 8.5 mm, about 9 mm, about 9.5 mm, or about 10 mm, including all values and ranges therebetween. In embodiments, the corneal implant diameter is about 6 mm to about 10 mm. In embodiments, the corneal implant diameter is about 8.75 mm.

[0041] In embodiments, the radius of curvature of the anterior and posterior surface of the corneal implant is about 4 mm to about 10 mm, including about 4 mm, about 5 mm, about 6 mm, about 7 mm, about 8 mm, about 9 mm, or about 10 mm, including all values and ranges therebetween. In embodiments, the radius of curvature of the anterior and posterior surface of the corneal implant is about 6 mm to about 10 mm.

[0042] In embodiments, the radius of curvature of the anterior surface is about 6 mm to about 12 mm, including about 6 mm, about 7 mm, about 8 mm, about 9 mm, about 10 mm, about 11 mm, or about 12 mm, including all values and ranges therebetween. In embodiments, the radius of curvature of the anterior surface is about 8 mm to about 10 mm.

[0043] In embodiments, the radius of curvature of the posterior surface is about 6 mm to about 12 mm, including about 6 mm, about 7 mm, about 8 mm, about 9 mm, about 10 mm, about 11 mm, or about 12 mm, including all values and ranges therebetween. In embodiments, the radius of curvature of the posterior surface is about 7 mm to about 10 mm.Base Membrane and First Crosslinked Polymer

[0044] The base membrane comprises a first crosslinked polymer.

[0045] In embodiments, the first crosslinked polymer comprises 25%-90% of PHEMA by weight. In embodiments, the first crosslinked polymer comprises 30%-90% of PHEMA byweight. In embodiments, the first crosslinked polymer comprises 35%-90% of PHEMA by weight. In embodiments, the first crosslinked polymer comprises 40%-85% of PHEMA by weight. In embodiments, the first crosslinked polymer comprises 45%-85% of PHEMA by weight. In embodiments, the first crosslinked polymer comprises 50%-80% of PHEMA by weight. In embodiments, the first crosslinked polymer comprises 55%-75% of PHEMA by weight. In embodiments, the first crosslinked polymer comprises 60%-75% of PHEMA by weight. In embodiments, the first crosslinked polymer comprises 65%-75% of PHEMA by weight. In embodiments, the first crosslinked polymer comprises 70%-75% of PHEMA by weight. In embodiments, the first crosslinked polymer comprises 70% of PHEMA by weight.

[0046] In embodiments, the first crosslinked polymer comprises PHEMA at about 40% to about 95%, including about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 82%, about 84%, about 85%, about 86%, about 88%, about 90%, about 91%, about 92%, about 93%, about 94%, or about 95%, including all values and ranges therebetween, by weight. In embodiments, the first crosslinked polymer comprises about 70% of PHEMA by weight. In embodiments, the first crosslinked polymer comprises about 92% of PHEMA by weight.

[0047] In embodiments, the first crosslinked polymer comprises l%-20% of PMMA. In embodiments, the first crosslinked polymer comprises 1%-19% of PMMA by weight. In embodiments, the first crosslinked polymer comprises 2%-18% of PMMA by weight. In embodiments, the first crosslinked polymer comprises 3%-15% of PMMA by weight. In embodiments, the first crosslinked polymer comprises 4%-14% of PMMA by weight. In embodiments, the first crosslinked polymer comprises 5%-14% of PMMA by weight. In embodiments, the first crosslinked polymer comprises 7%-12% of PMMA by weight. In embodiments, the first crosslinked polymer comprises 7%-l 1% of PMMA by weight. In embodiments, the first crosslinked polymer comprises 7%-10% of PMMA by weight.

[0048] In embodiments, the first crosslinked polymer comprises 7% of PMMA by weight. In embodiments, the first crosslinked polymer comprises 3.5% PMMA by weight.

[0049] In embodiments, the first crosslinked polymer comprises about l%-30% of PMMA by weight. In embodiments, the first crosslinked polymer comprises PMMA at about 1% to about30%, including about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about8%, about 8.5%, about 9%, about 9.5%, about 10%, about 10.5%, about 11%, about 11.5%, about 12%, about 12.5%, about 13%, about 13.5%, about 14%, about 14.5%, about 15%, about15.5%, about 16%, about 16.5%, about 17%, about 17.5%, about 18%, about 18.5%, about19%, about 19.5%, about 20%, about 20%, about 20.5%, about 21%, about 21.5%, about 22%, about 22.5%, about 23%, about 23.5%, about 24%, about 24.5%, about 25%, about 25.5%, about 26%, about 26.5%, about 27%, about 27.5%, about 28%, about 28.5%, about 29%, about 29.5%, or about 30% by weight, including all values and ranges therebetween.

[0050] In embodiments, the first crosslinked polymer comprises about 8% of PMMA by weight.

[0051] In embodiments, the first crosslinked polymer is prepared by thermal crosslinking. In embodiments, the crosslinking is mediated through radiation. In embodiments, the crosslinking is mediated through light. In embodiments, the first crosslinked polymer is chemically crosslinked.

[0052] In embodiments, the first crosslinked polymer is crosslinked by a crosslinking agent. In embodiments, the crosslinking agent is referred to as a crosslinker. In embodiments, the crosslinking agent is selected from genipin; glyoxal; glutaraldehyde; EDTA; urea; tripolyphosphate; terephthalaldehyde; epichlorohydrin; camphorquinone; fluorescein; riboflavin; ruthenium; oxidized sucrose; ethylene glycol dimethacrylate; pentaerythritol tetraacrylate; divinyl benzene; ethylene glycol diglycidyl ether; 4,4’-methylenebis (phenyl isocyanate); pentasodium triphosphate; periodate-oxidized sucrose; an Fe(III) salt; a Cu(II) salt; 2-hydroxy-l-[4-(2-hydroxyethoxy)phenyl]-2-methyl-l-propanone (referred to as “Irgacure 2959”); 1-hydroxy-cyclohexyl-phenyl-ketone (referred to as “Irgacure 184”); a, a- dimethoxy-alpha-phenylacetophenone (referred to as “Irgacure 651”); 2-benzyl-2- (dimethylamino)-l-[4-(4-morpholinyl) phenyl] -1-butanone (referred to as “Irgacure 369”); 2- methyl-l-[4-(methylthio)phenyl]-2-(4-morpholinyl)-l-propanone (referred to as “Irgacure 907”); Lithium phenyl-2,4,6-trimethylbenzoylphosphinate; methacrylic acid; glycidyl methacrylate; l-vinyl-2-pyrrolidinone; or a mixture thereof.

[0053] In embodiments, the crosslinking agent is 2-hydroxy-l-[4-(2-hydroxyethoxy)phenyl]- 2-methyl-l -propanone.

[0054] In embodiments, the crosslinking agent is divinyl benzene.

[0055] In embodiments, the crosslinking agent is ethylene glycol dimethacrylate.

[0056] In embodiments, the crosslinking agent is added to the first crosslinked polymer at a concentration of between 1 pg / mL and 1000 pg / mL of polymer. In embodiments, the crosslinking agent is added to the first crosslinked polymer at a concentration of between 5 pg / mL and 500 pg / mL of polymer. In embodiments, the crosslinking agent is added to the first crosslinked polymer at a concentration of between 10 pg / mL and 250 pg / mL of polymer. In embodiments, the crosslinking agent is added to the first crosslinked polymer at a concentrationof between 20 pg / mL and 200 pg / mL of polymer. In embodiments, the crosslinking agent is added to the first crosslinked polymer at a concentration of between 25 pg / mL and 175 pg / mL of polymer. In embodiments, the crosslinking agent is added to the first crosslinked polymer at a concentration of between 40 pg / mL and 150 pg / mL of polymer. In embodiments, the crosslinking agent is added to the first crosslinked polymer at a concentration of between 50 pg / mL and 125 pg / mL of polymer. In embodiments, the crosslinking agent is added to the first crosslinked polymer at a concentration of between 75 pg / mL and 100 pg / mL of polymer. In embodiments, the crosslinking agent is added to the first crosslinked polymer at a concentration of between 80 pg / mL and 95 pg / mL of polymer.

[0057] In embodiments, the crosslinking agent is added to the first crosslinked polymer at a weight percent of the crosslinked polymer of 0.001%-5%. In embodiments, the crosslinking agent is added to the first crosslinked polymer at a weight percent of the crosslinked polymer of 0.005%-4%. In embodiments, the crosslinking agent is added to the first crosslinked polymer at a weight percent of the crosslinked polymer of 0.01%-3%. In embodiments, the crosslinking agent is added to the first crosslinked polymer at a weight percent of the crosslinked polymer of 0.05%-5%. In embodiments, the crosslinking agent is added to the first crosslinked polymer at a weight percent of the crosslinked polymer of 0.1%-4%. In embodiments, the crosslinking agent is added to the first crosslinked polymer at a weight percent of the crosslinked polymer of 0.1%-4%. In embodiments, the crosslinking agent is added to the first crosslinked polymer at a weight percent of the crosslinked polymer of 0.5%-4%. In embodiments, the crosslinking agent is added to the first crosslinked polymer at a weight percent of the crosslinked polymer of about 0.1%. In embodiments, the crosslinking agent is added to the first crosslinked polymer at a weight percent of the crosslinked polymer of about 0.1% to about 0.3%. In embodiments, the crosslinking agent is added to the first crosslinked polymer at a weight percent of the crosslinked polymer of about 0.3%.

[0058] In embodiments, the first crosslinked polymer comprises about 0.1%-l% by weight of divinyl benzene.

[0059] In embodiments, a plasticizer is added to the first crosslinked polymer.

[0060] In embodiments, the first crosslinked polymer has an increase in plasticity as compared to the non-crosslinked polymer.

[0061] In embodiments, the thickness of the base membrane is 0.1-5 mm. In embodiments, the thickness of the base membrane is 0.2-4 mm. In embodiments, the thickness of the base membrane is 0.3-3 mm. In embodiments, the thickness of the base membrane is 0.4-2 mm. In embodiments, the thickness of the base membrane is 0.5-1 mm.

[0062] In embodiments, the diameter of the base membrane is 0.5-20 mm. In embodiments, the diameter of the base membrane is 0.75-15 mm. In embodiments, the diameter of the base membrane is 1-13 mm across. In embodiments, the diameter of the base membrane is 2-11 mm across. In embodiments, the base membrane is circular.

[0063] In embodiments, the radius of the curvature of the base membrane between the anterior and posterior surface is 1-10 mm. In embodiments, the radius of the curvature of the base membrane between the anterior and posterior surface is 2-9 mm. In embodiments, the radius of the curvature of the base membrane between the anterior and posterior surface is 4-8 mm. In embodiments, the radius of the curvature of the base membrane between the anterior and posterior surface is 5-7 mm. In embodiments, the radius of the curvature of the base membrane between the anterior and posterior surface is 6-7 mm.

[0064] In embodiments, the radius of the curvature of the base membrane between the anterior and posterior surface is about 5 mm to about 12 mm, including about 5 mm, about 6 mm, about 7 mm, about 8 mm, about 9 mm, about 10 mm, about 11 mm, or about 12 mm, including all values and ranges therebetween.

