A corneal implant and process of preparation thereof

Abstract

There is also provided a lenticule-shaped corneal implant formed from a composite material comprising: an outer surface having a convex dome shape; and an inner surface having a concave dome shape, wherein the inner surface comprises at least two indented grooves that are circular and concentric. There is also provided a corneal implant comprising a central body formed from a first composite material and having a dome shape configured to conform to a curvature of a cornea of a subject; and a peripheral zone contacting, is at least partially coextensive with, or fully surrounds an outer rim of the central body. There is also provided molding apparatus for producing the lenticule-shaped corneal implant.

Description

Attorney Docket No.: PNDM-021 / 01WO 345086-2117 A CORNEAL IMPLANT AND PROCESS OF PREPARATION THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to India Application No. 202441060006, filed August 8, 2024, which is incorporated herein by reference in its entirety. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (PNDM_021_01WO_SeqList_ST26.xml; Size: 17,559 bytes; and Date of Creation: August 06, 2025) are herein incorporated by reference in its entirety. FIELD OF INVENTION

[0003] The present disclosure broadly relates to the field of biocompatible hydrogels for application in tissue engineering. The present disclosure particularly relates to a corneal implant made of a biocompatible composite material comprising polymers. The implant is fabricated using a molding apparatus. BACKGROUND OF THE INVENTION

[0004] Corneal transplantation is the only effective clinical procedure known to treat corneal blindness. However, there is a global shortage of donor cornea with only one tissue available for every seventy needed (Gain, P. et al. Global survey of corneal transplantation and eye banking. JAMA Ophthalmol. 134, 167–173 (2016)). Other challenges in corneal transplantation include post-operative complications, neo-vascularization, infection, and graft failure. Newer technology like intrastromal implantation of the donor corneal tissue using femto-assisted pocket creation (Koulikovska, M. et al. Enhanced regeneration of corneal tissue via a bioengineered collagen construct implanted by a nondisruptive surgical technique. Tissue Eng. - Part A 21, 1116–1130 (2015)) is comparatively less invasive but relies on the availability of the human donor corneas and tissue banking, thereby limiting its use.

[0005] Alternative approaches to generate implantable tissues include electrospinning, three- dimensional (3D) bioprinting, and stereolithography (SLA) to fabricate synthetic corneal lenticules that mimics native ECM to support cell migration, adhesion, proliferation, and differentiation. Rafat et al. have designed double network bioengineered porcine construct 1 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 (BPCDX) for successful implantation in keratoconus patients with improvement of best-corrected visual acuity in 24 months (Rafat, M. et al. Bioengineered corneal tissue for minimally invasive vision restoration in advanced keratoconus in two clinical cohorts. Nat. Biotechnol. 41, 70–81 (2023)). In 2013, the first human donor lenticules implantation was reported by Pradhan et al. into a femtosecond laser (FSL)-created pocket with a patient of hyperopia (Pradhan, K. R. et al. Femtosecond Laser-Assisted Keyhole Endokeratophakia: Correction of Hyperopia by Implantation of an Allogeneic Lenticule Obtained by SMILE From a Myopic Donor. J. Refract. Surg. 29, 777–782 (2013)); (Moshirfar, M. et al. Med Hypothesis Discov Innov Ophthalmol. Discovery &Innovation Ophthalmology Journal Comparison to Lenticule Intrastromal Keratoplasty (LIKE vol. 7 (2018)). Another report describes gamma-irradiated corneal lenticules extracted from medically qualified donors for the treatment of partial and full-thickness keratoplasty (Mathews, P. M., Fogla, R., Samayoa, E., Vancourt, S. & Akpek, E. K. Long-term clinical outcomes of keratoplasty using gamma-irradiated corneal lenticules. BMJ Open Ophthalmol.4, (2019)). However, all of these remedies for treatment would require administration of immunosuppressant and there will be a risk of rejection.

[0006] A bioengineered corneal lenticule made up of non-toxic biomaterials can eliminate the requirement of immunosuppressing agents, and associated risks and complications with donor corneal transplant. Also, risk of rejection of thin corneal lenticules is theoretically less than full thickness corneal grafts due to indirect contact with tear resulting in less antigenic load. Moreover, bioengineered lenticule can be used as a drug carrier ensuring slow and prolonged release of the drug at the target site, thereby enhancing ocular bioavailability.

[0007] To date, several polymers have been successfully used in corneal tissue engineering electrospinning method, including natural polymers (e.g., hyaluronate (HA), chitosan, collagen, gelatin, silk fibroin (SF), etc.) and synthetic materials (e.g., poly-L-lactic acid (PLLA), polycaprolactone (PCL), polyethylene oxide (PEO), poly(lactide-co-glycolide) (PLGA), etc.). Dynamic light projector (DLP), a variant of stereolithography that crosslinks by flashing a two- dimensional image in each layer, is superior to other bioprinting technology since it prints much faster with high resolution, efficiency, and fidelity.

[0008] Although these advancements have attained interest in fabrication of various tissue constructs, the technologies need special instrumentation, and are extremely sensitive to bioink composition and viscosity. As such, there remains a need for improved material formulations and fabrication techniques. 2 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 SUMMARY OF INVENTION

[0009] In an aspect of the present disclosure, there is provided a biocompatible, lenticule- shaped corneal implant formed from a first composite material and configured to conform to a curvature of a cornea of a subject, comprising: an outer surface having a convex dome shape; and an inner surface having a concave dome shape, wherein the inner surface comprises at least two indented grooves that are circular and optionally concentric. Optionally, the at least two grooves are concentric with each other and with the center of inner surface.

[0010] In certain embodiments, each of the at least two circular grooves has a diameter of between about 1 mm and about 14 mm. In certain embodiments, each of the at least two circular grooves has a width of between about 20 nm and about 500 nm. In certain embodiments, each of the at least two circular grooves has a depth of between about 20 nm and about 500 nm.

[0011] In certain embodiments, the first composite material comprises at least one polymer is selected from the group consisting of: a hyaluronic acid; a gelatin; a polyethylene glycol; an alginate; a collagen; a synthetic polypeptide as set forth in SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3; and combinations thereof.

[0012] In another aspect of the present disclosure, there is provided a biocompatible corneal implant comprising: a central body formed from a first composite material and having a dome shape comprising an inner surface configured to conform to a curvature of a cornea of a subject; and a peripheral zone contacting, is at least partially coextensive with, or fully surrounds an outer rim of the central body, wherein the peripheral zone comprises a second composite material is characterized by: a higher tensile strength compared to the first composite material; a higher puncture resistance compared to the first composite material, a lower elastic modulus compared to the first composite material, or a combination thereof.

[0013] In certain embodiments, the first composite material and the second composite material are a same cross-linkable material, and the first composite material is characterized by a higher degree of cross-linking compared to the second composite material.

[0014] In certain embodiments, the first composite material and the second composite material are different composite materials.

[0015] In certain embodiments, the second composite material comprises methacrylated gelatin (Gel-MA) and a Hyaluronic acid-Aldehyde (HA-CHO). In certain embodiments, the second 3 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 composite material further comprises a methacrylated Hyaluronic acid (HA-MA), a Hyaluronic acid-Hydrazide (HA-NHNH2), or a combination thereof.

[0016] In certain embodiments, the second composite material comprises a thiolated hyaluronic acid (HA-SH) and a poly(ethylene glycol) diacrylate (PEGDA).

[0017] In another aspect of the present disclosure, there is provided a molding apparatus for manufacturing a lenticule-shaped corneal implant, the molding apparatus comprising: a base having a concave dome-shaped cavity configured to receive a cross-linkable composite material; a top configured to be placed on the base and comprising a convex dome-shaped elevation surface shaped and dimensioned so that a lenticule-shaped gap is formed between the cavity and the elevation surface when the top is situated on the base, and the cross-linkable composite material situated in the concave dome-shaped cavity would be formed having a shape corresponding to the lenticule-shaped gap; optionally a light source configured to emit light; and a light-transmitting surface positioned to allow passage of the light from the light source through a light-transmitting surface to the concave cavity for crosslinking of the cross-linkable composite material.

[0018] In certain embodiments, the top is formed of a transparent material, and the light- transmitting surface is the convex elevation surface.

[0019] In certain embodiments, the convex dome-shaped elevation surface comprises at least two circular ridges that are concentric with each other and the center of the convex dome-shaped elevation surface, such that the corneal implant formed in the gap would comprise at least two circular grooves on a concave surface of the corneal implant corresponding to the at least two circular ridges.

[0020] In certain embodiments, the distance between the elevation surface and the cavity is in the range of 50-300 μm.

[0021] In certain embodiments, the molding apparatus is an injection molding apparatus or compression molding apparatus.

[0022] In another aspect of the present disclosure, there is provided a process of preparing the corneal implant of the disclosure, comprising: applying a first composite material of the disclosure into a cavity in a molding apparatus the disclosure; exposing the first composite material to light for crosslinking of the first composite material, thereby forming the central body

[0023] In certain embodiments, the process further comprise applying a second composite material of the disclosure into the cavity so that the second composite material is placed on, near, or around the outer rim of the corneal implant formed with the first composite material; and 4 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 exposing the second composite material to light for crosslinking of the second composite material, thereby forming a peripheral zone.

[0024] In another aspect of the present disclosure, there is provided a process of treating a corneal disorder in a subject, said process comprising implanting the corneal implant of the disclosure on an implantation site on an eye of the subject.

[0025] These and other features, aspects, and advantages of the present subject matter will be better understood with reference to the following description. This summary is provided to introduce a selection of concepts in a simplified form. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter. BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS

[0026] The following drawings form a part of the present specification and are included to further illustrate aspects of the present disclosure. The disclosure may be better understood by reference to the drawings in combination with the detailed description of the specific embodiments presented herein.

[0027] FIG.1A depicts an image of the molding apparatus used for preparation of the lenticules, FIG. 1B depicts the graphical abstract representing the preparation / fabrication of the corneal implant, and FIG. 1C depicts an alternative design of the molding apparatus, in accordance with an embodiment of the present disclosure.

[0028] FIG. 1D depicts an alternative design of the molding apparatus in which the elevation surface comprises circular, concentric ridges for producing circular, concentric grooves in the lenticles produced thereby, in accordance with an embodiment of the present disclosure.

[0029] FIG. 1E depicts a cross-section of an exemplary elevation surface, in accordance with an embodiment of the present disclosure.

[0030] FIG. 2A a schematic of photo-crosslinking mechanism to form hydrogels.

[0031] FIG. 2B depicts a picture of the mold with detailed outline.

[0032] FIG. 2C depicts a compression-molded lenticule using HA-MA and Gel-MA biopolymers.

[0033] FIG. 2D depicts an example of sub-optimal lenticule resulted from other ratio of biopolymer combination in accordance with an embodiment of the present disclosure. 5 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117

[0034] FIGS. 3A-3D depicts the characterization of physical properties of HA-MA / Gel-MA lenticules in accordance with an embodiment of the present disclosure, including: crosslinking kinetics (FIG. 3A); stereomicroscope image of the lenticule (FIG. 3B); weight and volumetric swelling profile (FIG. 3C); and degradation profile (FIG. 3D).

[0035] FIGS. 4A-4D depicts the characterization of mechanical properties of HA-MA / Gel-MA lenticules in accordance with an embodiment of the present disclosure, including: compressive modulus (FIG. 4A); tensile strength (FIG. 4B); puncture resistance (FIG. 4C); and drag strength (FIG. 4D).

[0036] FIGS.5A-5D depict the results of ophthalmic imaging of Corneal Mimetic Lenticule Vs Native Cornea

[0037] FIG.5A depicts a representative image showing opacity score (indicator of transparency) in corneal mimetic lenticule and native cornea tissue at different diameters (central 0-2mm, mid peripheral 2-6mm and peripheral (6-10mm).

[0038] FIGS. 5B-5C depicts raster scan images (FIG. 5B) and pachymetry maps (FIG. 5C) obtained from Anterior Segment Optical Coherence Tomography (AS-OST) of corneal mimetic lenticule applied to native cornea tissue of a human volunteer, in accordance with an embodiment of the present disclosure. Pachymetry maps indicates corneal thickness with colour coding of thickness indicated by the grading scale, and mean thickness in μm indicated in each sector.

[0039] FIG.5D depicts a representative image showing keratometry values (measure of corneal curvature) in a corneal mimetic lenticule applied to native cornea tissue of a human volunteer.

[0040] FIGS. 6A-6C depict the results of in vitro cytocompatibility study of HA-MA / Gel-MA hydrogel in accordance with an embodiment of the present disclosure, with FIG.6A showing cells on the surface of a glass coverslip, FIG. 6B showing the cells spreading over 3 weeks in the lenticule depicted by fluorescent staining of live (green) and dead (red) cells, and FI. 6C showing a phase contrast image showing epithelial cell movement towards the lenticule.

[0041] FIGS. 7A-7C depicts the result of studies of HA-MA / Gel-SH hydrogels in accordance with an embodiment of the present disclosure, with FIG. 7A showing the volumetric swelling percentage, FIG. 7B showing the swelling percentage in weight, and FIG. 7C showing compressive modulus.