[0065] In embodiments, the curvature of the anterior surface of the base membrane is 5-15 mm. In embodiments, the curvature of the anterior surface of the base membrane has a curvature of 6-12 mm. In embodiments, the curvature of the anterior surface of the base membrane has a curvature of 7-11 mm. In embodiments, the curvature of the anterior surface of the base membrane has a curvature of 7-10 mm. In embodiments, the curvature of the anterior surface of the base membrane has a curvature of 7-8 mm. In embodiments, the curvature of the anterior surface of the base membrane has a curvature of 7.8 mm. In embodiments, the radius of the curvature of the anterior surface of the base membrane is about 5 mm to about 12 mm, including about 5 mm, about 6 mm, about 7 mm, about 8 mm, about 9 mm, about 10 mm, about 11 mm, or about 12 mm, including all values and ranges therebetween. In embodiments, the curvature of the anterior surface of the base membrane has a curvature of about 8 mm to about 10 mm.

[0066] In embodiments, the curvature of the posterior surface of the base membrane has a curvature of 5-15 mm. In embodiments, the curvature of the posterior surface of the base membrane has a curvature of 6-12 mm. In embodiments, the curvature of the posterior surface of the base membrane has a curvature of 6-11 mm. In embodiments, the curvature of the posterior surface of the base membrane has a curvature of 6-10 mm. In embodiments, the curvature of the posterior surface of the base membrane has a curvature of 6-7 mm. In embodiments, the posterior surface of the base membrane has a curvature of 6.5 mm. Inembodiments, the radius of the curvature of the posterior surface of the base membrane is about 5 mm to about 12 mm, including about 5 mm, about 6 mm, about 7 mm, about 8 mm, about 9 mm, about 10 mm, about 11 mm, or about 12 mm, including all values and ranges therebetween. In embodiments, the curvature of the posterior surface of the base membrane has a curvature of about 7 mm to about 10 mm.

[0067] In embodiments, an integration agent is added to the base membrane. In embodiments, these integration agent helps with adhesion of the base membrane to the subject. In embodiments, the integration agent is hyaluronic acid. In embodiments, the integration agent comprises one or more peptides. In embodiments, the peptide is an arginine, glycine, and aspartic acid (RGD) peptide. In embodiments, the peptide is a tyrosine, isoleucine, glycine, serine, and arginine (YIGSR (SEQ ID NO: 1)) peptide. In embodiments, the peptide is an arginine, glycine, aspartic acid, and serine (RGDS (SEQ ID NO: 2)) peptide. In embodiments, the peptide is a proline, aspartic acid, serine, glycine, and arginine (PDSGR (SEQ ID NO: 3)) peptide. In embodiments, the peptide is a proline, histidine, serine, arginine, and asparagine (PHSRN (SEQ ID NO: 4)) peptide. In embodiments, the integration agent comprises an RGD peptide, a YIGSR peptide (SEQ ID NO: 1), a PDSGR peptide (SEQ ID NO: 2), a PHSRN peptide (SEQ ID NO: 4), or a mixture thereof. In embodiments, the integration agent is collagen. In embodiments, the integration agent is type-1 collagen.

[0068] In embodiments, the perimeter (or edge) of the base membrane is modified (e.g., coated, polymerized, crosslinked, functionalized, activated) with an integration agent. In embodiments, the integration agents are conjugated to the perimeter of the base membrane. In embodiments, the integration agents are adsorbed on the perimeter of the base membrane. In embodiments, the integration agents are absorbed into the perimeter of the base membrane. In embodiments, the peptides are linked to the perimeter of the base membrane.

[0069] In embodiments, the integration agents are added to the anterior side of the base membrane. In embodiments, the integration agents are conjugated to the anterior surface of the base membrane. In embodiments, the integration agents are adsorbed on the anterior surface of the base membrane. In embodiments, the integration agents are absorbed into the anterior surface of the base membrane. In embodiments, the peptides are linked to the anterior surface of the base membrane. In embodiments, the anterior surface and the perimeter of the base membrane are modified (e.g., coated, polymerized, crosslinked, functionalized, activated) with one or more integration agents.

[0070] In embodiments, the base membrane fuses to the surrounding cornea tissue. In embodiments, there is a seal between the corneal implant and the surrounding cornea tissue.

[0071] In embodiments, the base membrane comprises an antifouling agent. In embodiments, the antifouling agent is zwitterionic. In embodiments, the antifouling agent is PEG. In embodiments, the PEG is functionalized. In embodiments, the antifouling agent is phosphorylcholine. In embodiments, the antifouling agent is a mixture of PEG and phosphorylcholine. In embodiments, the antifouling agent is conjugated to the base membrane. In embodiments, the antifouling agent is covalently linked to the base membrane. In embodiments, the antifouling agent is adsorbed on the surface of the base membrane. In embodiments, the antifouling agent is absorbed into the base membrane. In embodiments, the antifouling agent is added to the posterior and / or anterior surface of the base membrane.

[0072] In embodiments, the surface of the base membrane is modified (e.g., coated, polymerized, crosslinked, functionalized, activated) with one or more anti-fouling agents. In embodiments, the modification of the surface of the base membrane with the one or more antifouling agents reduces adhesion of environmental or biological agents to the surface. In embodiments, the environmental or biological agents are proteins or cells. In embodiments, the coating of the surface of the base membrane with the one or more antifouling agents reduces protein adhesion or accumulation on the surface of the base membrane. In embodiments, the coating of the surface of the base membrane maintains the optical clarity of the membrane for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, or 24 weeks.

[0073] In embodiments, the posterior surface of the base membrane is modified with one or more anti-fouling agents. In embodiments, the modified posterior surface of the base membrane comprises PEG surface modification. In embodiments, the posterior surface of the base membrane is modified with hyaluronic acid (HA).

[0074] In embodiments, the posterior and anterior surfaces of the base membrane are modified with one or more anti-fouling agents, and the perimeter of the base membrane is modified with one or more integration agents. In embodiments, the posterior and anterior surfaces of the base membrane are modified with PEG surface modification and coated with HA, and the perimeter of the base membrane is modified with collagen and / or any one of peptides selected from RGD peptide, RGDS peptide, YIGSR peptide, PDSGR peptide, PHSRN peptide, or a combination thereof.

[0075] In embodiments, the posterior surface of the base membrane is modified with one or more anti-fouling agents, and the anterior surface and perimeter of the base membrane are modified with one or more integration agents. In embodiments, the posterior surface of the base membrane is modified with PEG surface modification and HA, and the anterior surface and perimeter of the base membrane are modified with collagen, laminin, and / or any one ofpeptides selected from RGD peptide, RGDS peptide, YIGSR peptide, PDSGR peptide, PHSRN peptide, or a combination thereof. In embodiments the base membrane comprises an antibacterial agent. In embodiments, the antibacterial is selected from curcumin (Cur) or zinc oxide nanoparticles (ZnO). In embodiments, the antibacterial is added to the first crosslinked polymer before the crosslinked polymer is crosslinked. In embodiments, the antibacterial is added to the first crosslinked polymer after the crosslinked polymer is crosslinked.

[0076] In embodiments, the base membrane is modified by dip-coating. In embodiment the base membrane is modified by ink-jet printing. In embodiments, the base membrane is modified by extrusion printing.

[0077] In embodiments, the base membrane is functionalized by dip-coating. In embodiment the base membrane is functionalized by ink-jet printing. In embodiments, the base membrane is functionalized by extrusion printing.

[0078] In embodiments, the tensile strength of the base membrane is between 10 and 35000 kPa as measured by ASTM D638-10. In embodiments, the tensile strength of the base membrane is between 100 and 25000 kPa as measured by ASTM D638-10. In embodiments, the tensile strength of the base membrane is between 200 and 20000 kPa as measured by ASTM D638-10. In embodiments, the tensile strength of the base membrane is between 500 and 15000 kPa as measured by ASTM D638-10. In embodiments, the tensile strength of the base membrane is between 750 and 10000 kPa as measured by ASTM D638-10. In embodiments, the tensile strength of the base membrane is between 100 and 3500 kPa as measured by ASTM D638-10.

[0079] In embodiments, the allowable strain of the base membrane is between 15-200% as measured by ASTM D638-10. In embodiments, the allowable strain of the base membrane is between 25-175% as measured by ASTM D638-10. In embodiments, the allowable strain of the base membrane is between 50-150% as measured by ASTM D638-10.

[0080] In embodiments, the elastic modulus of the base membrane is 1-20 mPa as measured by ASTM D638-10. In embodiments, the elastic modulus of the base membrane is 2-18 mPa as measured by ASTM D638-10. In embodiments, the elastic modulus of the base membrane is 3-16 mPa as measured by ASTM D638-10. In embodiments, the elastic modulus of the base membrane is 5-15 mPa as measured by ASTM D638-10.

[0081] In embodiments, the base membrane is able to withstand UV degradation to the structure and function of the base membrane for 6 months as measured by ASTM G154.

[0082] In embodiments, the change in the mechanical strength of the base membrane after 6 months of use is less than 20% as compared to the mechanical strength of the base membranewhen the base membrane was initially transplanted into the subject. In embodiments, the change in the mechanical strength of the base membrane after 6 months of use is less than 10% as compared to the mechanical strength of the base membrane when the base membrane was initially transplanted into the subject. In embodiments, the change in the mechanical strength of the base membrane after 6 months of use is less than 5% as compared to the mechanical strength of the base membrane when the base membrane was initially transplanted into the subject.

[0083] In embodiments, the change in the transparency of the base membrane after 6 months of use is less than 20% as compared to the transparency of the base membrane when the base membrane was initially transplanted into the subject. In embodiments, the change in the transparency of the base membrane after 6 months of use is less than 10% as compared to the transparency of the base membrane when the base membrane was initially transplanted into the subject. In embodiments, the change in the transparency of the base membrane after 6 months of use is less than 5% as compared to the transparency of the base membrane when the base membrane was initially transplanted into the subject.

[0084] In embodiments, the change in mass transport through the base membrane after 6 months is less than 20% as compared to the mass transport through the base membrane when the base membrane was initially transplanted into the subject. In embodiments, the change in mass transport through the base membrane after 6 months is less than 10% as compared to the mass transport through the base membrane when the base membrane was initially transplanted into the subject. In embodiments, the change in mass transport through the base membrane after 6 months is less than 5% as compared to the mass transport through the base membrane when the base membrane was initially transplanted into the subject.

[0085] In embodiments, the hydrolytic degradation of the base membrane after 6 months is less than 20% as compared to the base membrane when the base membrane was initially transplanted into the subject. In embodiments, the hydrolytic degradation of the base membrane after 6 months is less than 10% as compared to the base membrane when the base membrane was initially transplanted into the subject. In embodiments, the hydrolytic degradation of the base membrane after 6 months is less than 5% as compared to the base membrane when the base membrane was initially transplanted into the subject. In embodiments, Mass transport is calculated by ([Mwet - Mdry] / Mwet) x 100; wherein "M = mass."

[0086] In embodiments, the transmittance of light at 400-700nm through the base membrane is greater than 60%. In embodiments, the transmittance of light at 400-700nm through the basemembrane is greater than 70%. In embodiments, the transmittance of light at 400-700nm through the base membrane is greater than, or equal to, 80%.