[0042] FIGS.8A-8C schematically depict a corneal implant in accordance with an embodiment of the present disclosure. 6 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117

[0043] FIGS. 8D-8E schematically depict a corneal implant comprising concentric grooves, in accordance with an embodiment of the present disclosure.

[0044] FIG. 9 schematically depict a corneal implant comprising a peripheral zone, in accordance with an embodiment of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0045] Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The disclosure also includes all such steps, features, compositions, and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any or more of such steps or features.

[0046] Sequence details, according to the present disclosure, are depicted in Table 1 below. Table 17 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117Definitions

[0047] For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are delineated here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have the meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.

[0048] The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.

[0049] The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as “consists of only”.

[0050] Throughout this specification, unless the context requires otherwise the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of elements or steps but not the exclusion of any other element or step or group of elements or steps.

[0051] The term “including” is used to mean “including but not limited to”. “Including” and “including but not limited to” are used interchangeably.

[0052] The terms “w / w,” as used herein, refers to percentage by weight, relative to the weight of the total composition, unless otherwise specified.

[0053] The term “photo-crosslinking” or “cross-linking”, used interchangeably herein, refers to polymer cross-linking in the presence of light to form a covalently crosslinked 3D network. 8 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117

[0054] The term “photo-crosslinked polymer matrix”, as used herein, refers to a network formed by the cross-linking of polymers in the presence of light.

[0055] The term “hydrogel”, as used herein, refers to polymeric network or matrix. It refers to a three-dimensional network of polymer chains capable of absorbing and retaining large amounts of water or biological fluids, or swelling in the presence of an aqueous environment.

[0056] The term “implanting” as used herein refers to inserting or fixing a tissue or object in a person’s body. The implanting is usually done by surgical methods. The process of implanting is referred to as implantation.

[0057] The term “biopolymer” or “polymer” as used herein refers to organic substances (large macromolecules) made up of repeating units and are present in natural sources.

[0058] The term “composite material” as used herein refers to a mixture of two or more components, having physical or chemical interactions between the components.

[0059] The term “implant” as used herein refers to a corneal implant which is manufactured by using the molding apparatus as described herein. The implant is comprised of a composite material as described herein. The terms “implant”, “lenticule”, “lenticular implant”, “corneal implant” have been used herein interchangeably.

[0060] The term “subject” as used herein is a mammalian subject, preferably human.

[0061] Ratios, concentrations, amounts, and other numerical data may be presented herein in a range format. It is to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub- ranges encompassed within that range as if each numerical value and sub-range is explicitly recited.

[0062] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described. All publications mentioned herein are incorporated herein by reference.

[0063] Human cornea is a transparent and avascular tissue which is situated in anterior part of the eye, and it protects the internal parts of the eye against harm or damage due to environmental factors, including harm from exposure to UV light, mechanical damage, and infections, etc. Corneal injuries and infections often lead to scarring, vision impairment and complete blindness. 9 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 Keratoconus (KC), a commonly occurring cornea deformity, is an asymmetrical progressive ecstatic disease resulting in corneal thinning, bulging, irregular astigmatism, and eventual Bowman’s layer breaks, hydrops, and scarring. Progression of the disease can be detected and halted in early stages with proper screening and specialist care, however, if not addressed, it can advance into a stage requiring surgical intervention. As discussed in the background section, currently transplantation with donor cornea is the only effective clinical procedure known to treat corneal blindness. Owing to the limitations of the present techniques, there is a need in the prior art to develop techniques, products and processes that can effectively treat corneal disorders and impairments.

[0064] To this end, the present disclosure provides corneal implants / lenticules and a method to construct corneal implants using compression molding method which is simple, easy to adopt, user-friendly and low-cost technique.

[0065] Compression molding is a molding process which employs a molding apparatus having lower (base) and upper (top) halves, and these two halves of the molds create a cavity when they meet, where the bioink is compressed to conform shape of the mold. Advantages of compression- molded corneal lenticules over other techniques is that they can be produced with high precision and consistency. The compression molding process allows for precise control over the thickness and curvature of the lenticule, which can result in better visual outcomes and fewer complications. Another advantage of compression-molded corneal lenticules is that they can be customized to the specific needs of individual patients. The lenticules can be designed with specific optical properties to correct refractive errors, such as myopia or astigmatism, and can be made in a range of sizes to fit different corneal shapes and sizes. Typically, compression-molded corneal lenticules are made from biocompatible and biodegradable materials that are well-tolerated by the body and have a low risk of rejection or other complications. This makes them a safe and effective option for patients with corneal damage or disease who are not good candidates for traditional corneal transplantation. Overall, the advantages of compression-molded corneal lenticules include high precision, customization, and biocompatibility, making them a promising option for patients in need of corneal replacement. This method has not been used before for the fabrication of corneal constructs. To design a corneal lenticule there are certain properties that needs to be satisfied, for example good transparency, biocompatible, higher mechanical properties, biodegradability which allow cells to migrate and proliferate. 10 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117

[0066] Here in, to achieve these properties in the compression molded implants, a combination of polymers or biopolymers (functionalized hyaluronic acid and gelatin as an example) has been used. The biopolymers were photopolymerized / crosslinked in the presence of photoinitiator to form a lenticular implant or corneal implant. The lenticules prepared in the present disclosure showed good transparency, suturability, and high biocompatibility.

[0067] Embodiments herein provide corneal implants, a molding apparatus for manufacturing the corneal implants, process of preparing the corneal implants, and a process of treating a corneal disorder using the corneal implants. The embodiments hereinbelow describe the features of the invention of the present disclosure. Corneal Implant:

[0068] Embodiments herein provide a corneal implant or corneal lenticule or lenticular implant comprising a biocompatible body having a dome-shaped configuration or shape, conforming to the curvature of the cornea. The biocompatible body may either be positioned on the surface of the cornea or may be partially integrated with a layer of the cornea. In some embodiments, the biocompatible body may comprise a peripheral zone. i.e., the outer zone of the implant for integrating the biocompatible body with the cornea or position the biocompatible body on the cornea to maintain stability of the corneal implant in a deployed state, i.e., in a state where the biocompatible body is positioned or placed over the cornea. The implant may be used to adjust corneal curvature, or replace and mimic cornea of an eye. In some embodiments, in the deployed state, the biocompatible body mimics natural curvature of the cornea to provide a seamless interface with the cornea. In some embodiments, the biocompatible body is formed from a composite material comprising at least one polymer.

[0069] In an embodiment, the at least one polymer is selected from the group consisting of hyaluronic acid; gelatin; polyethylene glycol; alginate; collagen type I; synthetic polypeptide as set forth in SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3; and combinations thereof. In yet another embodiment, the composite material further comprises a photoinitiator for cross-linking of the polymers upon exposure to light.

[0070] The corneal implant comprises a biocompatible body made of polymers. The term “biocompatible” used in the context of implant means that implant has an ability to be in contact with a living system without producing an adverse effect. In certain embodiments, the implant is a biocompatible corneal implant that is lenticule-shaped, such that it fits over the surface of the eye over the cornea, adjusts / aligns with the curvature of the cornea, or serves as a replacement 11 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 cornea where a portion of the cornea is missing (due to, e.g., damage or disease) or has been surgically removed.

[0071] With reference to FIG.8A, showing a cross section of a lenticule-shaped conreal implant, a lenticule shape may be characterized by certain dimensions, including a thickness as indicated by distance “a” in FIG. 8A, a diameter as indicated by distance “b” in FIG. 8A, and a height as indicated by distance “c” in FIG. 8A.

[0072] In some embodiments, the corneal implant of the present disclosure may have a diameter of between about 2 mm and about 15 mm, between about 2 mm and about 10 mm, between about 2 mm and about 5 mm, between about 2 mm and about 4mm, between about 5 mm and about 15 mm, between about 5 mm and about 10 mm, between about 10 mm and about 15 mm, between about 10 mm and about 12 mm, about 2 mm, or about 3 mm.

[0073] In some embodiments, the implant of the present disclosure may have a height of between about 0.05 mm and about 5 mm, between about 0.05 mm and about 4 mm, between about 0.05 mm and about 2 mm, between about 0.05 mm and about 1 mm, between about 0.05 mm and about 0.5 mm, between about 0.05 mm and about 0.1 mm, between about 0.07 mm and about 5 mm, between about 0.07 mm and about 4 mm, between about 0.07 mm and about 2 mm, between about 0.07 mm and about 1 mm, between about 0.07 mm and about 0.5 mm, between about 0.07 mm and about 0.1 mm, between about 0.1 mm and about 5 mm, between about 0.1 mm and about 4 mm, between about 0.1 mm and about 2 mm, between about 0.1 mm and about 1 mm, between about 0.1 mm and about 0.5 mm, between about 0.5 mm and about 5 mm, between about 0.5 mm and about 4 mm, between about 0.5 mm and about 3 mm, between about 0.5 mm and about 2 mm, between about 0.5 mm and about 1 mm, between about 1 mm and about 5 mm, between about 1 mm and about 4 mm, between about 1 mm and about 3 mm, between about 1 mm and about 2 mm, between about 2 mm and about 5 mm, between about 2 mm and about 4 mm, and between about 2 mm and about 3 mm.

[0074] In certain embodiments, the implant of the present disclosure may have a thickness in the range of between about 50 μm and about 300 μm, between about 50 μm and about 250 μm, between about 50 μm and about 200 μm, between about 50 μm and about 150 μm, between about 50 μm and about 100 μm, between about 100 μm and about 300 μm, between about 100 μm and about 250 μm, between about 100 μm and about 200 μm, between about 150 μm and about 300 μm, between about 200 μm and about 300 μm, between about 150 μm and about 250 μm, about 12 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 50 μm, about 75 μm, about 100 μm, about 125 μm, about 150 μm, about 175 μm, about 200 μm, about 225 μm, about 250 μm, about 275 μm, or about 300 μm.

[0075] In certain embodiments, the corneal implant may have a uniform thickness. In certain embodiments, the corneal implant has a myopic lenticule shape (FIG. 8B) in which the center of the lenticule is thinner than the edge, or has a hyperopic lenticule shape (FIG. 8C) in which the center of the lenticule is thicker than the edge. In the case of the corneal implant having a myopic or hyperopic shape, the thickness as provided herein is the average thickness. Concentric grooves on inner (concave) surface of corneal implant

[0076] FIG. 8D shown a cross-sectional view of a lenticule-shaped corneal implant 100 in accordance with an embodiment of the disclosure. As shown in FIG. 8D, a lenticule-shaped corneal implant 100 typically comprises two surfaces: an outer surface 120 having a convex dome shape and an inner surface 140 having a concave dome shape. FIG. 8E shows the inner surface 140 of the same corneal implant 100.

[0077] In certain embodiments, the corneal implant 100 comprises, on the inner surface 140, at least two circular grooves, each groove being an indentation formed on the inner surface 140 of the corneal implant 100. As shown in FIGS. 8D-8E, the corneal implant 100 comprises, by way of example, three circular grooves, a first circular groove 152, a second circular groove 154, and a third circular groove 156. In certain embodiments, as shown in FIGS. 8D-8E, each circular groove is concentric with respect to the other grooves. In certain embodiments, also as shown in FIGS. 8D-8E, each circular groove is concentric with respect to the other grooves.

[0078] In certain embodiments, a corneal implant may have 1, 2, 3, 4, 5, 6, or 7 circular grooves on the inner surface.

[0079] The diameter of a groove, or the respective diameters of a plurality of grooves, on an inner surface of a corneal implant, may depend of the diameter of the corneal implant and the number of grooves. In certain embodiments, a groove may have a diameter of between about 1 mm and about 14 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 7 mm, about 8 mm, about 9 mm, about 10 mm, about 11 mm, about 12 mm, about 13 mm, or about 14 mm.

[0080] In certain embodiments, the depth of the grooves may be designed in such a manner that the presence of a lower diameter indentation would not cut the lenticule to smaller size, if a lenticule of larger diameter is required. In certain embodiments, the width of a groove may be sufficiently small such that, once the corneal implant is placed in an eye, the swelling of the 13 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 biopolymer of the implant may cause the groove to narrow, in certain cases to not be functionally present.

[0081] In certain embodiments, the width of a groove may be between about 20 nanometers (nm) and about 1000 nm, between about 50 nm and about 1000 nm, between about 60 nm and about 1000 nm, between about 75 nm and about 1000 nm, between about 100 nm and about 1000 nm, between about 200 nm and about 1000 nm, between about 300 nm about 1000 nm, between about 400 nm and about 1000 nm, between about 500 nm and about 1000 nm, between about 750 nm and about 1000 nm, between bout 20 nm and about 750 nm, between about 50 nm and about 750 nm, between about 60 nm and about 750 nm between, about 75 nm and about 750 nm, between about 100 nm and about 750 nm, between about 200 nm and about 750 nm, between about 300 nm and about 750 nm, between about 400 nm and about 750 nm, between about 500 nm and about 750 nm, between about 20 nm and about 500 nm, between about 50 nm and about 500 nm, between about 60 nm and about 500 nm, between about 75 nm and about 500750 nm, between about 100 nm and about 500 nm, between about 200 nm and about 500 nm, between about 300 nm and about 500 nm, between about 400 nm and about 500 nm, between about 20 nm and about 300 nm, between about 50 nm and about 300 nm, between about 60 nm and about 300 nm, between about 75 nm and about 300 nm, between about 100 nm and about 300 nm, between about 200 nm and about 300 nm, between about 20 nm and about 200 nm, between about 50 nm and about 200 nm, between about 60 nm and about 200 nm, between about 75 nm and about 200 nm, between about 100 nm and about 200 nm, between about 20 nm and about 150 nm, between about 50 nm and about 150 nm, between about 60 nm and about 150 nm, between about 75 nm and about 150 nm, between about 100 nm and about 150 nm, between about 20 nm and about 100 nm, between about 50 nm and about 100 nm, between about 60 nm and about 100 nm, between about 75 nm and about 100 nm.

[0082] In certain embodiments, the depth of a groove may be between about 20 nanometers (nm) and about 1000 nm, between about 50 nm and about 1000 nm, between about 60 nm and about 1000 nm, between about 75 nm and about 1000 nm, between about 100 nm and about 1000 nm, between about 200 nm and about 1000 nm, between about 300 nm about 1000 nm, between about 400 nm and about 1000 nm, between about 500 nm and about 1000 nm, between about 750 nm and about 1000 nm, between bout 20 nm and about 750 nm, between about 50 nm and about 750 nm, between about 60 nm and about 750 nm between, about 75 nm and about 750 nm, between about 100 nm and about 750 nm, between about 200 nm and about 750 nm, between about 300 14 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 nm and about 750 nm, between about 400 nm and about 750 nm, between about 500 nm and about 750 nm, between about 20 nm and about 500 nm, between about 50 nm and about 500 nm, between about 60 nm and about 500 nm, between about 75 nm and about 500750 nm, between about 100 nm and about 500 nm, between about 200 nm and about 500 nm, between about 300 nm and about 500 nm, between about 400 nm and about 500 nm, between about 20 nm and about 300 nm, between about 50 nm and about 300 nm, between about 60 nm and about 300 nm, between about 75 nm and about 300 nm, between about 100 nm and about 300 nm, between about 200 nm and about 300 nm, between about 20 nm and about 200 nm, between about 50 nm and about 200 nm, between about 60 nm and about 200 nm, between about 75 nm and about 200 nm, between about 100 nm and about 200 nm, between about 20 nm and about 150 nm, between about 50 nm and about 150 nm, between about 60 nm and about 150 nm, between about 75 nm and about 150 nm, between about 100 nm and about 150 nm, between about 20 nm and about 100 nm, between about 50 nm and about 100 nm, between about 60 nm and about 100 nm, between about 75 nm and about 100 nm.

[0083] In certain embodiments, a higher diameter circular groove is deeper than a lower diameter circular groove. This is shown for example in FIG. 8D, in which circular groove 152, which has a larger diameter compared to circular groove 154, is formed as a deeper indentation compared to circular groove 154, Similarly, circular groove 154, which has a larger diameter compared to circular groove 156, is formed as a deeper indentation compared to circular groove 156.

[0084] The presence of grooves in corneal implant 100 may serve as a guide or scale for determining the diameter of the lenticules, in which multiple size lenticules may be generated from a single mold. For example, a corneal implant 100 having a diameter of, e.g., 14 mm may have concentric grooves on the inner surface 140 having a diameter of 3 mm, 5 mm and 10 mm respectively. These grooves may be used as guide for obtaining and cutting out a lenticule of desired size to be implanted into the patient. As such, the grooves advantageously remove the requirement of multiple trephines in the operation theatre. Physical properties of corneal implants

[0085] In certain embodiments, the corneal implant may have a compressive modulus of between about 300 kPa and about 550 kPa, between about 350 kPa and about 550 kPa, between about 400 kPa and about 550 kPa, between about 500 kPa and about 550 kPa, between about 300 kPa and about 500 kPa, between about 350 kPa and about 500 kPa, between about 400 kPa and 15 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 about 500 kPa, between about 450 kPa and about 500 kPa, between about 300 kPa and about 400 kPa, or between about 350 kPa and about 400 kPa.

[0086] In certain embodiments, the corneal implant may have a tensile strength of between about 30 kPa and about 70 kPa, between about 40 kPa and about 70 kPa, between about 50 kPa and about 70 kPa, between about 60 kPa and about 70 kPa, between about 30 kPa and about 60 kPa, between about 40 kPa and about 60 kPa, between about 50 kPa and about 60 kPa, between about 30 kPa and about 50 kPa, or between about 40 kPa and about 50 kPa.

[0087] In certain embodiments, the corneal implant may have a swelling degree of between about 8% and about 18%, between about 8% and about 15%, between about 8% and about 10%, between about 10% and about 18%, between about 10% and about 15%.

[0088] In certain embodiments, corneal implant may have a transmittance of t visible light between about 75% and about 95%, between about 80% and about 95%, between about 85% and about 95%, between about 90% and about 95%, between about 75% and about 90%, or between about 85% and about 90%. Composite material:

[0089] In some embodiments, the corneal implant of the present disclosure comprises a biocompatible body being formed from a composite material (or biopolymer formulation) comprising at least one polymer. In an embodiment the at least one polymer may be selected from the group consisting of hyaluronic acid; gelatin; polyethylene glycol; alginate; collagen type I; synthetic polypeptide as set forth in SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3; and combinations thereof. In a preferred embodiment, the polymers may optionally comprise a plurality of functional groups selected from the group consisting of thiol, monomethacrylate, dimethacrylate, polymethacrylate, aldehyde, amine, and mixtures thereof. In a further preferred embodiment, the functional groups are thiol, or monomethacrylate. Gel-SH and HA-MA

[0090] In certain embodiments, the composite material may comprise a thiolated gelatin (Gel- SH) and a methacrylated hyaluronic acid (HA-MA). The Gel-SH may have an average molecular weight of between 50 kDa and 300 kDa, and an average degree of substitution of between about 0.5 mmol / g and about 0.9 mmol / g (preferably between about 0.6 mmol / g and about 0.8 mmol / g). In certain embodiments, the HA-MA may have an average molecular weight of between 25 kDa and 40 kDa (preferably 33kDa), and an average degree of substitution of between about 0.7 mmol / g and about 0.9 mmol / g (preferably about 0.6 mmol / g and about 0.8 mmol / g). 16 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117

[0091] In certain embodiments, the Gel-SH and the HA-MA may be dissolved in a saline, for example a NaCl saline which may be a 0.9N NaCl saline. In certain embodiments, the Gel-SH may be at a concentration of between about 20 mg / ml and about 150 mg / ml; and the HA-MA may be at a concentration of between about 20 mg / ml and about 150 mg / ml. The Gel-SH and the HA- MA may be at a weight ratio of between about 1:7.5 and about 7.5:1, preferably between about 1:0.3 and about 1:0.7 in the composite material. Further, the Gel-SH has a bloom strength in the range of about 100 bloom and about 300 bloom. Gel-MA and HA-MA

[0092] In certain embodiments, the composite material may comprise a HA-MA and a methacrylated gelatin (Gel-MA).

[0093] In certain embodiments, the HA-MA may have a molecular weight in a range of 5 to 60 kDa (preferably 33kDa). In certain embodiments, the HA-MA may have an average molecular weight of between about 25 kDa and about 40 kDa, between about 30 kDa and about 40 kDa, between about 35 kDa and about 40 kDa, between about 25 kDa and about 35 kDa, between about 30 kDa and about 35 kDa, or between about 30 kDa and about 35 kDa.

[0094] In certain embodiments, the HA-MA may have an average degree of substitution of between about 20 and about 75%, between about 30 and about 75%, between about 40 and about 75%, between about 50 and about 75%, between about 60 and about 75%, between about 20 and about 60%,between about 30 and about 60%, between about 40 and about 60%, between about 50 and about 60%, between about 20 and about 50%,between about 30 and about 50%, between about 40 and about 50%, between about 20 and about 40%, or between about 30 and about 40%. In certain embodiments, the HA-MA may have an average degree of substitution of between about 0.7 mmol / g and about 0.9 mmol / g, or about 0.8 mmol / g.

[0095] In certain embodiments, the methacrylated gelatin (Gel-MA) may have a molecular weight in a range of between about 50 kDa and about 1000 kDa (preferably 90kDa) or between about 80 bloom and about 325 bloom. In certain embodiments, the average molecular weight of the Gel-MA is between about 100 bloom and about 250 bloom, between about 159 bloom and about 250 bloom, between about 200 bloom and about 250 bloom, between about 100 bloom and about 200 bloom, between about 150 bloom and about 200 bloom, or between about 100 bloom and about 150 bloom.

[0096] In certain embodiments, the Gel-MA may have an average degree of substitution of between about 30% to about 99%. In certain embodiments, the average degree of substitution of 17 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 the Gel-MA is between about 30% and about 50%, between about 35% and about 50%, between about 40% and about 50%, between about 45% and about 50%, between about 30% and about 45%, between about 35% and about 45%, between about 40% and about 45%, between about 30% and about 40%, between about 35% and about 40%.

[0097] In certain embodiments, the Gel-MA and the HA-MA may be at a weight ratio (Gel- MA:HA-MA) of between about 100:10 and about 100:20, between about 100:15 and about 100:20, or between about 100:10 and about 100:15.

[0098] In certain embodiments, the HA-MA acid may be at a concentration of between about 20 mg / ml and about 70 mg / ml, between about 30 mg / ml and about 70 mg / ml, between about 40 mg / ml and about 70 mg / ml, between about 50 mg / ml and about 70 mg / ml, between about 60 mg / ml and about 70 mg / ml, 20 mg / ml and about 60 mg / ml, between about 30 mg / ml and about 60 mg / ml, between about 40 mg / ml and about 60 mg / ml, between about 50 mg / ml and about 60 mg / ml, 20 mg / ml and about 50 mg / ml, between about 30 mg / ml and about 50 mg / ml, between about 40 mg / ml and about 50 mg / ml, 20 mg / ml and about 40 mg / ml, between about 30 mg / ml and about 40 mg / ml, 20 mg / ml and about 30 mg / ml, or about 30 mg / ml.

[0099] In certain embodiments, the Gel-MA may be at a concentration of between about 20 mg / ml and about 220 mg / ml, between about 50 mg / ml and about 220 mg / ml, between about 100 mg / ml and about 220 mg / ml, between about 150 mg / ml and about 220 mg / ml, between about 200 mg / ml and about 220 mg / ml, 20 mg / ml and about 200 mg / ml, between about 50 mg / ml and about 200 mg / ml, between about 100 mg / ml and about 200 mg / ml, between about 150 mg / ml and about 200 mg / ml, between about 20 mg / ml and about 150 mg / ml, between about 50 mg / ml and about 150 mg / ml, between about 100 mg / ml and about 150 mg / ml, between about 20 mg / ml and about 100 mg / ml, between about 50 mg / ml and about 100 mg / ml, between about 20 mg / ml and about 50 mg / ml.

[0100] In an additional embodiment, the composite material may further comprise saline in a weight range of 70 to 96% with respect to the total weight of the composite material. Other materials

[0100] In yet another embodiment, the composite material may be an elastomeric hydrogel comprising: (a) a synthetic polypeptide as set forth in SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3, (b) a photoinitiator for cross linking the synthetic polypeptide, and (c) a catalyst. In a preferred embodiment, the catalyst may be ammonium persulphate (APS). Therapeutic exosomes: 18 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117

[0101] The composite material as described herein may further comprise a therapeutic agent selected from exosomes and liposomes, preferably exosomes. The exosomes may have a size in the range of 30 to 200 nm. The exosomes may express at least one marker selected from CD9, CD63, CD81, Alix, TSG101, Flotillin, or combinations thereof. Further, the exosomes may comprise cargo molecules selected from HGF, NGF, sFlt-1, VEGF, IDO, SDF-1a, BDNF, CD63, or combinations thereof. The exosomes are therapeutically potent and may exhibit one or more of the following properties: anti-angiogenic property, neurogenesis activity, anti-fibrosis activity, anti-inflammatory activity and wound healing activity.

[0102] In an embodiment, the polymers may be mixed with the exosomes for preparing a composite material which is therapeutically potent. In another embodiment, a photoinitiator as described herein may be added to the polymers for crosslinking the polymers.