[0087] In embodiments, after the antifouling agent is added to the base membrane the optical transmittance of light at 400-700 nm is greater than 60%. In embodiments, after the antifouling agent is added to the base membrane the optical transmittance of light at 400-700 nm is greater than 70%. In embodiments, after the antifouling agent is added to the base membrane the optical transmittance of light at 400-700 nm is greater than, or equal to, 80%.

[0088] In embodiments, the base membrane prevents transmittance of light at 240-400 nm. In embodiments, the transmittance of light at 240-400 nm is less than 30%. In embodiments, the transmittance of light at 240-400 nm is less than 20%. In embodiments, the transmittance of light at 240-400 nm is less than 10%. In embodiments, the transmittance of light at 240-400 nm is less than 5%.

[0089] In embodiments, the base membrane has a refractive index of greater than 1. In embodiments, the refractive index of the base membrane is 1-2. In embodiments, the refractive index of the base membrane is 1-1.5. In embodiments, the refractive index of the base membrane is 1.3-1.4.Seal Ring and Second Crosslinked Polymer

[0090] The seal ring (or “suture impenetrable ring” or “hard ring”) comprises a second crosslinked polymer.

[0091] In embodiments, the second crosslinked polymer comprises 25%-90% of PHEMA by weight. In embodiments, the second crosslinked polymer comprises 30%-90% of PHEMA by weight. In embodiments, the second crosslinked polymer comprises 35%-90% of PHEMA by weight. In embodiments, the second crosslinked polymer comprises 40%-85% of PHEMA by weight. In embodiments, the second crosslinked polymer comprises 45%-85% of PHEMA by weight. In embodiments, the second crosslinked polymer comprises 50%-80% of PHEMA by weight. In embodiments, the second crosslinked polymer comprises 55%-75% of PHEMA by weight. In embodiments, the second crosslinked polymer comprises 60%-75% of PHEMA by weight. In embodiments, the second crosslinked polymer comprises 65%-75% of PHEMA by weight. In embodiments, the second crosslinked polymer comprises 70%-75% of PHEMA by weight. In embodiments, the second crosslinked polymer comprises 70% of PHEMA by weight.

[0092] In embodiments, the second crosslinked polymer comprises PHEMA at about 40% to about 90%, including about 40%, about 45%, about 50%, about 55%, about 60%, about 65%,about 70%, about 75%, about 80%, about 82%, about 84%, about 85%, about 86%, about 88%, or about 90% by weight, including all values and ranges therebetween. In embodiments, the second crosslinked polymer comprises about 70% of PHEMA by weight. In embodiments, the second crosslinked polymer comprises about 85% of PHEMA by weight. In embodiments, the second crosslinked polymer comprises about 80% of PHEMA by weight.

[0093] In embodiments, the second crosslinked polymer comprises l%-20% of PMMA. In embodiments, the second crosslinked polymer comprises 1%-19% of PMMA by weight. In embodiments, the second crosslinked polymer comprises 2%-18% of PMMA by weight. In embodiments, the second crosslinked polymer comprises 3%-15% of PMMA by weight. In embodiments, the second crosslinked polymer comprises 4%-15% of PMMA by weight. In embodiments, the second crosslinked polymer comprises 5%-15% of PMMA by weight. In embodiments, the second crosslinked polymer comprises 8%-15% of PMMA by weight. In embodiments, the second crosslinked polymer comprises 10%-l 5% of PMMA by weight. In embodiments, the second crosslinked polymer comprises 12%-15% of PMMA by weight. In embodiments, the second crosslinked polymer comprises 14% of PMMA by weight. In embodiments, the second crosslinked polymer comprises 15% of PMMA by weight.

[0094] In embodiments, the second crosslinked polymer comprises 20% of PMMA by weight.

[0095] In embodiments, the second crosslinked polymer comprises about l%-30% of PMMA by weight. In embodiments, the second crosslinked polymer comprises PMMA at about 1% to about 30%, In embodiments, the second crosslinked polymer comprises about l%-30% of PMMA by weight. In embodiments, the second crosslinked polymer comprises PMMA at about 1% to about 30%, including about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, about 10%, about 10.5%, about 11%, about 11.5%, about 12%, about 12.5%, about 13%, about 13.5%, about 14%, about 14.5%, about 15%, about 15.5%, about 16%, about 16.5%, about 17%, about 17.5%, about 18%, about 18.5%, about 19%, about 19.5%, about 20%, about 20%, about 20.5%, about 21%, about 21.5%, about 22%, about 22.5%, about 23%, about 23.5%, about 24%, about 24.5%, about 25%, about 25.5%, about 26%, about 26.5%, about 27%, about 27.5%, about 28%, about 28.5%, about 29%, about 29.5%, or about 30% by weight, including all values and ranges therebetween.

[0096] In embodiments, the second crosslinked polymer is prepared by thermal crosslinking. In embodiments, the crosslinking is mediated through radiation. In embodiments, thecrosslinking is mediated through light. In embodiments, the second crosslinked polymer is chemically crosslinked.

[0097] In embodiments, the second crosslinked polymer is crosslinked by a crosslinking agent. In embodiments, the crosslinking agent is referred to as a crosslinker. In embodiments, the crosslinking agent is selected from genipin; glyoxal; glutaraldehyde; EDTA; urea; tripolyphosphate; terephthalaldehyde; epichlorohydrin; camphorquinone; fluorescein; riboflavin; ruthenium; oxidized sucrose; ethylene glycol dimethacrylate; pentaerythritol tetraacrylate; divinyl benzene; ethylene glycol diglycidyl ether; 4,4’-methylenebis (phenyl isocyanate); pentasodium triphosphate; periodate-oxidized sucrose; an Fe(III) salt; a Cu(II) salt; 2-hydroxy-l-[4-(2-hydroxyethoxy)phenyl]-2-methyl-l-propanone (referred to as “Irgacure 2959”); 1-hydroxy-cyclohexyl-phenyl-ketone (referred to as “Irgacure 184”); a, a- dimethoxy-alpha-phenylacetophenone (referred to as “Irgacure 651”); 2-benzyl-2- (dimethylamino)-l-[4-(4-morpholinyl) phenyl] -1-butanone (referred to as “Irgacure 369”); 2- methyl-l-[4-(methylthio)phenyl]-2-(4-morpholinyl)-l-propanone (referred to as “Irgacure 907”); Lithium phenyl-2,4,6-trimethylbenzoylphosphinate; methacrylic acid; glycidyl methacrylate; 1 -vinyl -2-pyrrolidinone; or a mixture thereof.

[0098] In embodiments, the crosslinking agent is 2-hydroxy-l-[4-(2-hydroxyethoxy)phenyl]- 2-methyl-l -propanone.

[0099] In embodiments, the crosslinking agent is divinyl benzene.

[0100] In embodiments, the crosslinking agent is added to the second crosslinked polymer at a concentration of between 1 pg / mL and 1000 pg / mL of polymer. In embodiments, the crosslinking agent is added to the second crosslinked polymer at a concentration of between 5 pg / mL and 500 pg / mL of polymer. In embodiments, the crosslinking agent is added to the second crosslinked polymer at a concentration of between 10 pg / mL and 250 pg / mL of polymer. In embodiments, the crosslinking agent is added to the second crosslinked polymer at a concentration of between 20 pg / mL and 200 pg / mL of polymer. In embodiments, the crosslinking agent is added to the second crosslinked polymer at a concentration of between 25 pg / mL and 175 pg / mL of polymer. In embodiments, the crosslinking agent is added to the second crosslinked polymer at a concentration of between 40 pg / mL and 150 pg / mL of polymer. In embodiments, the crosslinking agent is added to the second crosslinked polymer at a concentration of between 50 pg / mL and 125 pg / mL of polymer. In embodiments, the crosslinking agent is added to the second crosslinked polymer at a concentration of between 75 pg / mL and 100 pg / mL of polymer. In embodiments, the crosslinking agent is added to the second crosslinked polymer at a concentration of between 80 pg / mL and 95 pg / mL of polymer.

[0101] In embodiments, the crosslinking agent is added to the second crosslinked polymer at a weight percent of the crosslinked polymer of 0.001%-5%. In embodiments, the crosslinking agent is added to the second crosslinked polymer at a weight percent of the crosslinked polymer of 0.005%-4%. In embodiments, the crosslinking agent is added to the second crosslinked polymer at a weight percent of the crosslinked polymer of 0.01%-3%. In embodiments, the crosslinking agent is added to the second crosslinked polymer at a weight percent of the crosslinked polymer of 0.05%-5%. In embodiments, the crosslinking agent is added to the second crosslinked polymer at a weight percent of the crosslinked polymer of 0.1%-4%. In embodiments, the crosslinking agent is added to the second crosslinked polymer at a weight percent of the crosslinked polymer of 0.1%-4%. In embodiments, the crosslinking agent is added to the second crosslinked polymer at a weight percent of the crosslinked polymer of 0.5%-4%. In embodiments, the crosslinking agent is added to the second crosslinked polymer at a weight percent of the crosslinked polymer of about 0.1%. In embodiments, the crosslinking agent is added to the second crosslinked polymer at a weight percent of the crosslinked polymer of about 0.2%. In embodiments, the crosslinking agent is added to the second crosslinked polymer at a weight percent of the crosslinked polymer of about 0.1% to about 0.3%.

[0102] In embodiments, the second crosslinked polymer comprises about 0.1% - 1% by weight of divinyl benzene.

[0103] In embodiments, a plasticizer is added to the second crosslinked polymer.

[0104] In embodiments, the second crosslinked polymer has an increase in plasticity as compared to the non-crosslinked polymer.

[0105] In embodiments, the thickness of the seal ring is 50-500 pm. In embodiments, the thickness of the seal ring is about 50-500 pm, including about 50 pm, about 60 pm, about 70 pm, about 80 pm, about 90 pm, about 100 pm, about 110 pm, about 120 pm, about 130 pm, about 140 pm, about 150 pm, about 160 pm, about 170 pm, about 180 pm, about 190 pm, about 200 pm, about 250 pm, about 300 pm, about 350 pm, about 400 pm, about 450 pm, or about 500 pm, including all values and ranges therebetween. In embodiments, the thickness of the seal ring is 100-400 pm. In embodiments, the thickness of the seal ring is 100-250 pm. In embodiments, the thickness of the seal ring is 100-200 pm.

[0106] In embodiments, the thickness of the seal ring is from about 0.1 mm to about 1 mm, including about 0.1 mm, about 0.15 mm, about 0.2 mm, about 0.25 mm, about 0.3 mm, about0.35 mm, about 0.4 mm, about 0.45 mm, about 0.5 mm, about 0.55 mm, about 0.6 mm, about0.65 mm, about 0.7 mm, about 0.75 mm, about 0.8 mm, about 0.85 mm, about 0.9 mm, about0.95 mm, or about 1 mm, including all values and ranges therebetween.

[0107] In embodiments, the diameter of the seal ring is 0.5-20 mm. In embodiments, the diameter of the seal ring is 0.75-15 mm. In embodiments, the diameter of the seal ring is 1-13 mm across. In embodiments, the diameter of the seal ring is 2-11 mm across. In embodiments, the seal ring is circular.

[0108] In embodiments, the seal ring has an inner lacuna of 1-10 mm. In embodiments, the inner lacuna is 2-9 mm. In embodiments, the inner lacuna is 3-7 mm. In embodiments, the inner lacuna is 4-5 mm. In embodiments, the inner lacuna has a diameter of about 0.1 mm to about 5 mm, including about 0.1 mm, about 0.2 mm, about 0.3 mm, about 0.4 mm, about 0.5 mm, about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.9 mm, about 1.0 mm, about 1.2 mm, about 1.4 mm, about 1.6 mm, about 1.8 mm, about 2 mm, about 2.2 mm, about 2.4 mm, about 2.6 mm, about 2.8 mm, about 3 mm, about 3.2 mm, about 3.4 mm, about 3.6 mm, about 3.8 mm, about 4.0 mm, about 4.2 mm, about 4.4 mm, about 4.6 mm, about 4.8 mm, or about 5.0 mm, including all values and ranges therebetween. In embodiments, the inner lacuna has a diameter of about 0.1 mm to aboutl mm. In embodiments, the seal ring is attached to the posterior side of the base membrane.

[0109] In embodiments, the seal ring is attached to the anterior side of the base membrane.

[0110] In embodiments, the width of the seal ring as shown FIG. 11A is 1 mm. In embodiments, the width of the seal ring is about 0.5 mm to about 3 mm, including about 0.5 mm, about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.9 mm, about 1.0 mm, about 1.2 mm, about 1.4 mm, about 1.6 mm, about 1.8 mm, about 2 mm, about 2.2 mm, about 2.4 mm, about 2.6 mm, about 2.8 mm, or about 3 mm, including all values and ranges therebetween. In embodiments, the width of the seal ring is 2 mm. In embodiments, the width of the seal ring is 3 mm.[OHl] In embodiments the seal ring comprises an antibacterial agent. In embodiments, the antibacterial is selected from curcumin (Cur) or zinc oxide nanoparticles (ZnO). In embodiments, the antibacterial is added to the second crosslinked polymer before the crosslinked polymer is crosslinked. In embodiments, the antibacterial is added to the second crosslinked polymer after the crosslinked polymer is crosslinked.

[0112] In embodiments, the tensile strength of the seal ring is between 10 and 35000 kPa as measured by ASTM D638-10. In embodiments, the tensile strength of the seal ring is between 100 and 25000 kPa as measured by ASTM D638-10. In embodiments, the tensile strength of the seal ring is between 200 and 20000 kPa as measured by ASTM D638-10. In embodiments, the tensile strength of the seal ring is between 500 and 15000 kPa as measured by ASTM D638- 10. In embodiments, the tensile strength of the seal ring is between 750 and 10000 kPa asmeasured by ASTM D638-10. In embodiments, the tensile strength of the seal ring is between 100 and 3500 kPa as measured by ASTM D638-10.

[0113] In embodiments, the allowable strain of the seal ring is between 15-200% as measured by ASTM D638-10. In embodiments, the allowable strain of the seal ring is between 25-175% as measured by ASTM D638-10. In embodiments, the allowable strain of the seal ring is between 50-150% as measured by ASTM D638-10.

[0114] In embodiments, the elastic modulus of the seal ring is 1-20 mPa as measured by ASTM D638-10. In embodiments, the elastic modulus of the seal ring is 2-18 mPa as measured by ASTM D638-10. In embodiments, the elastic modulus of the seal ring is 3-16 mPa as measured by ASTM D638-10. In embodiments, the elastic modulus of the seal ring is 5-15 mPa as measured by ASTM D638-10.

[0115] In embodiments, the seal ring is able to withstand UV degradation to the structure and function of the seal ring for 6 months as measured by ASTM G154.

[0116] In embodiments, the change in the mechanical strength of the seal ring after 6 months of use is less than 20% as compared to the mechanical strength of the seal ring when the seal ring was initially transplanted into the subject. In embodiments, the change in the mechanical strength of the seal ring after 6 months of use is less than 10% as compared to the mechanical strength of the seal ring when the seal ring was initially transplanted into the subject. In embodiments, the change in the mechanical strength of the seal ring after 6 months of use is less than 5% as compared to the mechanical strength of the seal ring when the seal ring was initially transplanted into the subject.

[0117] In embodiments, the change in the transparency of the seal ring after 6 months of use is less than 20% as compared to the transparency of the seal ring when the seal ring was initially transplanted into the subject. In embodiments, the change in the transparency of the seal ring after 6 months of use is less than 10% as compared to the transparency of the seal ring when the seal ring was initially transplanted into the subject. In embodiments, the change in the transparency of the seal ring after 6 months of use is less than 5% as compared to the transparency of the seal ring when the seal ring was initially transplanted into the subject.

[0118] In embodiments, the change in mass transport through the seal ring after 6 months is less than 20% as compared to the mass transport through the seal ring when the seal ring was initially transplanted into the subject. In embodiments, the change in mass transport through the seal ring after 6 months is less than 10% as compared to the mass transport through the seal ring when the seal ring was initially transplanted into the subject. In embodiments, the change in mass transport through the seal ring after 6 months is less than 5% as compared tothe mass transport through the seal ring when the seal ring was initially transplanted into the subject.

[0119] In embodiments, the hydrolytic degradation of the seal ring after 6 months is less than 20% as compared to the seal ring when the seal ring was initially transplanted into the subject. In embodiments, the hydrolytic degradation of the seal ring after 6 months is less than 10% as compared to the seal ring when the seal ring was initially transplanted into the subject. In embodiments, the hydrolytic degradation of the seal ring after 6 months is less than 5% as compared to the seal ring when the seal ring was initially transplanted into the subject. In embodiments, Mass transport is calculated by ([Mwet - Mdry] / MWet) x 100; wherein "M = mass."

[0120] In embodiments, the transmittance of light at 400-700nm through the seal ring is greater than 60%. In embodiments, the transmittance of light at 400-700nm through the seal ring is greater than 70%. In embodiments, the transmittance of light at 400-700nm through the seal ring is greater than, or equal to, 80%.

[0121] In embodiments, the seal ring prevents transmittance of light at 240-400 nm. In embodiments, the transmittance of light at 240-400 nm is less than 30%. In embodiments, the transmittance of light at 240-400 nm is less than 20%. In embodiments, the transmittance of light at 240-400 nm is less than 10%. In embodiments, the transmittance of light at 240-400 nm is less than 5%.

[0122] In embodiments, the seal ring has a refractive index of greater than 1. In embodiments, the refractive index of the seal ring is 1-2. In embodiments, the refractive index of the base membrane is 1-1.5. In embodiments, the refractive index of the base membrane is 1.3-1.4.

[0123] In embodiments, the base membrane comprises the first crosslinked polymer that comprises about 70% by weight of PHEMA, about 7% by weight of PMMA, and about 0.1% by weight of divinyl benzene. In embodiments, the seal ring comprises the second crosslinked polymer that comprises about 70% by weight of PHEMA, about 14% by weight of PMMA, and about 0.1% by weight of divinyl benzene.

[0124] In embodiments, the base membrane comprises the first crosslinked polymer that comprises about 92% by weight of PHEMA and about 8% by weight of PMMA. In embodiments, the seal ring comprises the second crosslinked polymer that comprises about 85% by weight of PHEMA and about 15% by weight of PMMA. In embodiments, the seal ring comprises the second crosslinked polymer that comprises about 80% by weight of PHEMA and about 20% by weight of PMMA.

[0125] In embodiments, the base membrane is more permeable to a needle than the seal ring. In embodiments, the force needed to puncture the seal ring is more than the force need to puncture the base membrane.

[0126] In embodiments, the seal ring deflects the needle 1-90 degrees relative to the angle of insertion. In embodiments, the seal ring deflects the needle 10-75 degrees relative to the angle of insertion. In embodiments, the seal ring deflects the needle 20-60 degrees relative to the angle of insertion. In embodiments, the seal ring deflects the needle 25-45 degrees relative to the angle of insertion.

[0127] In embodiments, the seal ring comprises lacuna as seen in FIG. 12A. In embodiments the lacuna are evenly spaced around the entire seal ring. In embodiments, the lacuna are used to direct the needle during suturing of the corneal implant in a subject.

[0128] In embodiments, the method for fabricating the base membrane or seal ring comprises solvent casting. In embodiments, the method for fabricating the base membrane or seal ring comprises photo-crosslinking. In embodiments, the method for fabricating the base membrane or seal ring comprises 3D-printing. In embodiments, the method for fabricating the base membrane or seal ring comprises electrospinning. In embodiments, the method for fabricating the base membrane or seal ring comprises solvent casting, photo-crosslinking, 3D-printing, and electrospinning.

[0129] In embodiments, the base membrane and the seal ring are fabricated separately and the base membrane has a notch that the seal ring can fit in. In embodiments, the seal ring is fabricated first and then added to the base membrane during the fabrication of the base membrane. In embodiments, the seal ring is first crosslinked and then added to the base membrane and the base membrane is crosslinked.

[0130] In embodiments, the corneal implant further comprises an anti-fouling agent. In embodiments, the base membrane comprises the anti-fouling agent. In embodiments, the antifouling agent resists the adhesion of biological materials to the corneal implant. In embodiments, the anti-fouling agent is one or more of carboxylated phosphorycholine (PC- COOH), m-PEG 37 MW acid, methoxy PEG carboxylic acid (Mp 2000) and / or hyaluronic acid (HA). In embodiments, a corneal implant that comprises an anti-fouling agent maintains greater than 60% light transmittance in the visible light range (-400-700 nm) as compared to a corneal implant that does not comprise the anti-fouling agent. In embodiments, a corneal implant that comprises an anti-fouling agent maintains greater than 70% light transmittance in the visible light range (-400-700 nm) as compared to a corneal implant that does not comprise the antifouling agent. In embodiments, a corneal implant that comprises an anti-fouling agentmaintains greater than 80% light transmittance in the visible light range (-400-700 nm) as compared to a corneal implant that does not comprise the anti-fouling agent. In embodiments, a corneal implant that comprises an anti-fouling agent maintains greater than 85% light transmittance in the visible light range (-400-700 nm) as compared to a corneal implant that does not comprise the anti-fouling agent.

[0131] In embodiments, the corneal implant is modified with the anti-fouling agent by dipcoating. In embodiments, the corneal implant is modified with the anti-fouling agent by extrusion printing. In embodiments, the corneal implant is modified with the anti-fouling agent by ink-jet printing.

[0132] In embodiments, the posterior and / or anterior surface of the corneal implant comprises the anti -fouling agent.Soft Edge and Third Crosslinked Polymer

[0133] In embodiments, the corneal implants further comprise a soft edge (or “outer skirt” or “the perimeter”). The soft edge comprises a third crosslinked polymer.