[0103] The exosomes maybe obtained by methods known in the art. In an exemplary embodiment, the exosomes are obtained by culturing mesenchymal stem cells (MSCs) in expansion media comprising at least one inducer. In some embodiments, the inducer may be a Nrf-2 activator, which may, be selected from dimethyl fumarate (DMF), Imidazole derivative of 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oic acid (CDDO-Im), 4-octyl itaconate, Arylcyclohexyl pyrazoles, Sulfonyl coumarins, Benzenesulfonyl-pyrimidone, 1, 4- Diaminonaphthalene core containing compounds, 1,2,3,4- Tetrahydroisoquinoline core containing compounds, Nrf-2 inducing peptides (LDEETGEFL-NH2 (SEQ ID NO: 4), (NH2- RKKRRQRRRPLFAERLDEETGEFLPNH2) (SEQ ID NO: 5), Ac-DPETGEL-OH (SEQ ID NO: 6), Ac-DEETGEF-OH (SEQ ID NO: 7), LQLDEETGEFLPIQGK(MR121)-OH (SEQ ID NO: 8), Ac-LDEETGEFL-NH (SEQ ID NO: 9), AcDPETGEL-NH2 (SEQ ID NO: 10), Ac-NPETGEL- OH(SEQ ID NO: 11), or mixtures thereof. In certain embodiments, the inducer is DMF. In certain embodiments, the at least one inducer comprises a first inducer and a second inducer. In certain embodiments, the first inducer may be a secretome of human corneal stromal stem cells (CSSC); and the second inducer may an Nrf-2 activator (e.g., DMF or any of those provide above). In certain embodiments, the first inducer is HGF (e.g., form a secretome derived from human CSSC) and the second inducer is dimethyl fumarate (DMF). Photoinitiator:

[0104] A “photoinitiator” or “photo-initiator” or “photoactivator”, as used in the present disclosure, refers to a molecule that creates reactive species (e.g.: free radicals, cations, or anions) when exposed to light or radiation (UV or visible). Photoinitiator, in the present disclosure, is 19 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 added to the polymers in the composite material to initiate the polymerization process. In various embodiments herein, it refers to the molecules which facilitates the formation of cross-linked or interconnected polymeric matrix of polymers, upon exposure to light. A person of skill in the art may select an appropriate photoinitiator for selected polymers. In an embodiment, the photoinitiator may be selected from eosin Y, triethanolamine, riboflavin, 2-hydroxy-4'-(2- hydroxyethoxy)-2-methylpropiophenone (Irgacure), lithium phenyl (2,4,6-trimethylbenzoyl) phosphinate (LAP), sodium persulphate (SPS), ruthenium-sodium persulfate, chloro (pentamethylcyclopentadienyl) bis(triphenylphosphine) ruthenium (II); or mixtures thereof. In certain embodiments, the photoinitiator may be a combination of ruthenium(II) tris(bipyridyl) chloride and sodium persulphate (SPS), which may be referred to herein as “Ru / SPS”). In certain embodiments, the photoinitiator may be in a weight range of 0.005 to 0.7% (1-30mM) with respect to the total weight of the composite material.

[0105] The composite material further may comprise a photoabsorber selected from tartrazine, fast green FCF, new coccine, methylene blue, or mixtures thereof, preferably tartrazine. In another embodiment, the photoabsorber is in a weight percentage range of 0.007 to 0.04% (0.1635 mM – 0.754 mM) in respect of the composite material. Peripheral zone

[0106] In certain embodiments, a corneal implant in accordance with the disclosure may comprise a peripheral zone that is characterized by different physical parameter compared to a central portion. In certain embodiments, the peripheral zone may be characterized, compared to a central portion of the corneal implant by: a higher tensile strength; a higher puncture resistance, a lower elastic modulus, or a combination thereof. FIG. 9 shows, by way of example, a corneal implant 200 with a central portion 210 and a peripheral zone 220.

[0107] In certain embodiments, the central portion 210 may be characterized by a higher degree of cross-linking compared to the peripheral zone 220.

[0108] In certain embodiments, the composite material of the peripheral zone 220 may be different from the composite material of central portion 210. Methacrylated gelatin (Gel-MA) and a Hyaluronic acid-Aldehyde (HA-CHO)

[0109] In certain embodiments, the composite material of the peripheral zone may comprise a methacrylated gelatin (Gel-MA) and a Hyaluronic acid-Aldehyde (HA-CHO).

[0110] In certain embodiments, the average molecular weight of the Gel-MA may be between about 100 bloom and about 250 bloom, between about 159 bloom and about 250 bloom, between 20 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 about 200 bloom and about 250 bloom, between about 100 bloom and about 200 bloom, between about 150 bloom and about 200 bloom, or between about 100 bloom and about 150 bloom.

[0111] In certain embodiments, the average degree of substitution of the Gel-MA may be between about 30% and about 50%, between about 35% and about 50%, between about 40% and about 50%, between about 45% and about 50%, between about 30% and about 45%, between about 35% and about 45%, between about 40% and about 45%, between about 30% and about 40%, between about 35% and about 40%.

[0112] In certain embodiments, the HA-CHO may have an average molecular weight of between about 200 kDa and about 300 kDa, between about 220 kDa and about 300 kDa, between about 240 kDa and about 300 kDa, between about 260 kDa and about 300 kDa, between about 280 kDa and about 300 kDa, between about 200 kDa and about 280 kDa, between about 220 kDa and about 280 kDa, between about 240 kDa and about 280 kDa, between about 260 kDa and about 280 kDa, between about 200 kDa and about 260 kDa, between about 220 kDa and about 260 kDa, between about 240 kDa and about 260 kDa, between about 200 kDa and about 240 kDa, between about 220 kDa and about 240 kDa, or between about 200 kDa and about 220 kDa.

[0113] In certain embodiments, the HA-CHO may have an average degree of substitution of between about 2% and about 10%, between about 4% and about 10%, between about 6% and about 10%, between about 8% and about 10%, between about 2% and about 8%, between about 4% and about 8%, between about 6% and about 8%, between about 2% and about 6%, between about 4% and about 6%, or between about 2% and about 4%.

[0114] In certain embodiments, the Gel-MA and the HA-CHO may be at a weight ratio (Gel- MA:HA-CHO) of between about 100:15 and about 100:50, between about 100:20 and about 100:50, between about 100:30 and about 100:50, between about 100:40 and about 100:50, between about 100:15 and about 100:40, between about 100:20 and about 100:40, between about 100:30 and about 100:40, between about 100:15 and about 100:30, between about 100:20 and about 100:30, or between about 100:15 and about 100:20.

[0115] In certain embodiments, the composite material of the peripheral zone may further compris a methacrylated Hyaluronic acid (HA-MA), a Hyaluronic acid-Hydrazide (HA-NHNH2), or a combination thereof.

[0116] In certain embodiments, the HA-NHNH2 may have an average molecular weight of between about 30 kDa and about 70 kDa, between about 40 kDa and about 70 kDa, between about 50 kDa and about 70 kDa, between about 60 kDa and about 70 kDa, between about 30 kDa and 21 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 about 60 kDa, between about 40 kDa and about 60 kDa, between about 50 kDa and about 60 kDa, between about 30 kDa and about 50 kDa, between about 40 kDa and about 50 kDa, or between about 30 kDa and about 40 kDa.

[0117] In certain embodiments, the HA-MA may have an average molecular weight of between about 25 kDa and about 40 kDa, between about 30 kDa and about 40 kDa, between about 35 kDa and about 40 kDa, between about 25 kDa and about 35 kDa, between about 30 kDa and about 35 kDa, or between about 30 kDa and about 35 kDa.

[0118] In certain embodiments, the HA-MA may have an average degree of substitution of between about 0.7 mmol / g and about 0.9 mmol / g, or about 0.8 mmol / g.

[0119] In certain embodiments, the Gel-MA and the HA-MA may be at a weight ratio (Gel- MA:HA-MA) of between about 100:10 and about 100:20, between about 100:15 and about 100:20, or between about 100:10 and about 100:15.

[0120] In certain embodiments, the composite material of the peripheral zone may comprise the Gel-MA and the HA-NHNH2 at a weight ratio (Gel-MA:HA-NHNH2) of between about 100:2 and about 100:10, between about 100:4 and about 100:10, between about 100:5 and about 100:10, between about 100:5 and about 100:10. between about 100:2 and about 100:8, between about 100:4 and about 100:8, between about 100:6 and about 100:8, between about 100:2 and about 100:6, between about 100:4 and about 100:6, or between about 100:2 and about 100:4.

[0121] In certain embodiments, the composite material of the peripheral zone may comprises a combination of ruthenium(II) tris(bipyridyl) chloride and sodium persulphate (SPS) as a photoinitiator.

[0122] In certain embodiments, the composite material of the corneal implant as a whole may comprise a methacrylated gelatin (Gel-MA) and a Hyaluronic acid-Aldehyde (HA-CHO), and optionally one or both of a HA-MA and a HA-NHNH2, as described herein above. HA-SH and PEGDA

[0123] In certain embodiments, the composite material of the peripheral zone may comprise a thiolated hyaluronic acid (HA-SH) and a poly(ethylene glycol) diacrylate (PEGDA).

[0124] In certain embodiments, the HA-SH may have an average molecular weight of between about 30 kDa and about 70 kDa, between about 40 kDa and about 70 kDa, between about 50 kDa and about 70 kDa, between about 60 kDa and about 70 kDa, between about 30 kDa and about 60 kDa, between about 40 kDa and about 60 kDa, between about 50 kDa and about 60 kDa, between 22 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 about 30 kDa and about 50 kDa, between about 40 kDa and about 60 kDa, between about 30 kDa and about 40 kDa.

[0125] In certain embodiments, the HA-SH may have an average degree of substitution of between about 40% and about 60%, between about 45% and about 60%, between about 50% and about 60%, between about 55% and about 60%, between about 40% and about 50%, or between about 45% and about 50%.

[0126] In certain embodiments, the PEGDA may have an average molecular weight of between about 3 kDa and about 5 kDa, or about 4 kDa.

[0127] In certain embodiments, the PEGDA may have an average degree of substitution of at least 60%, at least 70%, at least 90%, at least 90%, between about 60% and about 80%.

[0128] In certain embodiments, the HA-SH and the PEGDA may be comprised in the composite material at a weight ratio (HA-SH:PEGDA) of between about 1:2 and about 2:1, or about 1:1.

[0129] In certain embodiments, the composite material of the peripheral zone may further comprise a combination of ruthenium(II) tris(bipyridyl) chloride and sodium persulphate (SPS) as a photoinitiator and dimethyl sulfoxide (DMSO) as a crosslinker.

[0130] In certain embodiments, the composite material of the corneal implant as a whole may comprise a thiolated hyaluronic acid (HA-SH) and a poly(ethylene glycol) diacrylate (PEGDA), as described herein above. Molding Apparatus:

[0131] The present disclosure provides embodiments of a molding apparatus for manufacturing a corneal implant of the present disclosure. Examples of the molding apparatus are shown in FIGS. 1A-1C and FIG. 2B. In some embodiments, the molding apparatus comprises a (lower) base and an top that may be transparent. The base may comprise a negative dome-shaped (i.e., concave) cavity configured to receive a cross-linkable composite material and characterized by a shape and dimensions corresponding to that of a corneal implant. The top may be configured to be placed on the base and comprise a convex dome-shaped elevation surface shaped and dimensioned so that a lenticule-shaped gap is formed between the cavity and the elevation surface when the top is situated on the base, and the cross-linkable composite material situated in the concave dome- shaped cavity would be formed therein having a shape corresponding to the lenticule-shaped gap. The molding apparatus may comprise a light source configured to emit light, and a light- transmitting surface positioned to allow passage of the light from the light source through the 23 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 light-transmitting surface to the concave cavity for crosslinking of the cross-linkable composite material. In an embodiment, the light is selected from white light (visible light), blue light or green light.

[0132] In certain embodiments, the base may be composed of a material that is non-reactive with the composite material of the corneal implant. In certain embodiments, the base may comprise structures for releasing the molded corneal implant once formed. Examples of structures for releasing the molded corneal implant includes: small movable pillars or spacers embedded in the cavity that can be lifted, or a clips type mechanism comprising a click lock or hold back assembly to secure the top with the base, as well as release the base and the top without disturbing the lenticule formed therebetween. In certain embodiments, the molding apparatus may further comprise an alignment mechanism to position the composite material within the cavity during the manufacturing of the corneal implant.

[0133] In certain embodiments (e.g. as shown in FIG 1B), the top is composed of a transparent material, and the convex elevation surface of the top functions as the light-transmitting surface that allows passage of light from the light source through to the base for crosslinking of polymers within the composite material of the corneal implant. In certain embodiment, the base is comprised of a transparent material, and the concave cavity of the base functions as the light-transmitting surface, and the light source is situated so that the light from the light source passes through the concave cavity serving as the light-transmitting surface for crosslinking of polymers withing the composite material.

[0134] In certain embodiments (e.g., as shown in FIGS. 1A-1C and 2B), the material of the transparent top can be acrylic resin, and the material of the base can be acrylic resin or stainless steel.

[0135] The elevation surface and the cavity are generally matched in shape and dimensions. However, there may be some differences. In certain embodiments, to create an implant with a myopic lenticule shape (FIG. 8B) in which the center of the lenticule is thinner than the edge, the elevation surface is more curved (e.g. has a shorter radius of curvature) than the cavity. In certain embodiments, to create an implant with a hyperopic lenticule shape (FIG.8B) in which the center of the lenticule is thicker than the edge, the elevation surface is less curved (e.g. has a longer radius of curvature) than the cavity.

[0136] Generally, the diameter of the elevation surface and the cavity correspond to the diameter of the corneal implant formed thereby. In some embodiments, the elevation surface or the cavity 24 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 may have a diameter of between about 2 mm and about 15 mm, between about 2 mm and about 10 mm, between about 2 mm and about 5 mm, between about 2 mm and about 4mm, between about 5 mm and about 15 mm, between about 5 mm and about 10 mm, between about 10 mm and about 15 mm, between about 10 mm and about 12 mm, about 2 mm, or about 3 mm.