[0134] In embodiments, the third crosslinked polymer comprises 25%-90% of PHEMA by weight. In embodiments, the third crosslinked polymer comprises 30%-90% of PHEMA by weight. In embodiments, the third crosslinked polymer comprises 35%-90% of PHEMA by weight. In embodiments, the third crosslinked polymer comprises 40%-85% of PHEMA by weight. In embodiments, the third crosslinked polymer comprises 45%-85% of PHEMA by weight. In embodiments, the third crosslinked polymer comprises 50%-80% of PHEMA by weight. In embodiments, the third crosslinked polymer comprises 55%-75% of PHEMA by weight. In embodiments, the third crosslinked polymer comprises 60%-75% of PHEMA by weight. In embodiments, the third crosslinked polymer comprises 65%-75% of PHEMA by weight. In embodiments, the third crosslinked polymer comprises 70%-75% of PHEMA by weight. In embodiments, the third crosslinked polymer comprises 70% of PHEMA by weight.

[0135] In embodiments, the third crosslinked polymer comprises PHEMA at about 40% to about 90%, including about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90% by weight, including all values and ranges therebetween. In embodiments, the third crosslinked polymer comprises about 70% of PHEMA by weight. In embodiments, the third crosslinked polymer comprises about 85% of PHEMA by weight.

[0136] In embodiments, the third crosslinked polymer comprises l%-20% of PMMA. In embodiments, the third crosslinked polymer comprises 1%-19% of PMMA by weight. Inembodiments, the third crosslinked polymer comprises 2%-l 8% of PMMA by weight. In embodiments, the third crosslinked polymer comprises 3%-15% of PMMA by weight. In embodiments, the third crosslinked polymer comprises 3%-14% of PMMA by weight. In embodiments, the third crosslinked polymer comprises 3%-10% of PMMA by weight. In embodiments, the third crosslinked polymer comprises 3%-8% of PMMA by weight. In embodiments, the third crosslinked polymer comprises 3%-7% of PMMA by weight. In embodiments, the third crosslinked polymer comprises 3%-5% of PMMA by weight. In embodiments, the third crosslinked polymer comprises 3.5% of PMMA by weight.

[0137] In embodiments, the third crosslinked polymer comprises about l%-30% of PMMA by weight. In embodiments, the third crosslinked polymer comprises PMMA at about 1% to about 30%, including about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about8%, about 8.5%, about 9%, about 9.5%, about 10%, about 10.5%, about 11%, about 11.5%, about 12%, about 12.5%, about 13%, about 13.5%, about 14%, about 14.5%, about 15%, about 15.5%, about 16%, about 16.5%, about 17%, about 17.5%, about 18%, about 18.5%, about 19%, about 19.5%, about 20%, about 20%, about 20.5%, about 21%, about 21.5%, about 22%, about 22.5%, about 23%, about 23.5%, about 24%, about 24.5%, about 25%, about 25.5%, about 26%, about 26.5%, about 27%, about 27.5%, about 28%, about 28.5%, about 29%, about 29.5%, or about 30% by weight, including all values and ranges therebetween. In embodiments, the third crosslinked polymer comprises about 11% of PMMA by weight. In embodiments, the third crosslinked polymer comprises about 10% of PMMA by weight.

[0138] In embodiments, the soft edge comprises l%-20% polyvinylpyrrolidone (PVP). In embodiments, the soft edge comprises 2%-20% polyvinylpyrrolidone (PVP). In embodiments, the soft edge comprises 2%-15% polyvinylpyrrolidone (PVP). In embodiments, the soft edge comprises 2%-12% polyvinylpyrrolidone (PVP). In embodiments, the soft edge comprises 5%- 12% polyvinylpyrrolidone (PVP). In embodiments, the soft edge comprises 5%-10% polyvinylpyrrolidone (PVP). In embodiments, the soft edge comprises 8%-10% polyvinylpyrrolidone (PVP).

[0139] In embodiments, the soft edge comprises about 1% to about 20% PVP, for example, about 1% to about 20%, including about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, about 10%, about 10.5%, about 11%, about 11.5%, about 12%, about 12.5%, about 13%, about 13.5%, about 14%, about 14.5%, about 15%, about 15.5%, about 16%, about 16.5%, about 17%, about 17.5%, about18%, about 18.5%, about 19%, about 19.5%, about 20%, or about 20% by weight, including all values and ranges therebetween.

[0140] In embodiments, the soft edge comprises 10% PVP by weight. In embodiments, the soft edge comprises about 4% PVP by weight.

[0141] In embodiments, the third crosslinked polymer is prepared by thermal crosslinking. In embodiments, the crosslinking is mediated through radiation. In embodiments, the crosslinking is mediated through light. In embodiments, the third crosslinked polymer is chemically crosslinked.

[0142] In embodiments, the third crosslinked polymer is crosslinked by a crosslinking agent. In embodiments, the crosslinking agent is referred to as a crosslinker. In embodiments, the crosslinking agent is selected from genipin; glyoxal; glutaraldehyde; EDTA; urea; tripolyphosphate; terephthalaldehyde; epichlorohydrin; camphorquinone; fluorescein; riboflavin; ruthenium; oxidized sucrose; ethylene glycol dimethacrylate; pentaerythritol tetraacrylate; divinyl benzene; ethylene glycol diglycidyl ether; 4,4’-methylenebis (phenyl isocyanate); pentasodium triphosphate; periodate-oxidized sucrose; an Fe(III) salt; a Cu(II) salt; 2-hydroxy-l-[4-(2-hydroxyethoxy)phenyl]-2-methyl-l-propanone (referred to as “Irgacure 2959”); 1-hydroxy-cyclohexyl-phenyl-ketone (referred to as “Irgacure 184”); a, a- dimethoxy-alpha-phenylacetophenone (referred to as “Irgacure 651”); 2-benzyl-2- (dimethylamino)-l-[4-(4-morpholinyl) phenyl] -1-butanone (referred to as “Irgacure 369”); 2- methyl-l-[4-(methylthio)phenyl]-2-(4-morpholinyl)-l-propanone (referred to as “Irgacure 907”); Lithium phenyl-2,4,6-trimethylbenzoylphosphinate; methacrylic acid; glycidyl methacrylate; 1 -vinyl -2-pyrrolidinone; or a mixture thereof.

[0143] In embodiments, the crosslinking agent is 2-hydroxy-l-[4-(2-hydroxyethoxy)phenyl]- 2-methyl-l -propanone.

[0144] In embodiments, the crosslinking agent is divinyl benzene.

[0145] In embodiments, the crosslinking agent is added to the third crosslinked polymer at a concentration of between 1 pg / mL and 1000 pg / mL of polymer. In embodiments, the crosslinking agent is added to the third crosslinked polymer at a concentration of between 5 pg / mL and 500 pg / mL of polymer. In embodiments, the crosslinking agent is added to the third crosslinked polymer at a concentration of between 10 pg / mL and 250 pg / mL of polymer. In embodiments, the crosslinking agent is added to the third crosslinked polymer at a concentration of between 20 pg / mL and 200 pg / mL of polymer. In embodiments, the crosslinking agent is added to the third crosslinked polymer at a concentration of between 25 pg / mL and 175 pg / mL of polymer. In embodiments, the crosslinking agent is added to the thirdcrosslinked polymer at a concentration of between 40 pg / mL and 150 pg / mL of polymer. In embodiments, the crosslinking agent is added to the third crosslinked polymer at a concentration of between 50 pg / mL and 125 pg / mL of polymer. In embodiments, the crosslinking agent is added to the third crosslinked polymer at a concentration of between 75 pg / mL and 100 pg / mL of polymer. In embodiments, the crosslinking agent is added to the third crosslinked polymer at a concentration of between 80 pg / mL and 95 pg / mL of polymer.

[0146] In embodiments, the crosslinking agent is added to the third crosslinked polymer at a weight percent of the crosslinked polymer of 0.001%-5%. In embodiments, the crosslinking agent is added to the third crosslinked polymer at a weight percent of the crosslinked polymer of 0.005%-4%. In embodiments, the crosslinking agent is added to the third crosslinked polymer at a weight percent of the crosslinked polymer of 0.01%-3%. In embodiments, the crosslinking agent is added to the third crosslinked polymer at a weight percent of the crosslinked polymer of 0.05%-5%. In embodiments, the crosslinking agent is added to the third crosslinked polymer at a weight percent of the crosslinked polymer of 0.1%-4%. In embodiments, the crosslinking agent is added to the third crosslinked polymer at a weight percent of the crosslinked polymer of 0.1%-4%. In embodiments, the crosslinking agent is added to the third crosslinked polymer at a weight percent of the crosslinked polymer of 0.5%- 4%. In embodiments, the crosslinking agent is added to the third crosslinked polymer at a weight percent of the crosslinked polymer of about 0.1%. In embodiments, the crosslinking agent is added to the third crosslinked polymer at a weight percent of the crosslinked polymer of about 0.2%. In embodiments, the crosslinking agent is added to the third crosslinked polymer at a weight percent of the crosslinked polymer of about 0.1% to about 0.3%.

[0147] In embodiments, the third crosslinked polymer comprises about 0.1%-l% by weight of divinyl benzene.

[0148] In embodiments, the corneal implant comprises abase membrane, a seal ring, and a soft edge. In embodiments, wherein the soft edge comprises the integration agent.

[0149] In embodiments, the posterior and / or anterior surface of the base membrane is modified with one or more anti-fouling agents, and the soft edge is modified with one or more integration agents.

[0150] In embodiments, the base membrane comprises 70% PHEMA and 7% PMMA; the seal ring comprises 70% PHEMA and 20% PMMA; and the soft edge comprises 70% PHEMA, 3.5% PMMA, and 10% PVP. In embodiments, the base membrane comprises about 92% PHEMA and about 8% PMMA by weight; the seal ring comprises about 80% PHEMA andabout 20% PMMA; and the soft edge comprises about 85% PHEMA, about 10% PMMA, and about 4% PVP by weight. An exemplary embodiment is shown in FIG. 12B.

[0151] In embodiments, the base membrane comprises 70% PHEMA, 7% PMMA, 0.1 % divinyl benzene; the seal ring comprises 70% PHEMA, 20% PMMA, and 0.1 % divinyl benzene; and the soft edge comprises 70% PHEMA, 3.5% PMMA, 10% PVP, and 0.1 % divinyl benzene. In embodiments, the base membrane comprises about 92% PHEMA, about 8% PMMA, about 0.1% to about 0.3 % divinyl benzene; the seal ring comprises about 80% PHEMA, about 20% PMMA, and about 0.1% to about 0.3 % divinyl benzene; and the soft edge comprises about 85% PHEMA, about 10% PMMA, about 4% PVP, and about 0.1% to about 0.2 % divinyl benzene.

[0152] In embodiments, the integration agents are conjugated to the perimeter of the soft edge. In embodiments, the integration agents are adsorbed on the perimeter of the soft edge. In embodiments, the integration agents are absorbed into the perimeter of the soft edge. In embodiments, the peptides are linked to the perimeter of the soft edge.

[0153] In embodiments, the corneal implant is fabricated by the following: The base membrane is cut from PHEMA / PMMA polymer crosslinked via divinyl benzene. The PHEMA / PMMA seal ring composition is then poured into a mold and the polymerized base membrane is inserted. Pressure is placed on the center of the polymerized base membrane to squeeze out the seal ring from just below the middle of the base membrane. The remaining PHEMA / PMMA seal ring composition is then polymerized via divinyl benzene. Lastly, the soft edge PHEMA / PMMA / PVP composition is poured into the top of the mold that already comprises the polymerized base membrane and seal ring, and the soft edge PHEMA / PMMA / PVP composition is then polymerized via divinyl benzene. This results in the three-component corneal implant. Exemplary images are shown in FIG. 12A-FIG. 12B.