[0137] In some embodiments, the elevation surface or the cavity may have a height of between about 0.05 mm and about 5 mm, between about 0.05 mm and about 4 mm, between about 0.05 mm and about 2 mm, between about 0.05 mm and about 1 mm, between about 0.05 mm and about 0.5 mm, between about 0.05 mm and about 0.1 mm, between about 0.07 mm and about 5 mm, between about 0.07 mm and about 4 mm, between about 0.07 mm and about 2 mm, between about 0.07 mm and about 1 mm, between about 0.07 mm and about 0.5 mm, between about 0.07 mm and about 0.1 mm, between about 0.1 mm and about 5 mm, between about 0.1 mm and about 4 mm, between about 0.1 mm and about 2 mm, between about 0.1 mm and about 1 mm, between about 0.1 mm and about 0.5 mm, between about 0.5 mm and about 5 mm, between about 0.5 mm and about 4 mm, between about 0.5 mm and about 3 mm, between about 0.5 mm and about 2 mm, between about 0.5 mm and about 1 mm, between about 1 mm and about 5 mm, between about 1 mm and about 4 mm, between about 1 mm and about 3 mm, between about 1 mm and about 2 mm, between about 2 mm and about 5 mm, between about 2 mm and about 4 mm, and between about 2 mm and about 3 mm.

[0138] In certain embodiments, when the transparent top is placed on top of, and aligned with, the base, the gap distance between the elevation surface and the cavity may be in the range of between about 50 μm and about 300 μm, between about 50 μm and about 250 μm, between about 50 μm and about 200 μm, between about 50 μm and about 150 μm, between about 50 μm and about 100 μm, between about 100 μm and about 300 μm, between about 100 μm and about 250 μm, between about 100 μm and about 200 μm, between about 150 μm and about 300 μm, between about 200 μm and about 300 μm, between about 150 μm and about 250 μm, about 50 μm, about 75 μm, about 100 μm, about 125 μm, about 150 μm, about 175 μm, about 200 μm, about 225 μm, about 250 μm, about 275 μm, or about 300 μm. In the case of the corneal implant having a myopic or hyperopic shape, the gap distance as provided herein is the average gap distance.. Ridges for groove formation

[0139] As all the requirement for the donor tissue for transplanting or substitute for implanting into patient’s damaged corneas are not of exact matching size always, a surgeon may want to resize the donated cornea tissues using, e.g., a circular surgical blade, also known as trephine. This 25 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 procedure requires the availability of multiple size of trephines or often resizing the circular tissue, cut using a trephine of standard (larger) diameter, or with scissors to match the size of transplantation site. The same applies for the use of corneal lenticules for implantation.

[0140] Alternatively, to generate a corneal lenticule of a specific size, pre-designed molds of various sizes may be used, which generate the lenticules of specific size (one mold-one size lenticule), this approach demands multiple molds for generating varied size lenticules.

[0141] Alternatively, in an embodiment of the disclosure, presence of indentations or grooves in the lenticules may act as a guide or scale for determining the diameter of the lenticules, in which multiple size lenticules may be generated from a single mold. For example, a lenticule may have grooves on the inner surface of the lenticule at, e.g., 3 mm, 5 mm and 10 mm in a 14 mm diameter lenticule, which can be used as a guide for obtaining a lenticule of desired size to be implanted into the patient. As such, the grooves advantageously remove the requirement of multiple trephines in the operation theatre.

[0142] In certain embodiments, the depth of the grooves may be designed in such a manner that the presence of a lower diameter indentation would not cut the lenticule to smaller size, if a lenticule of larger diameter is required. In certain embodiments, a groove may be narrow enough to be covered by the swelling property of the polymer from which the lenticule is made, for example after the lenticule is placed on an eye of a patient.

[0143] In order to form the grooves in the lenticules, in some embodiments, the convex elevation surface of the molding apparatus may comprise a plurality of circular ridges for forming guiding grooves in the corneal implant formed in the gap between the elevation surface and the concave cavity. In some embodiments, the ridges on the elevation surface are of radially increasing heights and aid in obtaining implants of variable diameter (see, FIGS. 1D and 1E). The term “radially” used herein refers to the arrangement of the ridges on the elevation surface. Herein, the smallest ridge will be at the center of the elevation surface, while the largest grove will be at the outer most side of the elevation surface, i.e., the ridges spread out from a central point of the elevation surface. In some of the embodiments, these ridges are termed as guiding ridges as they guide or direct the formation of grooves in the implant in the crater surface.

[0144] In another embodiment, the elevation surface is without ridges. In an exemplary embodiment, the elevation surface and the cavity of the base of the apparatus can be of different sizes to facilitate the manufacturing of implants of different sizes (refer Figure 1(c)). In some embodiments the size or diameter of the elevation surface and the cavity of the apparatus may 26 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 range from about 2 mm to 15 mm. In few exemplary embodiments, the size of the elevation surface and the cavity of the apparatus may be 2 mm, 3 mm, 5 mm, or 7 mm.

[0145] In certain embodiments, the elevation surface may have 1, 2, 3, 4, 5, 6, or 7 circular ridges on its surface.

[0146] The diameter of the ridge, or the respective diameter of each of a plurality of ridges, on the elevation surface, may depend of the diameter of the elevation surface and the number of grooves. In certain embodiments, a ridge may have a diameter of between about 1 mm and about 14 mm, about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 7 mm, about 8 mm, about 9 mm, about 10 mm, about 11 mm, about 12 mm, about 13 mm, or about 14 mm.

[0147] In certain embodiments, the width of a ridge may be between about 20 nanometers (nm) and about 1000 nm, between about 50 nm and about 1000 nm, between about 60 nm and about 1000 nm, between about 75 nm and about 1000 nm, between about 100 nm and about 1000 nm, between about 200 nm and about 1000 nm, between about 300 nm about 1000 nm, between about 400 nm and about 1000 nm, between about 500 nm and about 1000 nm, between about 750 nm and about 1000 nm, between bout 20 nm and about 750 nm, between about 50 nm and about 750 nm, between about 60 nm and about 750 nm between, about 75 nm and about 750 nm, between about 100 nm and about 750 nm, between about 200 nm and about 750 nm, between about 300 nm and about 750 nm, between about 400 nm and about 750 nm, between about 500 nm and about 750 nm, between about 20 nm and about 500 nm, between about 50 nm and about 500 nm, between about 60 nm and about 500 nm, between about 75 nm and about 500750 nm, between about 100 nm and about 500 nm, between about 200 nm and about 500 nm, between about 300 nm and about 500 nm, between about 400 nm and about 500 nm, between about 20 nm and about 300 nm, between about 50 nm and about 300 nm, between about 60 nm and about 300 nm, between about 75 nm and about 300 nm, between about 100 nm and about 300 nm, between about 200 nm and about 300 nm, between about 20 nm and about 200 nm, between about 50 nm and about 200 nm, between about 60 nm and about 200 nm, between about 75 nm and about 200 nm, between about 100 nm and about 200 nm, between about 20 nm and about 150 nm, between about 50 nm and about 150 nm, between about 60 nm and about 150 nm, between about 75 nm and about 150 nm, between about 100 nm and about 150 nm, between about 20 nm and about 100 nm, between about 50 nm and about 100 nm, between about 60 nm and about 100 nm, between about 75 nm and about 100 nm. 27 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117

[0148] In certain embodiments, the height of a ridge may be between about 20 nanometers (nm) and about 1000 nm, between about 50 nm and about 1000 nm, between about 60 nm and about 1000 nm, between about 75 nm and about 1000 nm, between about 100 nm and about 1000 nm, between about 200 nm and about 1000 nm, between about 300 nm about 1000 nm, between about 400 nm and about 1000 nm, between about 500 nm and about 1000 nm, between about 750 nm and about 1000 nm, between bout 20 nm and about 750 nm, between about 50 nm and about 750 nm, between about 60 nm and about 750 nm between, about 75 nm and about 750 nm, between about 100 nm and about 750 nm, between about 200 nm and about 750 nm, between about 300 nm and about 750 nm, between about 400 nm and about 750 nm, between about 500 nm and about 750 nm, between about 20 nm and about 500 nm, between about 50 nm and about 500 nm, between about 60 nm and about 500 nm, between about 75 nm and about 500750 nm, between about 100 nm and about 500 nm, between about 200 nm and about 500 nm, between about 300 nm and about 500 nm, between about 400 nm and about 500 nm, between about 20 nm and about 300 nm, between about 50 nm and about 300 nm, between about 60 nm and about 300 nm, between about 75 nm and about 300 nm, between about 100 nm and about 300 nm, between about 200 nm and about 300 nm, between about 20 nm and about 200 nm, between about 50 nm and about 200 nm, between about 60 nm and about 200 nm, between about 75 nm and about 200 nm, between about 100 nm and about 200 nm, between about 20 nm and about 150 nm, between about 50 nm and about 150 nm, between about 60 nm and about 150 nm, between about 75 nm and about 150 nm, between about 100 nm and about 150 nm, between about 20 nm and about 100 nm, between about 50 nm and about 100 nm, between about 60 nm and about 100 nm, between about 75 nm and about 100 nm.

[0149] The molding apparatus may be an injection molding apparatus or a compression molding apparatus. In an exemplary embodiment, the apparatus is compression molding apparatus.

[0150] In some embodiment, the molding apparatus may be configured with a locking mechanism. In an exemplary embodiment, the locking mechanism is a “click lock”. Preferably, the “click lock” is placed between the transparent top and the base to secure the top and the base of the apparatus or the gap between the top and the base of the apparatus. Process of preparing the corneal implant:

[0151] The embodiments of the present disclosure also provide a process of preparing the corneal implant as described herein. In some embodiments, the process may comprise: introducing the composite material into the cavity in the molding apparatus as described herein, and exposing 28 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 the composite material to light for crosslinking of one or more cross-linkable polymers comprised in the composite material in the presence of a photoinitiator for preparation of the corneal implant. In an exemplary embodiment, the light is selected from white light (visible light), blue light or green light.

[0152] Where the corneal implant comprises a peripheral zone, the process may comprise: applying the first composite material into the cavity in the molding apparatus and exposing the first composite material to light for crosslinking, thereby forming a central portion; applying the second composite material into the cavity in the molding apparatus, so that the second composite material is placed on, near, or around the outer rim of the central portion; and exposing the second composite material to light for crosslinking of the second composite material, thereby forming the peripheral zone. Treatment method / process:

[0153] The present disclosure also provides embodiments of methods and / or processes of implanting a corneal implant of the disclosure in an eye of a subject. In certain embodiments, the cornea of the eye may be damaged, or removed or resected (partially or fully) prior to implantation of the implant. For example, a damaged or diseased portion of the cornea may be resected to create gap in the cornea, into which the implant is implanted and attached. Alternately, the corneal implant may be placed and attached on an existing corneal surface.

[0154] The corneal implant may be attached to the surrounding or adjacent tissue by a number of methods.

[0155] In certain embodiment, the attaching comprises applying a thin layer of a surgical adhesive at a central region on the inner face of the implant or on a portion of the eye where the implant will be placed (the application site), then applying the implant on the application site. In certain embodiments, the surgical adhesive may be a composite material of the disclosure from which a corneal implant may be formed, in a non-crosslinked state. In certain embodiments, the composite material used for the adhesion and the composite material of the corneal implant may be the same, or different. Where the adhesive is composite material of the disclosure, the placement of the implant onto the application site may be followed by exposure to light to crosslink the crosslinkable polymers comprised in the composite material. The frequency and duration of the light exposure will depend on the composite material, but may be, for example, between 30 seconds and 1 minute. 29 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117

[0156] In certain embodiments, the corneal implant may sutured onto surrounding tissue, e.g., corneal tissue. In certain embodiments, the sutures may be done at a peripheral zone of the corneal implant in accordance with an embodiment of the disclosure.

[0157] The present disclosure also provides embodiments of methods and / or processes of treating a subject with corneal disorders using the corneal implant as described herein. In a particular embodiment, the corneal disorder is selected from the group consisting of corneal thinning, advanced keratoconus, corneal degeneration and corneal defects requiring transplant or graft. In an exemplary embodiment, the treatment comprises implanting the corneal implant in the subject.

[0158] Although the subject matter has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the subject matter, will become apparent to persons skilled in the art upon reference to the description of the subject matter. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present subject matter as defined. LIST OF ABBREVIATIONS AS-OCT Anterior segment optical coherence tomography α‐SMA alpha smooth muscle actin BSA Bovine Serum Albumin CO2Carbon Dioxide CD Cluster of Differentiation D power of cornea in diameter DAPI 4′,6-diamidino-2-phenylindole DMEM / F12 1:1 mixture of Dulbecco's Modified Eagle's Medium (DMEM) and Ham's F-12 Nutrient Mixture ECM Extracellular Matrix EGF Epidermal Growth factor FBS Fetal Bovine Serum °C degree Celsius g gram ×g gravity 30 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 Gel-MA Methacrylated gelatin Gel-SH Thiolated gelatin GSU Gray scale units h hours HA-MA Methacrylated hyaluronic acid HCLE cells Human Cornea limbal epithelial cells hCSCs Human corneal stromal cells H2O water Hz hertz IOP Intraocular pressure kg kilogram kN kilo-Newton kPa kilopascal KSFM Keratinocyte- serum free media μL microliter mL milliliter mg milligram mm millimeter min minute μM micro-Molar mM milli-Molar mW milli-watts Newton nm nanometer OCT Optical coherence tomography OD Optical Density % Percentage PBS Phosphate Buffered Saline rpm rotations per minute Ru Ruthenium s seconds SLA stereolithography 31 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 SPS Sodium persulfate U units 3D three-dimensional Numbered embodiments

[0159] Embodiment I-1. A corneal implant comprising: a biocompatible body having a dome-shaped configuration conforming to the curvature of the cornea, the biocompatible body being either positionable on the surface of the cornea or at least partially integrable with a layer of the cornea, the biocompatible body having a peripheral zone to integrate the biocompatible body with or position the biocompatible body on the cornea to maintain stability of the corneal implant in a deployed state, wherein, in the deployed state, the biocompatible body is to mimic a natural curvature of the cornea to provide a seamless interface with the cornea, the biocompatible body being formed from a composite material comprising at least one polymer.

[0160] Embodiment I-2. The corneal implant of embodiment I-1, wherein the at least one polymer is selected from the group consisting of hyaluronic acid; gelatin; polyethylene glycol; alginate; collagen type I; synthetic polypeptide as set forth in SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3; and combinations thereof.

[0161] Embodiment I-3. The corneal implant of embodiment I-1, wherein the composite material comprises a photoinitiator for cross-linking the polymers upon exposure to light.

[0162] Embodiment I-4. The corneal implant of embodiments I-1 to I-3, wherein the polymers optionally comprise a plurality of functional groups selected from the group consisting of thiol, monomethacrylate, dimethacrylate, polymethacrylate, aldehyde, amine, and mixtures thereof.

[0163] Embodiment I-5. The corneal implant of embodiments I-1 to I-4, wherein the composite material comprises a thiolated gelatin having an average molecular weight of between 50 kDa and 200 kDa, and with an average degree of substitution of between about 0.5 mmol / g and about 0.9 mmol / g; and a methacrylated hyaluronic acid having an average molecular weight of between 25 kDa and 40 kDa, and with an average degree of substitution of between about 0.7 mmol / g and about 0.9 mmol / g.

[0164] Embodiment I-6. The corneal implant of embodiment I-5, wherein the thiolated gelatin is at a concentration of between about 20 mg / ml and about 150 mg / ml; and wherein the 32 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 methacrylated hyaluronic acid is at a concentration of between about 20 mg / ml and about 150 mg / ml.

[0165] Embodiment I-7. The corneal implant of embodiments I-5 to I-6, wherein the thiolated gelatin and the methacrylated hyaluronic acid are at a weight ratio of between about 1:7.5 and 7.5: 1, preferably between about 1:0.3 and about 1:0.7.

[0166] Embodiment I-8. The corneal implant of embodiments I-1 to I-4, wherein the composite material comprises methacrylated hyaluronic acid having molecular weight in a range of 5 to 60 kDa and with an average degree of substitution of between about 20 to 75%; and methacrylated gelatin having molecular weight in a range of 50 to 1000 kDa and with an average degree of substitution of between about 40 to 99%.

[0167] Embodiment I-9. The corneal implant of embodiment I-8, wherein the methacrylated hyaluronic acid is at a concentration of between about 20-70 mg / ml; and wherein the methacrylated gelatin is at a concentration of between about 20-220 mg / ml.

[0168] Embodiment I-10. The corneal implant of embodiments I-8 to I-9, wherein the composite material further comprises a photoabsorber selected from tartrazine, fast green FCF, new coccine, methylene blue, or mixtures thereof, preferably tartrazine.

[0169] Embodiment I-11. The corneal implant of embodiment I-1, wherein the composite material is an elastomeric hydrogel comprising: (a) a synthetic polypeptide as set forth in SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3, (b) a photoinitiator for cross linking the synthetic polypeptide, and (c) a catalyst.

[0170] Embodiment I-12. The corneal implant of embodiments I-1 to I-11, wherein the composite material further comprises a therapeutic agent selected from exosomes and liposomes, preferably exosomes.

[0171] Embodiment I-13. The corneal implant of embodiment I-3, wherein the photoinitiator is selected from eosin Y, triethanolamine, riboflavin, 2-hydroxy-4'-(2-hydroxyethoxy)-2- methylpropiophenone (Irgacure), lithium phenyl (2,4,6-trimethylbenzoyl) phosphinate (LAP), sodium persulphate (SPS), ruthenium-sodium persulfate, chloro (pentamethylcyclopentadienyl) bis (triphenylphosphine) ruthenium (II); or mixtures thereof, and is in a weight range of 0.005 to 0.7% (1-30mM) with respect to the total weight of the composite material.

[0172] Embodiment I-14. The corneal implant of embodiment I-1, wherein the composite material further comprises saline in a weight range of 70 to 96% with respect to the total weight of the composite material. 33 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117

[0173] Embodiment I-15. The corneal implant of embodiment I-1, wherein the implant has a diameter ranging from 2mm to 15mm.

[0174] Embodiment I-16. The corneal implant of embodiment I-1, wherein the implant has a height ranging from 0.05mm to 5mm.

[0175] Embodiment I-17. The corneal implant of embodiment I-1, wherein the implant has a thickness in the range of 50- 300 μm.

[0176] Embodiment I-18. The corneal implant of embodiment I-3, wherein the light is selected from white light (visible light), blue light or green light.

[0177] Embodiment I-19. A molding apparatus for manufacturing a corneal implant of any one of embodiments I-1 to I-18, the molding apparatus comprising: a base having a cavity formed as a negative dome-shaped configuration corresponding to the configuration of the corneal implant, the base being composed of a material that is non-reactive with the composite material of the corneal implant and having structures for releasing molded corneal implant; an alignment mechanism to position the composite material within the cavity during the manufacturing of the corneal implant; and a light-transmitting surface positioned to allow passage of light through the light- transmitting surface to the base for crosslinking of the polymers within the composite material of the corneal implant.

[0178] Embodiment I-20. The molding apparatus of embodiment I-19, wherein the light- transmitting surface comprises a transparent top with a positive dome-shaped elevation surface.

[0179] Embodiment I-21. The molding apparatus of embodiment I-20, wherein the transparent top is made of acrylic resin and the base is made of either acrylic resin or stainless steel.

[0180] Embodiment I-22. The molding apparatus of embodiment I-20, wherein the distance between the elevation surface and the cavity is in the range of 50-300 μm.

[0181] Embodiment I-23. The molding apparatus of embodiment I-19, wherein the molding apparatus is an injection molding apparatus or compression molding apparatus.

[0182] Embodiment I-24. A process of preparing the corneal implant of embodiments I-1 to I- 3, comprising: introducing the composite material into the cavity in the molding apparatus of embodiment I-19; and 34 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 exposing the composite material to light for crosslinking of the polymers for preparation of the corneal implant.

[0183] Embodiment I-25. The process of embodiment I-24, wherein the light is selected from white light (visible light), blue light or green light.

[0184] Embodiment I-26. A process of treating a corneal disorder in a subject, said process comprising implanting the corneal implant of embodiment I-1 in the subject.

[0185] Embodiment I-27. The process of embodiment I-26, wherein the corneal disorder is selected from the group consisting of corneal thinning, advanced keratoconus, corneal degeneration and corneal defects requiring transplant or graft.

[0186] Embodiment II-1. A biocompatible, lenticule-shaped corneal implant formed from a first composite material and configured to conform to a curvature of a cornea of a subject, comprising: an outer surface having a convex dome shape; and an inner surface having a concave dome shape, wherein the inner surface comprises at least two indented grooves that are circular and concentric.

[0187] Embodiment II-2. The corneal implant of embodiment II-1, wherein the at least two grooves are concentric with each other and with the center of inner surface.

[0188] Embodiment II-3. The corneal implant of embodiment II-1 or II-2, wherein the at least two circular grooves comprise a higher diameter circular groove and a lower diameter circular groove, and the depth of the higher diameter circular groove is higher than the depth of the lower diameter circular groove.

[0189] Embodiment II-4. The corneal implant of any one of embodiments II-1 to II-3, wherein the corneal implant has a myopic lenticule shape or a hyperopic lenticule shape, or wherein the thickness of the corneal implant is uniform.

[0190] Embodiment II-5. The corneal implant of any one of embodiments II-1 to II-4, wherein each of the at least two circular grooves has a diameter of between about 1 mm and about 14 mm.

[0191] Embodiment II-6. The corneal implant of any one of embodiments II-1 to II-5, wherein each of the at least two circular grooves has a width of between about 20 nm and about 500 nm.

[0192] Embodiment II-7. The corneal implant of any one of embodiments II-1 to II-6, wherein each of the at least two circular grooves has a depth of between about 20 nm and about 500 nm.

[0193] Embodiment II-8. The corneal implant of any one of embodiments II-1 to II-7, wherein the first composite material comprises at least one polymer is selected from the group consisting 35 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 of: a hyaluronic acid; a gelatin; a polyethylene glycol; an alginate; a collagen; a synthetic polypeptide as set forth in SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3; and combinations thereof.

[0194] Embodiment II-9. The corneal implant of any one of embodiments II-1 to II-8, wherein the first composite material comprises a photoinitiator for cross-linking at least one polymer upon exposure to light.

[0195] Embodiment II-10. The corneal implant of embodiment II-8 or II-9, wherein the first composite material comprises a thiolated gelatin (Gel-SH) having an average molecular weight of between 50 kDa and 200 kDa, and with an average degree of substitution of between about 0.1 mmol / g and about 0.9 mmol / g; and a methacrylated hyaluronic acid (HA-MA) having an average molecular weight of between 25 kDa and 40 kDa, and with an average degree of substitution of between about 0.7 mmol / g and about 0.9 mmol / g.

[0196] Embodiment II-11. The corneal implant of embodiment II-10, wherein the Gel-SH is at a concentration of between about 20 mg / ml and about 150 mg / ml; and wherein the HA-MA is at a concentration of between about 20 mg / ml and about 150 mg / ml.

[0197] Embodiment II-12. The corneal implant of embodiment II-8 or II-9, wherein the first composite material comprises methacrylated hyaluronic acid (HA-MA) having molecular weight in a range of 5 to 60 kDa and with an average degree of substitution of between about 20 to 75%; and methacrylated gelatin (Gel-MA) having molecular weight in a range of 50 to 1000 kDa and with an average degree of substitution of between about 30 to 99%.

[0198] Embodiment II-13. The corneal implant of embodiment II-12, wherein the HA-MA is at a concentration of between about 20 mg / ml and about 70 mg / ml; and the Gel-MA is at a concentration of between about 20 mg / ml and about 220 mg / ml.

[0199] Embodiment II-14. The corneal implant of embodiment II-8 or II-9, wherein the first composite material is an elastomeric hydrogel comprising: (a) a synthetic polypeptide as set forth in SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3, (b) a photoinitiator for cross linking the synthetic polypeptide, and (c) a catalyst.

[0200] Embodiment II-15. The corneal implant of any one of embodiments II-1 to II-14, wherein the first composite material further comprises a therapeutic agent selected from exosomes and liposomes.

[0201] Embodiment II-16. A biocompatible corneal implant comprising: 36 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 a central body formed from a first composite material and having a dome shape comprising an inner surface configured to conform to a curvature of a cornea of a subject; and a peripheral zone contacting, is at least partially coextensive with, or fully surrounds an outer rim of the central body, wherein the peripheral zone comprises a second composite material is characterized by: a higher tensile strength compared to the first composite material; a higher puncture resistance compared to the first composite material, a lower elastic modulus compared to the first composite material, or a combination thereof.

[0202] Embodiment II-17. The corneal implant of embodiment II-16, wherein the first composite material and the second composite material are a same cross-linkable material, and the first composite material is characterized by a higher degree of cross-linking compared to the second composite material.

[0203] Embodiment II-18. The corneal implant of embodiment II-16 or II-17, wherein the first composite material and the second composite material are different composite materials.

[0204] Embodiment II-19. The corneal implant of embodiment II-18, wherein the second composite material comprises a methacrylated gelatin (Gel-MA) and a Hyaluronic acid-Aldehyde (HA-CHO).

[0205] Embodiment II-20. The corneal implant of embodiment II-19, wherein the Gel-MA has an average molecular weight of between about 100 bloom and about 250 bloom and an average degree of substitution of between about 30% and about 50%.

[0206] Embodiment II-21. The corneal implant of embodiment II-19 or II-20, wherein HA- CHO has an average molecular weight of between about 200 kDa and about 300 kDa and an average degree of substitution of between about 2% and about 10%.

[0207] Embodiment II-22. The corneal implant of any one of embodiments II-19 to II-21, wherein the Gel-MA and the HA-CHO are comprised in the second composite material at a weight ratio (Gel-MA:HA-CHO) of between about 100:15 and about 100:50.