[0154] In embodiments, the corneal implant is used in a scleral repair treatment. In embodiments, the base membrane is used in a keratoplasty.

[0155] In embodiments, the corneal implant is sutured to the subject. In embodiments, the sutures are 8-0 filaments. In embodiments, the sutures are 9-0 filaments. In embodiments, the sutures are 10-0 filaments. In embodiments, the sutures are 11-0 filaments. In embodiments, the sutures are a mixture of filaments.

[0156] In embodiments, the suture comprises nylon. In embodiments, the sutures comprise silk. In embodiments, the suture comprises polydioxanone. In embodiments, the suture comprises polyglactin 910. In embodiments, the suture comprises polypropylene.

[0157] In embodiments, the sutures are absorbable. In embodiments, the sutures are absorbed after 3 months. In embodiments, the sutures are absorbed after 4 months. In embodiments, the sutures are absorbed after about 5 months. In embodiments, the sutures are absorbed after 6 months.

[0158] In embodiments, the sutures are non-absorbable.

[0159] In embodiments, one month after a corneal implantation of an implant described herein to a subject in need thereof, the subject can open the eye, the subject experiences moderate conjunctival hyperemia, the subject experiences minimal white mucoid discharge near the implant, and / or there is host tissue formation on the posterior side of the implant.NUMBERED EMBODIMENTS1. A corneal implant, comprising: a base membrane comprising a first crosslinked polymer comprising poly(2- hydroxyethyl methacrylate) (PHEMA), poly(methyl methacrylate) (PMMA), or a mixture thereof; wherein i. the posterior surface and the anterior surface of the base membrane are modified with one or more anti-fouling agents, and the perimeter of the base membrane is modified with one or more integration agents; or ii. the posterior surface of the base membrane is modified with one or more anti-fouling agents, and the anterior surface and the perimeter of the base membrane are modified with one or more integration agents; and a seal ring attached to the posterior surface of the base membrane; and wherein the seal ring comprises a second crosslinked polymer comprising PHEMA, PMMA, or a mixture thereof.2. A corneal implant, comprising: a base membrane comprising a first crosslinked polymer comprising poly(2- hydroxyethyl methacrylate) (PHEMA), poly(methyl methacrylate) (PMMA), or a mixture thereof;wherein the posterior surface and / or anterior surface of the base membrane is modified with one or more anti-fouling agents; a seal ring attached to the anterior surface of the base membrane; and wherein the seal ring comprises a second crosslinked polymer comprising PHEMA, PMMA, or a mixture thereof; and a soft edge comprising a third crosslinked polymer and wherein the soft edge comprises a third crosslinked polymer comprising PHEMA, PMMA, polyvinylpyrrolidone (PVP), or a mixture thereof; and wherein the soft edge has been modified with one or more integration agents. The corneal implant of embodiment 1 or embodiment 2, wherein the first crosslinked polymer comprises about 55% to about 90% by weight of PHEMA and about 1% to about 20% by weight of PMMA. The corneal implant of any one of embodiments 1-3, wherein the second crosslinked polymer comprises about 55% to about 90% by weight of PHEMA and about 1% to about 20% by weight of PMMA. The corneal implant of any one of embodiments 2-4, wherein the third crosslinked polymer comprises about 55% to about 90% by weight of PHEMA, about 1% to about 20% by weight of PMMA, and about 1% to about 20% by weight of PVP. The corneal implant of any one of embodiments 1-5, wherein the base membrane seal ring, and / or soft edge is prepared by solvent casting, photo-crosslinking, electrospinning, or 3D printing. The corneal implant of any one of embodiments 1-5, wherein the first, second, and / or third crosslinked polymer are crosslinked by a crosslinking agent. The corneal implant of embodiment 7, wherein the crosslinking agent is genipin; glyoxal; glutaraldehyde; EDTA; urea; tripolyphosphate; terephthalaldehyde; epichlorohydrin; camphorquinone; fluorescein; riboflavin; ruthenium; oxidized sucrose; ethylene glycol diglycidyl ether; ethylene glycol dimethacrylate; pentaerythritol tetraacrylate; divinyl benzene; 4,4’-methylenebis (phenyl isocyanate); pentasodium triphosphate; periodate-oxidized sucrose; a Fe(III) salt; a Cu(II) salt; 2-hydroxy-l-[4-(2 -hydroxy ethoxy )phenyl]-2-methyl-l -propanone; 1 -hydroxy - cyclohexyl-phenyl-ketone; a, a-dimethoxy-alpha-phenylacetophenone; 2-benzyl-2- (dimethylamino)-l-[4-(4-morpholinyl) phenyl] -1-butanone; 2-methyl-l-[4-(methylthio)phenyl]-2-(4-morpholinyl)-l -propanone; or a mixture thereof. The corneal implant of any one of embodiments 1-8, wherein the first crosslinked polymer comprises about 70% by weight of PHEMA, about 7% by weight of PMMA, and < 4% by weight of a crosslinking agent. The corneal implant of embodiment 9, wherein the crosslinking agent is 2-hydroxy-l- [4-(2-hydroxyethoxy)phenyl]-2-methyl-l-propanone or divinyl benzene. The corneal implant of any one of embodiments 1-10, wherein the second crosslinked polymer comprises about 70% by weight of PHEMA, about 14% by weight of PMMA, and < 1% by weight of a crosslinking agent. The corneal implant of embodiment 11, wherein the crosslinking agent is 2-hydroxy-l- [4-(2 -hydroxyethoxy )phenyl]-2-methyl-l-propanone or divinyl benzene. The corneal implant of any one of embodiments 1-12, wherein the third crosslinked polymer comprises about 70% by weight of PHEMA, about 3.5% by weight of PMMA, about 10% by weight of PVP, and < 1% by weight of a crosslinking agent. The corneal implant of any one of embodiments 1-13, wherein the anti-fouling agent is a hydrophilic or zwitterionic molecule. The corneal implant of embodiment 14, wherein the anti-fouling agent is polyethylene glycol, phosphorylcholine, hyaluronic acid, or a mixture thereof. The corneal implant of any one of embodiments 1-15, wherein the posterior surface and / or anterior surface of the base membrane is modified with the anti-fouling agent by dip-coating, extrusion printing, or ink-jet printing. The corneal implant of any one of embodiments 1-13, wherein the integration agent is hyaluronic acid, peptides, or extracellular matrix materials. The corneal implant of embodiment 17, wherein the integration agent is collagen, laminin, or an RGD peptide.The comeal implant of any one of embodiments 2-18, wherein the perimeter and / or anterior surface of the base membrane or the perimeter of the soft edge is modified with the integration agent by extrusion, dip-coating, or ink-jet printing. The corneal implant of any one of embodiments 1-19, wherein the corneal implant transmits at least as much visible light as natural cornea (80% of 400 nm light) as determined by spectrophotometry according to ASTM D1003-21. The corneal implant of any one of embodiments 1-20, wherein the corneal implant transmits at least 85% of 500 nm light as determined by spectrophotometry according to ASTM DI 003 -21. The corneal implant of any one of embodiments 1-21, wherein the corneal implant provides a refractive index that approximates natural cornea as determined by ISO 18369-4. The corneal implant of any one of embodiments 1-22, wherein the tensile strength of the corneal implant is about 100 to about 3500 kPa as determined by ASTM D638 - 22. The corneal implant of any one of embodiments 1-23, wherein the nominal strain at break of the corneal implant is about 50% to about 150% as determined by ASTM D638 - 22. The corneal implant of embodiment 24, wherein the elastic modulus of the corneal implant is about 100 to about 3500 kPa as determined by ASTM D638 - 22. The corneal implant of any one of embodiments 1-25, wherein the corneal implant thickness is from about 0.2 mm to about 1 mm. The corneal implant of any one of embodiments 1-26, wherein the corneal implant diameter is from about 2 mm to about 10 mm. The corneal implant of any one of embodiments 1-27, wherein the radius of curvature of the anterior and posterior surface of the corneal implant is about 6 mm to about 8 mm.The corneal implant of any one of embodiments 1-28, wherein the corneal implant thickness is about 0.5 mm, the corneal implant diameter is about 10 mm, the radius of curvature of the anterior surface is about 7.8 mm, and the radius of curvature of the posterior surface is about 6.5 mm. The corneal implant of any one of embodiments 1-29, wherein the seal ring has an inner lacuna. The corneal implant of embodiment 30, wherein the seal ring diameter is 6-10 mm. The corneal implant of any one of embodiments 30-31, wherein the inner lacuna diameter is 3-7 mm. The corneal implant of any one of embodiments 30-32, wherein the seal ring width is between 1-3 mm. The corneal implant of any one of embodiments 1-33, wherein the seal ring thickness is 100-200 pm. The corneal implant of any one of embodiments 1-34, wherein a. the first crosslinked polymer comprises about 70% by weight of PHEMA, about 7% by weight of PMMA, and about 0.1% by weight of divinyl benzene; and b. the second crosslinked polymer comprises about 70% by weight of PHEMA, about 14% by weight of PMMA, and about 0.1% divinyl benzene. The corneal implant of any one of embodiments 2-35, wherein a. the first crosslinked polymer comprises about 70% by weight of PHEMA, about 7% by weight of PMMA, and 0.1% by weight of divinyl benzene; b. the second crosslinked polymer comprises about 70% by weight of PHEMA, about 14% by weight of PMMA, and 0.1% by weight of divinyl benzene; and c. the third crosslinked polymer comprises about 70% by weight of PHEMA, about 3.5% by weight of PMMA, about 10% by weight of PVP, and 0.1% by weight of divinyl benzene.A method of making a corneal implant, the method comprising: a) providing a base membrane comprising a first crosslinked polymer; wherein the first crosslinked polymer comprises poly(2-hydroxyethyl methacrylate) (PHEMA), poly(methyl methacrylate) (PMMA), or a mixture thereof; b) modifying the posterior surface and the anterior surface of the base membrane with one or more anti-fouling agents, and c) modifying the perimeter of the base membrane with one or more integration agents; or b) modifying the posterior surface of the base membrane with one or more anti-fouling agents, and c) modifying the anterior surface and the perimeter of the base membrane with one or more integration agents; and d) attaching a seal ring comprising a second crosslinked polymer to the posterior surface of the base membrane; wherein the second crosslinked polymer comprises PHEMA, PMMA, or a mixture thereof. A method of making a corneal implant, the method comprising: a) providing a base membrane comprising a first crosslinked polymer; wherein the first crosslinked polymer comprises poly(2-hydroxyethyl methacrylate) (PHEMA), poly(methyl methacrylate) (PMMA), or a mixture thereof; b) modifying the posterior surface and / or anterior surface of the base membrane with one or more anti-fouling agents; c) attaching a seal ring comprising a second crosslinked polymer to the anterior surface of the base membrane; wherein the second crosslinked polymer comprises PHEMA, PMMA, or a mixture thereof;d) further attaching a soft edge comprising a third crosslinked polymer to the perimeter of the base membrane; wherein the third crosslinked polymer comprises PHEMA, PMMA, PVP or a mixture thereof; and(e) modifying the soft edge with one or more integration agents.39. The method of any one of embodiments 37-38, wherein the base membrane, the seal ring, and / or the soft edge are prepared by solvent casting.40. The method of embodiment 39, wherein the posterior surface and / or anterior surface of the base membrane is modified with the anti-fouling agent by ink-jet, dip-coating, or extrusion printing.41. The method of any one of embodiments 37 or 39-40, wherein the perimeter and / or anterior surface of the base membrane or the perimeter of the soft edge is modified with the integration agent by extrusion printing, dip-coating, or ink-jet printing.42. A method of replacing a cornea or sclera of a patient in need thereof, the method comprising: a) removing the damaged or diseased portion of the patient’s cornea; and b) inserting the corneal implant of any one of embodiments 1 to 36.43. The method of embodiment 42, wherein the corneal implant is inserted by suturing the corneal implant to the patient’s corneal rim.EXAMPLESExample 1 : Poly(2-hydroxyethyl methacrylate) (PHEMA)- Poly(methyl methacrylate) (PMMA) Base Membrane Fabrication Protocol

[0160] Mix components according to Table 1. The total volume for each mix is 1 ml.