[0208] Embodiment II-23. The corneal implant of any one of embodiments II-19 to II-21, wherein the second composite material further comprises a methacrylated Hyaluronic acid (HA- MA), a Hyaluronic acid-Hydrazide (HA-NHNH2), or a combination thereof.

[0209] Embodiment II-24. The corneal implant of embodiment II-23, wherein the HA-NHNH2 has an average molecular weight of between about 30 kDa and about 70 kDa and an average degree of substitution of between about 40% and about 60%. 37 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117

[0210] Embodiment II-25. The corneal implant of embodiment II-23, wherein the HA-MA has an average molecular weight of between about 25 kDa and about 40 kDa and an average degree of substitution of between about 0.7 mmol / g and about 0.9 mmol / g.

[0211] Embodiment II-26. The corneal implant of any one of embodiments II-23 to II-25, wherein the second composite material comprises the HA-MA, and the Gel-MA and the HA-MA are at a weight ratio (Gel-MA:HA-MA) of between about 100:10 and about 100:20.

[0212] Embodiment II-27. The corneal implant of any one of embodiments II-19 to II-26, wherein the second composite material comprises the HA-NHNH2, and the Gel-MA and the HA- NHNH2are at a weight ratio (Gel-MA:HA-NHNH2) of between about 100:2 and about 100:10.

[0213] Embodiment II-28. The corneal implant of any one of embodiments II-19 to II-26, wherein the second composite material further comprises a combination of ruthenium(II) tris(bipyridyl) chloride and sodium persulphate (SPS) as a photoinitiator.

[0214] Embodiment II-29. The corneal implant of embodiment II-18, wherein the second composite material comprises a thiolated hyaluronic acid (HA-SH) and a poly(ethylene glycol) diacrylate (PEGDA).

[0215] Embodiment II-30. The corneal implant of embodiment II-29, wherein the HA-SH has an average molecular weight of between about 30 kDa and about 70 kDa and an average degree of substitution of between about 40% and about 60%.

[0216] Embodiment II-31. The corneal implant of embodiment II-29 or II-30, wherein the PEGDA has an average molecular weight of between about 3 kDa and about 5 kDa and an average degree of substitution of at least 60%

[0217] Embodiment II-32. The corneal implant of any one of embodiments II-29 to II-31, wherein the second composite material further comprises a combination of ruthenium(II) tris(bipyridyl) chloride and sodium persulphate (SPS) as a photoinitiator and dimethyl sulfoxide (DMSO) as a crosslinker.

[0218] Embodiment II-33. The corneal implant of any one of embodiments II-29 to II-32, wherein the HA-SH and the PEGDA are comprised in the second composite material at a weight ratio (HA-SH:PEGDA) of between about 1:2 and about 2:1.

[0219] Embodiment II-34. The corneal implant of any one of embodiments II-16 to II-33, wherein the first composite material comprised at least one polymer is selected from the group consisting of: a hyaluronic acid; a gelatin; a polyethylene glycol; an alginate; a collagen; a 38 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 synthetic polypeptide as set forth in SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3; and combinations thereof.

[0220] Embodiment II-35. The corneal implant of any one of embodiments II-16 to II-34, wherein the first composite material comprises a photoinitiator for cross-linking at least one polymer upon exposure to light.

[0221] Embodiment II-36. The corneal implant of embodiment II-16, wherein the first composite material comprises a thiolated gelatin (Gel-SH) having an average molecular weight of between 50 kDa and 200 kDa, and with an average degree of substitution of between about 0.1 mmol / g and about 0.9 mmol / g; and a methacrylated hyaluronic acid (HA-MA) having an average molecular weight of between 25 kDa and 40 kDa, and with an average degree of substitution of between about 0.7 mmol / g and about 0.9 mmol / g.

[0222] Embodiment II-37. The corneal implant of embodiment II-36, wherein the Gel-SH is at a concentration of between about 20 mg / ml and about 150 mg / ml; and wherein the HA-MA is at a concentration of between about 20 mg / ml and about 150 mg / ml.

[0223] Embodiment II-38. The corneal implant of embodiment II-16, wherein the first composite material comprises methacrylated hyaluronic acid (HA-MA) having molecular weight in a range of 5 to 60 kDa and with an average degree of substitution of between about 20 to 75%; and methacrylated gelatin (Gel-MA) having molecular weight in a range of 50 to 1000 kDa and with an average degree of substitution of between about 30 to 99%.

[0224] Embodiment II-39. The corneal implant of embodiment II-38, wherein the HA-MA is at a concentration of between about 20 mg / ml and about 70 mg / ml; and the Gel-MA is at a concentration of between about 20 mg / ml and about 220 mg / ml.

[0225] Embodiment II-40. The corneal implant of embodiment II-16, wherein the first composite material is an elastomeric hydrogel comprising: (a) a synthetic polypeptide as set forth in SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3, (b) a photoinitiator for cross linking the synthetic polypeptide, and (c) a catalyst.

[0226] Embodiment II-41. The corneal implant of any one of embodiments II-16 to II-40, wherein the first composite material further comprises a therapeutic agent selected from exosomes and liposomes.

[0227] Embodiment II-42. The corneal implant of any one of embodiments II-16 to II-41, wherein the implant has a diameter ranging from 2mm to 15mm. 39 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117

[0228] Embodiment II-43. The corneal implant of any one of embodiments II-16 to II-42, wherein the implant has a height ranging from 0.05mm to 5mm.

[0229] Embodiment II-44. The corneal implant of any one of embodiments II-16 to II-43, wherein the implant has a thickness in the range of 50- 300 μm.

[0230] Embodiment II-45. A molding apparatus for manufacturing a lenticule-shaped corneal implant, the molding apparatus comprising: a base having a concave dome-shaped cavity configured to receive a cross-linkable composite material; a top configured to be placed on the base and comprising a convex dome-shaped elevation surface shaped and dimensioned so that a lenticule-shaped gap is formed between the cavity and the elevation surface when the top is situated on the base, and the cross-linkable composite material situated in the concave dome-shaped cavity would be formed having a shape corresponding to the lenticule-shaped gap; a light source configured to emit light; and a light-transmitting surface positioned to allow passage of the light from the light source through a light-transmitting surface to the concave cavity for crosslinking of the cross-linkable composite material.

[0231] Embodiment II-46. The molding apparatus of embodiment II-45, wherein the top is formed of a transparent material, and the light-transmitting surface is the convex elevation surface.

[0232] Embodiment II-47. The molding apparatus of embodiment II-45, wherein the base is formed of a transparent material, and the light-transmitting surface is the concave cavity.

[0233] Embodiment II-48. The molding apparatus of any one of embodiments II-45 to II-47, wherein the lenticule-shaped gap has a myopic lenticule shape or a hyperopic lenticule shape, or wherein the height between the concave cavity and the convex elevation surface is uniform.

[0234] Embodiment II-49. The molding apparatus of any one of embodiments II-45 to II-48, wherein the convex dome-shaped elevation surface comprises at least two circular ridges that are concentric with each other and the center of the convex dome-shaped elevation surface, such that the corneal implant formed in the gap would comprise at least two circular grooves on a concave surface of the corneal implant corresponding to the at least two circular ridges.

[0235] Embodiment II-50. The molding apparatus of embodiment II-49, wherein each of the at least two circular ridges has a diameter of between about 1 mm and about 14 mm. 40 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117

[0236] Embodiment II-51. The molding apparatus of embodiment II-49 or II-50, wherein each of the at least two circular ridges has a width of between about 20 nm and about 500 nm.

[0237] Embodiment II-52. The molding apparatus of any one of embodiments II-49 to II-51, wherein each of the at least two circular ridges has a height of between about 20 nm and about 500 nm.

[0238] Embodiment II-53. The molding apparatus of embodiment II-49, wherein the at least two concentric ridges do not contact the concave dome-shaped cavity when the top is situated on the base.

[0239] Embodiment II-54. The molding apparatus of embodiment II-49 or II-53, wherein the at least two circular ridges comprises a higher diameter circular ridge and a lower diameter circular ridge, and the height of the higher diameter circular ridge is higher than the height of the lower diameter circular ridge.

[0240] Embodiment II-55. The molding apparatus of any one of embodiments II-45, II-46, and II-48 to II-54, wherein the top is made of a glass or a transparent acrylic resin and the base is made of a non-transparent acrylic resin or a metal.

[0241] Embodiment II-56. The molding apparatus of any one of embodiments II-45 to II-55, wherein the distance between the elevation surface and the cavity is in the range of 50-300 μm.

[0242] Embodiment II-57. The molding apparatus of any one of embodiments II-45 to II-56, wherein the molding apparatus is an injection molding apparatus or compression molding apparatus.

[0243] Embodiment II-58. A process of preparing a corneal implant, comprising: applying a first composite material into the cavity in the molding apparatus of any one of embodiments II-45 to II-57; and exposing the first composite material to light for crosslinking of the first composite material, thereby forming the corneal implant.

[0244] Embodiment II-59. A process of preparing a corneal implant, comprising: applying a first composite material into the cavity in the molding apparatus of any one of embodiments II-45 to II-57; exposing the first composite material to light for crosslinking of the first composite material, thereby forming a central body; 41 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 applying a second composite material into the cavity in the molding apparatus of embodiment II-45, so that the second composite material is placed on, near, or around the outer rim of the central body; and exposing the second composite material to light for crosslinking of the second composite material, thereby forming the peripheral zone.

[0245] Embodiment II-60. The process of embodiment II-58 or II-59, wherein the light is selected from white light (visible light), blue light or green light.

[0246] Embodiment II-61. The process of embodiment II-59, wherein the first composition material are a same composite material.

[0247] Embodiment II-62. The process of embodiment II-59, wherein the first composition material are different composite materials.

[0248] Embodiment II-63. A process of treating a corneal disorder in a subject, said process comprising implanting the corneal implant of any one of embodiments II-1 to II-44 on an implantation site on an eye of the subject.

[0249] Embodiment II-64. The process of embodiment II-63, wherein the corneal disorder is selected from the group consisting of corneal thinning, advanced keratoconus, corneal degeneration and corneal defects requiring transplant or graft.

[0250] Embodiment II-65. The process of embodiment II-63 or II-64, wherein the implanting of the corneal implant comprises applying a surgical adhesive on the inner surface of the corneal implant or the implantation site, following by placing the corneal implant on the implantation site.

[0251] Embodiment II-66. The process of embodiment II-65, wherein the surgical adhesive is the first composite material in a non-crosslinked state.

[0252] Embodiment II-67. The process of embodiment II-66, wherein the placing of the implant onto the application site is followed by exposing the first composite material to light to crosslink the first composite material.

[0253] Embodiment II-68. The process of embodiment II-63 or II-64, wherein the implanting of the corneal implant comprises suturing the corneal implant to tissue surrounding the implantation site. EXAMPLES

[0254] The disclosure will now be illustrated with following examples, which is intended to illustrate the working of disclosure and not intended to take restrictively to imply any limitations 42 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 on the scope of the present disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice of the disclosed methods and compositions, the exemplary methods, devices and materials are described herein. It is to be understood that this disclosure is not limited to particular methods, and experimental conditions described, as such methods and conditions may vary. Materials

[0255] Porcine gelatin, methacrylic anhydride, and formalin were obtained from Sigma- Aldrich, HA-MA was obtained from Blafar Ltd, Ireland. Ruthenium (Ru) and sodium persulfate (SPS) were obtained from Advanced Biomatrix. Hyaluronidase was procured from Sigma (H1136) and Collagenase I from Thermofisher (17100017). Vectashield antifade mounting medium containing DAPI (#H1200) was obtained from Vector Labs, Burlingame, CA, USA. Human Cornea limbal epithelial cells (HCLE) was a kind gift from Dr. Ilene Gipson, Harvard Medical School, Boston, MA, USA. Statistical methods

[0256] All quantitative measurements were performed in triplicates as mean ± standard deviation. Each experiment was performed at least thrice. Statistical differences were determined using a t-test, and differences were considered significant for p values less than 0.05. EXAMPLE 1 - The Molding Apparatus:

[0257] FIGS. 1A-1E and 2B depict an exemplary molding apparatus 300 in accordance with an embodiment of the disclosure. The molding apparatus 300 comprises two parts, a base 310 having a concave dome-shaped cavity 312 (note that FIGS.1C, and a transparent top 350 having a convex dome-shaped elevation surface 352. The base (with cavity) was fabricated using stainless steel (ss316) and the top (with elevation) was made of acrylic. Stainless steel provided a smooth surface while the acrylic transparent top enabled light-mediated crosslinking of the biopolymers. The dimension of the cavity in the mold was similar to the human cornea (about 12mm diameter and radius of curvature 7.8mm) with approximately 200μm thickness.

[0258] Further, as shown in FIG.1D, the elevation surface 352 of the top 350 may also comprise concentric ridges 356, for forming corresponding grooves in the corneal implant 410 molded in 43 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 the apparatus 300. These ridges 356 may be of radially increasing height and can be used as a guide for obtaining implants of different diameter. As cross-sectional view of an exemplary elevation surface 352 with the ridges 356 is shown in FIG. 1E.