[0161] Table 1: PHEMA and PHEMA-PMMA membranes.

[0162] Cast each separate polymeric material in a glass dish to create a 0.5 mm thin membrane.

[0163] Polymerize under UV light (365 nm long wave) for 40 minutes.

[0164] Following polymerization incubate the membranes in deionized water to release them from the mold.

[0165] FIG. 5 shows the percent transmittance of the PHEMA 70% (p44E), PHEMA 70% v / v - PMMA 7% v / v (p 47F), and PHEMA 70% v / v - PMMA 14% v / v (p50E) polymer formulations.

[0166] FIG. 6A shows the modulus of the polymer formulations. There were three replicates of the PHEMA 70% and the PHEMA 70% v / v - PMMA 14% v / v formulations, and two replicates of the PHEMA 70% v / v - PMMA 7% v / v formulation.

[0167] FIG. 7 shows the cell growth after 7 days on non-functionalized membrane. The red stains are actin filaments and the blue stains are cell nuclei. Cell attachment is important for integration of the implant with the adjacent tissue. The optic (the anterior and posterior surface of the lens) remains clear of any biological or environmental agents to maintain its clarity, and the modifications are applied in the final implant to deter the adherence of those agents, thereby keeping the base membrane optically clear.Example 2 : Base Membrane Fabrication Protocol

[0168] A PHEMA-PMMA solution was prepared as disclosed in Example 1. 0.3 ml of solution was added to the mold.

[0169] The polymer was polymerized for 40 minutes under a UV lamp (Vendor: Analytik Jena, Model: UVP Blak-Ray B-100A) through the top of the mold which is transparent to UV light.

[0170] The corneal shaped material was removed from the mold.

[0171] FIG. 4A-FIG 4C. show examples of the base membrane that is removed from the mold and cut to 6.5 mm.

[0172] Anti-fouling agent'.

[0173] Carboxylated phosphorylcholine (PC-COOH) and / or polyethylene glycol (PEG) serves as the anti-fouling coating. To add PC and / or PEG to the surface of the base membrane, the base membrane was then plasma treated for 10 minutes at 200W, and the base membrane is incubated in the deionized water solution for 24 hours: EDC (Sigma, 03449 )-NHS (Sigma, 130672) 2.5 mg / mL (at 4 weight units of EDC per 1 weight unit of NHS) and 0.5% w / v (g / mL) PC-COOH. Base membranes are then rinsed thoroughly three times with deionized water.

[0174] Integration agent:

[0175] A 6 - 10 mm section was cut out of the membrane and placed in a swallow pool of a 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) / N-Hydroxysuccinimide (NHS) solution on ice for 3 hours. The membrane was then rinsed three times with nanopure water. The edge of the membrane was then placed in a shallow pool of the integration agent for 24 hours at room temperature and rinsed 3 times with nanopure water.

[0176] Alternatively, to enable tissue integration, hyaluronic acid (HA) and / or peptides (i.e., RGD and / or YIGSR) are printed on the edge of the anti-fouling coated implant. Components are printed using a 3 -axis EV Series automated dispensing system.

[0177] Sterilization'.

[0178] The cell-adhesion containing membrane was then sterilized by conducting ethanol sterilization in a sterile biosafety cabinet (BSC). Briefly, the cell-adhesion containing membrane was incubated in the BSC in 70% ethanol for 1 hour and then in sterile water for 24 hours.

[0179] The ethanol soak opacifies the membrane. The 24-hour incubation in sterile water removes all ethanol from the unit. Restoration of optical clarity is an indicator that the ethanol has been removed.

[0180] The finished membrane (CorneaClear™) unit was then stored in a sealed sterile container in sterile water at room temperature.Example 3 : Functionalization of the Base Membrane

[0181] The base membrane was functionalized via dip-coating with either collagen type-1 or RGD.

[0182] FIG. 8A-FIG.8D verifies that adding integration agents can be added to the membrane to assist in cell growth around the membrane. FIG. 8C (20-micron-field-view) and FIG. 8D (5-micron-field-view) show collagen being deposited on the membrane.

[0183] The membranes are further characterized in FIG. 9A-9C showing the shift in the XPS analysis demonstrating that either RGD (FIG. 9B) or type-1 collagen (FIG. 9C) can be deposited on the membrane. As shown in FIG 9B and FIG. 9C, a small Nitrogen signal are shown in the RGD and collagen type 1 -modified membranes but not the unmodified sample (FIG. 9A), yielding a percent Nitrogen of 0.69% and 0.97% for the RGD-modified and collagen type 1 -modified samples, respectively. This was further explored in FIG. 10A-FIG. 10D, which shows the deconvoluted Cis peaks and Nls peaks. Here, a defined Nitrogen peak appears in the RGD (FIG. 10B) and collagen type 1 -modified membranes (FIG. 10D) as compared to the unmodified membranes.

[0184] In the Cis scans, the green spectra are the unmodified membranes, and the red spectra were the RGD or collagen type 1 -modified membranes. In the Nls scans, the red spectra are the unmodified membranes, and the green spectra were the RGD or collagen type 1 -modified membranes.Example 4: Seal Ring

[0185] To maintain the seal around base membrane a seal ring is added to the base membrane. The seal between the implant and the external environment must be complete.

[0186] The seal ring is either separately crosslinked and later added to the base membrane or the base membrane is fabricated with a notch to fit the seal ring within it. A PHEMA / PMMA containing ring is added to the posterior side of the implant to achieve a complete seal. Suturing introduces micron sized small holes in the base membrane. A transparent, thin, suture impenetrable PHEMA / PMMA ring (FIG. 11A-FIG. 11B) is added to the posterior edge of the base membrane prior to the addition of surface modifications. The PHEMA / PMMA seal ring is 100-200 pm thin and 1 - 3 mm wide.

[0187] The corneal implant can also comprise a soft edge. The base membrane can be cut from polymerized PHEMA / PMMA polymer. The PHEMA / PMMA seal ring composition is then poured into a mold and the polymerized base membrane is inserted. Pressure is placed on the center of the polymerized base membrane to squeeze out the seal ring from just below the middle of the base membrane. The remaining PHEMA / PMMA seal ring composition is then polymerized. Lastly, the soft edge PHEMA / PMMA / PVP composition is poured into the top of the mold that already comprises the polymerized base membrane and seal ring, and the soft edge PHEMA / PMMA / PVP composition is then polymerized. This results in the three component corneal implant. Exemplary images are shown in FIG. 12A-FIG. 12B.

[0188] Another example of three-part corneal implant is shown in FIG. 13A-FIG. 13C. The corneal implant comprises (1) a polymerized base membrane (“Inner Core”) containing >70 % PHEMA and >3.5 % PMMA; (2) a seal ring (“SIR” or “suture impenetrable ring” or “hard ring”) containing <100% PMMA or any mixture of >20% PMMA and PHEMA; and (3) a soft edge (“outer skirt”) consisting of <70% PHEMA, PMMA, and polyvinylpyrrolidone (PVP) (FIG. 13A). The seal ring includes inner lacunae that guide the needle during suturing. The inner lacunae are configured to allow the needle to penetrate the full thickness of the implant (FIG. 13B) or alternatively, configured to penetrate only a portion of the implant’s thickness (FIG. 13C). The side view is presented as flat for simplicity of the drawing, but the actual device is curved in the shape of cornea.Example 5: Penetrating Keratoplasty in Rabbits

[0189] A PHEMA 70% - PMMA 3.5% coated in collagen type 1 (Thermo Fisher, A1048301) was tested in a rabbit model. Integration or healing was expected between the collagen coated membrane and the adjacent rabbit cornea. Slit lamp evaluation of the collagen coated membrane at day 28 revealed: 1) a comfortable open eye, 2) moderate conjunctival hyperemia, 3) minimal white mucoid discharge, 4) host tissue formation on the posterior side, 5) and the implant progressively raising above the level of the surrounding cornea. Taken together, these observations suggest that while the implant was overall well tolerated in the eye, it did not integrate with the adjacent host cornea tissue.

[0190] Table 2 shows the life scores of the operative eye out until day 28. The life scores of the operative rabbit eye (right eye) show the implant was overall tolerated well in the eye up to 28 days. Generally, scores range from 0 (normal or not observed) to 4 (severe or notable observation). The scores by day 28 show that conjunctival congestion presented with a flushed reddish color in parts of the eye (score = 1) and discharge was above normal (score = 1); conjunctival swelling was normal (score = 0). The 0 score for aqueous flair indicated that theanterior chamber was not inflamed. While the iris was initially moderately impacted by the implant presumably due to anterior chamber fluid loss (score = 3), this improved by day 28 presenting minimal injection of secondary vessels (score = 1). For the adjacent cornea tissue, there was some loss of corneal clarity (score = 1 for corneal clarity loss - severity) and up to 25% of stromal cloudiness (score = 1 for corneal clarity loss - extent) by day 28. The pannus score at day 28 showed that vessels have invaded 2 mm or more around the entire corneal circumference (score = 2). The absence of fluorescein shows that corneal epithelialization of the implant did not occur by day 28. The intraocular pressure of the operative eye (right) was slightly elevated by day 28 as compared to the baseline; medical implications of this slight increase are unclear and longer-term observation would provide better insight. The corneal implant showed some loss of transparency by day 28 (score = 1). This study shows that the collagen coating (on the edge and anterior surfaces) is overall compatible with the ocular environment.

[0191] Table 2: Life scores of a rabbit with a corneal implant after 28 days

Claims

1. Claims1. A corneal implant, comprising: a base membrane comprising a first crosslinked polymer comprising poly(2- hydroxyethyl methacrylate) (PHEMA), poly(methyl methacrylate) (PMMA), or a mixture thereof; wherein i. the posterior surface and the anterior surface of the base membrane are modified with one or more anti -fouling agents, and the perimeter of the base membrane is modified with one or more integration agents; or ii. the posterior surface of the base membrane is modified with one or more anti-fouling agents, and the anterior surface and the perimeter of the base membrane are modified with one or more integration agents; and a seal ring attached to the posterior surface of the base membrane; and wherein the seal ring comprises a second crosslinked polymer comprising PHEMA, PMMA, or a mixture thereof.

2. A corneal implant, comprising: a base membrane comprising a first crosslinked polymer comprising poly(2- hydroxyethyl methacrylate) (PHEMA), poly(methyl methacrylate) (PMMA), or a mixture thereof; wherein the posterior surface and / or anterior surface of the base membrane is modified with one or more anti-fouling agents; a seal ring attached to the anterior surface of the base membrane; and wherein the seal ring comprises a second crosslinked polymer comprising PHEMA, PMMA, or a mixture thereof; and a soft edge comprising a third crosslinked polymer comprising PHEMA, PMMA, polyvinylpyrrolidone (PVP), or a mixture thereof; and wherein the soft edge is modified with one or more integration agents.

3. A corneal implant, comprising:a base membrane comprising a first crosslinked polymer comprising poly(2- hydroxyethyl methacrylate) (PHEMA), poly(methyl methacrylate) (PMMA), or a mixture thereof; wherein the posterior surface and / or anterior surface of the base membrane is modified with one or more anti-fouling agents; a seal ring comprising a second crosslinked polymer comprising PHEMA, PMMA, or a mixture thereof; and a soft edge comprising a third crosslinked polymer comprising PHEMA, PMMA, polyvinylpyrrolidone (PVP), or a mixture thereof, wherein the seal ring is embedded in the anterior surface of the soft edge, and the seal ring and / or soft edge is modified with one or more integration agents.

4. The corneal implant of any one of claims 1-3, wherein the first crosslinked polymer comprises about 55% to about 95% by weight of PHEMA and about 1% to about 20% by weight of PMMA.

5. The corneal implant of any one of claims 1-4, wherein the second crosslinked polymer comprises about 55% to about 90% by weight of PHEMA and about 1% to about 20% by weight of PMMA.

6. The corneal implant of any one of claims 2-5, wherein the third crosslinked polymer comprises about 55% to about 90% by weight of PHEMA, about 1% to about 20% by weight of PMMA, and about 1% to about 20% by weight of PVP.

7. The corneal implant of any one of claims 1-6, wherein the base membrane seal ring, and / or soft edge is prepared by solvent casting, photo-crosslinking, electrospinning, or 3D printing.

8. The corneal implant of any one of claims 1-6, wherein the first, second, and / or third crosslinked polymer are crosslinked by a crosslinking agent.

9. The corneal implant of claim 8, wherein the crosslinking agent is genipin; glyoxal; glutaraldehyde; EDTA; urea; tripolyphosphate; terephthalaldehyde; epichlorohydrin; camphorquinone; fluorescein; riboflavin; ruthenium; oxidized sucrose; ethylene glycoldiglycidyl ether; ethylene glycol dimethacrylate; pentaerythritol tetraacrylate; divinyl benzene; 4,4’-methylenebis (phenyl isocyanate); pentasodium triphosphate; periodate- oxidized sucrose; a Fe(III) salt; a Cu(II) salt; 2-hydroxy-l-[4-(2-hydroxyethoxy)phenyl]-2- m ethyl- 1 -propanone; 1-hydroxy-cyclohexyl-phenyl-ketone; a, a-dimethoxy-alpha- phenylacetophenone; 2-benzyl-2-(dimethylamino)-l-[4-(4-morpholinyl) phenyl]- 1- butanone; 2-methyl-l-[4-(methylthio)phenyl]-2-(4-morpholinyl)-l-propanone; or a mixture thereof.

10. The corneal implant of any one of claims 1-9, wherein the first crosslinked polymer comprises about 92% by weight of PHEMA, about 8% by weight of PMMA, and < 4% by weight of a crosslinking agent.

11. The corneal implant of claim 10, wherein the crosslinking agent is 2-hydroxy-l-[4-(2- hydroxyethoxy)phenyl]-2-methyl-l -propanone or divinyl benzene.

12. The corneal implant of any one of claims 1-11, wherein the second crosslinked polymer comprises about 80% by weight of PHEMA, about 20% by weight of PMMA, and < 1% by weight of a crosslinking agent.

13. The corneal implant of claim 12, wherein the crosslinking agent is 2-hydroxy-l-[4-(2- hydroxyethoxy)phenyl]-2-methyl-l -propanone or divinyl benzene.

14. The corneal implant of any one of claims 1-13, wherein the third crosslinked polymer comprises about 85% by weight of PHEMA, about 10% by weight of PMMA, about 4% by weight of PVP, and < 1% by weight of a crosslinking agent.

15. The corneal implant of any one of claims 1-14, wherein the anti-fouling agent is a hydrophilic or zwitterionic molecule.

16. The corneal implant of claim 15, wherein the anti -fouling agent is polyethylene glycol, phosphorylcholine, hyaluronic acid, or a mixture thereof.

17. The corneal implant of any one of claims 1-16, wherein the posterior surface and / or anterior surface of the base membrane is modified with the anti-fouling agent by dipcoating, extrusion printing, or ink-jet printing.

18. The corneal implant of any one of claims 1-14, wherein the integration agent is hyaluronic acid, peptides, or extracellular matrix materials.

19. The corneal implant of claim 18, wherein the integration agent is collagen, laminin, or an RGD peptide.

20. The corneal implant of any one of claims 2-19, wherein the perimeter and / or anterior surface of the base membrane or the perimeter of the soft edge is modified with the integration agent by extrusion, dip-coating, or ink-jet printing.

21. The corneal implant of any one of claims 1-20, wherein the corneal implant transmits at least as much visible light as natural cornea (80% of 400 nm light) as determined by spectrophotometry according to ASTM D1003-21.

22. The corneal implant of any one of claims 1-21, wherein the corneal implant transmits at least 85% of 500 nm light as determined by spectrophotometry according to ASTM D1003-21.

23. The corneal implant of any one of claims 1-22, wherein the corneal implant provides a refractive index that approximates natural cornea as determined by ISO 18369-4.

24. The corneal implant of any one of claims 1-23, wherein the tensile strength of the corneal implant is about 100 to about 3500 kPa as determined by ASTM D638 - 22.

25. The corneal implant of any one of claims 1-24, wherein the nominal strain at break of the corneal implant is about 50% to about 150% as determined by ASTM D638 - 22.

26. The corneal implant of claim 25, wherein the elastic modulus of the corneal implant is about 100 to about 3500 kPa as determined by ASTM D638 - 22.

27. The corneal implant of any one of claims 1-26, wherein the corneal implant thickness is from about 0.2 mm to about 1 mm.

28. The corneal implant of any one of claims 1-27, wherein the corneal implant diameter is from about 2 mm to about 10 mm.

29. The corneal implant of any one of claims 1-28, wherein the radius of curvature of the anterior and posterior surface of the corneal implant is about 7 mm to about 10 mm.

30. The corneal implant of any one of claims 1-29, wherein the corneal implant thickness is about 0.5 mm, the corneal implant diameter is about 10 mm, the radius of curvature of the anterior surface is about 8 mm to about 10 mm, and the radius of curvature of the posterior surface is about 7 mm to about 10 mm.

31. The corneal implant of any one of claims 1-30, wherein the seal ring has an inner lacuna.

32. The corneal implant of claim 31, wherein the seal ring diameter is 6-10 mm.

33. The corneal implant of any one of claims 31-32, wherein the inner lacuna diameter is 0.1-1 mm.

34. The corneal implant of any one of claims 31-33, wherein the seal ring width is between 1-3 mm.

35. The corneal implant of any one of claims 1-34, wherein the seal ring thickness is 100- 200 pm.

36. The corneal implant of any one of claim 1-35, wherein a. the first crosslinked polymer comprises about 92% by weight of PHEMA, about 8% by weight of PMMA, and about 0.1% to about 0.3% by weight of divinyl benzene; and b. the second crosslinked polymer comprises about 80% to about 85% by weight of PHEMA, about 14% to about 20% by weight of PMMA, and about 0.1% to about 0.3% by weight of divinyl benzene.

37. The corneal implant of any one of claim 1-36, wherein a. the first crosslinked polymer comprises about 92% by weight of PHEMA, about 8% by weight of PMMA, and about 0.1% to about 0.3% by weight of divinyl benzene; b. the second crosslinked polymer comprises about 80% by weight of PHEMA, about 20% by weight of PMMA, and about 0.1% to about 0.3% by weight of divinyl benzene; andc. the third crosslinked polymer comprises about 85% by weight of PHEMA, about 10% by weight of PMMA, about 4% by weight of PVP, and about 0.1% to about 0.3% by weight of divinyl benzene.

38. A method of making a corneal implant, the method comprising: a) providing a base membrane comprising a first crosslinked polymer; wherein the first crosslinked polymer comprises poly(2-hydroxyethyl methacrylate) (PHEMA), poly(methyl methacrylate) (PMMA), or a mixture thereof; b) modifying the posterior surface and the anterior surface of the base membrane with one or more anti-fouling agents, and c) modifying the perimeter of the base membrane with one or more integration agents; or b) modifying the posterior surface of the base membrane with one or more anti-fouling agents, and c) modifying the anterior surface and the perimeter of the base membrane with one or more integration agents; and d) attaching a seal ring comprising a second crosslinked polymer to the posterior surface of the base membrane; wherein the second crosslinked polymer comprises PHEMA, PMMA, or a mixture thereof.

39. A method of making a corneal implant, the method comprising: a) providing a base membrane comprising a first crosslinked polymer; wherein the first crosslinked polymer comprises poly(2-hydroxyethyl methacrylate) (PHEMA), poly(methyl methacrylate) (PMMA), or a mixture thereof; b) modifying the posterior surface and / or anterior surface of the base membrane with one or more anti-fouling agents; c) attaching a seal ring comprising a second crosslinked polymer to the anterior surface of the base membrane;wherein the second crosslinked polymer comprises PHEMA, PMMA, or a mixture thereof; d) further attaching a soft edge comprising a third crosslinked polymer to the perimeter of the base membrane; wherein the third crosslinked polymer comprises PHEMA, PMMA, PVP or a mixture thereof; and(e) modifying the soft edge with one or more integration agents.

40. The method of any one of claims 38-39, wherein the base membrane, the seal ring, and / or the soft edge are prepared by solvent casting.

41. The method of claim 40, wherein the posterior surface and / or anterior surface of the base membrane is modified with the anti-fouling agent by ink-jet, dip-coating, or extrusion printing.

42. The method of any one of claims 38 or 40-41, wherein the perimeter and / or anterior surface of the base membrane or the perimeter of the soft edge is modified with the integration agent by extrusion printing, dip-coating, or ink-jet printing.

43. A method of replacing a cornea or sclera of a patient in need thereof, the method comprising: a) removing the damaged or diseased portion of the patient’s cornea; and b) inserting the corneal implant of any one of claims 1 to 37.

44. The method of claim 43, wherein the corneal implant is inserted by suturing the corneal implant to the patient’s corneal rim.

Images