[0259] The production process for a corneal implant 410 using the molding apparatus 300 is depicted in FIG. 1B. 100μl pre-gel solution 420 (composite material) was filled in the cavity 312 of the base 310. Alternatively, an alignment mechanism may also be used for positioning the composite material or the pre-gel solution in the cavity. The top 350, with elevation 352, was placed over the cavity 312 filled with pre-gel solution 420. A reservoir surrounding the cavity was designed to accommodate any overflown solution (FIG. 2B), and to facilitate easy detachment of the main crosslinked implant from the overflown solution. The assembly (the transparent top or the light-transmitting surface) was exposed to light of specified wavelength and intensity, produced by an integrated light source 360, to facilitate the gelation of the pre-gel solution filled in the cavity to form the implant 410. The molds were also equipped with channels for liquid perfusion into the cavity for assisting demolding (Figure 2(B)). The inlet and outlet channels were connected to the perfusion pump, where the phosphate buffered saline was perfused at the rate of 1mL / min to wet the photo-crosslinked lenticules and then generate force for separation of the two halves of the mold and assist in demolding of the cornea lenticules. Alternately, the mold or the molding apparatus may also be equipped with structures for releasing the molded corneal implant. EXAMPLE 2 - Corneal Implant / Lenticule preparation: 2.1 Synthesis of Methacrylated gelatin (Gel-MA)

[0260] The Gel-MA was synthesized by dissolving 10g of porcine gelatin in water by heating at 60oC for 1h. Further, 1mL of methacrylic anhydride was added into the aqueous gelatin solution in a dropwise manner, maintaining 60oC over a period of 1.5h. The reaction mixture was then subjected to dialysis for 48h to remove any unreacted starting material followed by lyophilization to obtain Gel-MA powder. The HA-MA was procured commercially. 2.2 Preparation of pre-gel solution and hydrogel

[0261] A first exemplary biopolymer lenticule was prepared as follows. A pre-gel solution was prepared by blending two polymers, HA-MA (30mg / mL) and Gel-MA (200mg / mL) in 1X phosphate buffered saline (PBS). This solution was incubated for 10min at 40°C while protected from light. The photo-initiator solution comprising Ru / SPS, at a concentration of 1mM / 10mM was mixed with the polymer solution to prepare a biopolymer formulation, and poured into the 44 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 mold (i.e., the cavity) of Example 1. After placing the top (transparent top with elevation surface) of the mold, it was exposed to blue light (405nm) of 2.8mW / cm2for 1min for photo-crosslinking and obtaining the corneal lenticule or the implant (refer, Figures 1 and 2). A detailed formulation of the biopolymer lenticule is provided in Table 2 below. Table 2

[0262] A second exemplary biopolymer lenticule was prepared as follows. Similar to the above process, corneal implants were prepared using: a combination of the functionalized biopolymers, thiolated gelatin (Gel-SH) and methacrylated hyaluronic acid (HA-MA). The functionalized biopolymers were mixed in specific concentration ratios, where HA-MA was 20-150 mg / ml and Gel-SH was 20-150 mg / mL. The biopolymers were weighed and dissolved in separate batches of normal saline (0.9% NaCl) kept at 37°C in a water bath for 30 min. The dissolved polymer solutions were then mixed together to obtain desired concentration ratio. Photoinitiator solution, comprising of eosin Y (0.05 mM) and triethanolamine (0.075% v / v) in 1X to 5X concentration was added in polymer solution to obtain a biopolymer formulation. This biopolymer formulation was then dispensed in the cavity of the molds and exposed to white light for about 1 to 40 minute, to obtain the corneal implant. A detailed formulation of the biopolymer lenticule is provided in Table 3 below. Table 345 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117

[0263] Additional exemplary lenticules were prepared using a synthetic polypeptide as set forth in SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3 as disclosed herein. The polymer was allowed to cross-link using RUBP at 0.1 mM as a photo-activated cross-linker and 5 mM APS as catalyst to form an elastomeric hydrogel. The biopolymer formulation was then dispensed on the molds and exposed to white light for about 1 minute, to obtain the lenticules. Crosslinking Kinetics

[0264] Crosslinking kinetics study was performed using a rheometer (MCR102, Anton Paar) to determine the gelation point of the biopolymer formulation. Briefly, 300μl biopolymer formulation was placed between the rheometer's parallel plates (about 25mm diameter, and about 0.2mm gap) and subjected to oscillatory shear deformation at a fixed frequency of 1Hz and strain amplitude of 0.2%. As the crosslinking reaction proceeds, storage modulus and loss modulus were recorded over time. The gelation point was identified as the time at which the storage modulus reached a plateau, indicating complete crosslinking of the biopolymer formulation. Results

[0265] The crosslinking kinetics of Ru / SPS induced MA-MA crosslinks in HA-MA / Gel-MA hydrogels were observed. The formulations prepared using Ru / SPS show a storage modulus (G’) saturation of 1min when exposed to blue light (400-500nm) at 2.8mW / cm2(Figure 3a). The results indicate that 1min should be sufficient to transform the pre-gel solution or the biopolymer formulation with Ru / SPS into hydrogels. EXAMPLE 3 - Physical characterization: Morphology

[0266] To understand the morphology of the molded corneal implants, for example those described in Example 2, bright-field images were captured using stereomicroscope (Leica M205A) and processed using inbuilt software (LASX). The diameter of the lenticule was determined from the pictures using ImageJ software. Optical Transmittance 46 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117

[0267] Hydrogel samples of 50μL were prepared in a 96-well plate. The absorbance of the samples was recorded using a spectrophotometer (Perkin Elmer Enspire) in the visible region (400-700nm). The transmittance of the samples was calculated using the formula: % Transmittance = 10(2 - Absorbance)

[0268] The average transmittance values, using saline as blank, was represented as the transparency value of the hydrogels. Swelling profile

[0269] The swelling behavior of the lenticules was evaluated using both gravimetric and volumetric methods. Cylindrical hydrogels of 6mm diameter and 1mm height were prepared using the lenticule formulation for the assessment. Dry weights (t0) and dimensions were recorded, and the hydrogels were immersed in phosphate buffered saline (PBS) at room temperature to allow swelling. The weights were measured using an analytical balance, while the dimensions were measured using a micrometer and Vernier caliper at predetermined time points (t').

[0270] The volume of the cylindrical hydrogels was calculated using the formula: Volume = π * (radius)2* height

[0271] The swelling percentage was calculated as follows: Weight-based Swelling % = [(Weight (t') - Weight (t0)) / Weight (t0)] * 100 Volume-based Swelling % = [(Volume (t') - Volume (t0)) / Volume (t0)] * 100 Degradation Profile

[0272] The degradation of the scaffolds was assessed by measuring weight loss over time in the presence of enzymes. Hydrogels of 50μL were prepared in pre-weighed HPLC vials and incubated in an enzyme cocktail consisting of 1U / mL Hyaluronidase and 0.35U / mL Collagenase I for 4 weeks, with continuous agitation on an orbital shaker set at 400rpm at 37℃. Degradation media was changed every alternative day to maintain enzymatic activity. Hydrogels incubated in PBS were used as control. Samples were retrieved at predetermined time-points, washed with distilled water, and lyophilized for 24h. A set of hydrogels incubated for only 30min in enzyme solution followed by lyophilization were considered as initial weight (W0). Next, dry weights of the samples were recorded for different samples with different incubation period and used to calculate the degradation percentage using the formula: Degradation % = [(Wt – W0) / W0] * 100, where, Wtis the weight of the scaffold at time t, and W0is the initial weight of the scaffold. 47 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117

[0273] Degradation behavior of the hydrogels was examined for an extended period of 28 days, both in the presence and absence of the enzyme cocktail. Compressive Modulus

[0274] Cylindrical hydrogel discs were fabricated utilizing molds with a diameter of 6mm and a height of 1mm. The specimens were then subjected to a crosshead speed of 1mm / min and compressed to a maximum strain of 50% in a BiSS mechanical tester, specifically the OmniTest 5kN with Vector Pro NT with a 40N load cell. The compressive strain (mm) and load (N) values were documented, and the compressive moduli were determined by calculating the slope of the linear region within the stress (kPa) versus strain (mm / mm) curves, specifically between 0.1– 0.2mm / mm strain. Elastic modulus

[0275] The elastic modulus, also known as the modulus of elasticity or Young’s modulus, is a fundamental property that measures a material’s resistance to elastic deformation when a force is applied. A high elastic modulus means the material is stiff and resists deformation, and a low elastic modulus means the material is flexible and deforms easily.

[0276] ARFEM (Acoustic Radiation Force Elasticity Microscopy) is a technique for quantifying an elastic modulus that uses focused ultrasound to create a localized acoustic radiation force on a microbubble, which is then used to measure the elasticity of surrounding tissue or material. It combines a low-frequency, high-intensity acoustic force to displace the microbubble and a high- frequency, low-intensity ultrasound to monitor the bubble's displacement. By analyzing the bubble's displacement in response to the force, ARFEM can map out the mechanical properties, like elasticity, of the tissue or material. The ARFEM system comprises of three core components, a femtosecond laser, a dual element ultrasound transducer, and a sample chamber.

[0277] Sample analysis: The focal point of the laser is confocally aligned with the ultrasonic elements, and A-scan signal from a laser-created bubble is maximized, also focusing the 3-D sample stage to the same location. The sample, embedded in gelatin is placed within the sample chamber, and the chamber is filled with degassed, distilled water for acoustic coupling. The chamber is mounted to a 3-D microstage, allowing for the placement of the microbubble anywhere within the sample. The laser is focused through an objective creating a microbubble (d = 22 ± 2 μm) within the sample with a single pulse. The measurement sequence is initiated where the ultrasound transducer generates an acoustic radiation force chirp (2 ms in duration) that displaces the microbubble within the cornea, which is tracked by the ultrasound element with an A-scan at 48 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 a pulse repetition frequency of 5 kHz. The position / movement of the bubble in response to the acoustic radiation force is measured every 200 μs. The elastic modulus is inversely proportional to the bubble displacement and is calculated using:where “I” is the acoustic intensity, “a” is the bubble radius, “c” is the speed of sound in the cornea, and “xmax” is the maximum bubble displacement. The acoustic intensity and bubble radius are calibrated before the experiment, while maximum bubble displacement is measured experimentally with an A-scan. The speed of sound “c” in water (1500 m / s) is used for calculation. Tensile strength

[0278] Tensile strength of a gel refers to how much pulling force the gel can withstand before it breaks. Samples of the specimens were subjected stretching until tearing, then calculating as: Tensile strength (kPa) = Force at break (N) ÷ Cross-sectional area (m²) ÷ 1000 Tear and Puncture resistance

[0279] The resistance of hydrogels to needle insertion was gauged by measuring their Drag and Puncture forces. This was accomplished using a BiSS mechanical tester, specifically the OmniTest 5kN with Vector Pro NT and a 10N load cell, with the needle being fastened to the load cell using screw action grips. Three needle insertion speeds, namely 1, 60, 100, and 200mm / min, were examined during the experiments, with 10-0 suture needles being used. Cylindrical hydrogel discs were fabricated using molds with a diameter of 6mm and a height of 1mm, with the needles being inserted 80% of the way into the gel at a constant velocity. The maximum force required to pierce the 10-0 suture needle from the bottom of the hydrogel discs was measured to determine the drag force. The puncture resistance is the maximum force a sample (hydrogel) can handle before it gets pierced by the needle. Whereas the drag or tear force is the force readings recorded right after the force required to puncture the sample till it breaks apart [either the needle passes through (=drag) or the sample tears into two or more pieces (=tear)]. Refractive index

[0280] A digital refractometer (HI96800, 2 Hanna Instruments) was used to measure the refractive index of hydrogels. The device was calibrated with deionized water. Then the hydrogel samples were placed onto the surface of the prism and their refractive index was measured. 49 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 Adhesion strength

[0281] The adhesion strength of the hydrogel to the biological tissue (such as porcine skin) was assessed following the ASTM F2458-05 standards, using the method described elsewhere (Sani, E. S. et al. Sutureless repair of corneal injuries using naturally derived bioadhesive hydrogels. Sci Adv 5, (2019). Results

[0282] The physical parameters of the HA-MA / Gel-MA and HA-MA / Gel-SH lenticules described in Example 2, were evaluated with the evaluation methods described above, and the results are provide herein below. Lenticule morphology via Stereo Microscope:

[0283] The fabrication technique of compression molding of the present invention yielded smooth corneal lenticules of diameters which closely mimics that of the native human cornea. The thickness of the fabricated lenticules was around 0.257mm. The process of compression molding does not imprint any pattern or lines on the surface of the lenticule thereby leaving a smooth surface topography which ensures clear vision. Optical Transmittance

[0284] The optical transmittance of an artificial corneal lenticule refers to its ability to transmit light through it. This property is important for the use of artificial corneal lenticules in corneal transplant surgeries and for correcting various visual disorders. The HA-MA / Gel-MA formulation with Ru / SPS had a transmittance of 79.21±0.86%. Similarly, the HA-MA / Gel-SH formulation had an average transmittance of 91.18%. The collagen hydrogels were optically transparent with an optical transmission of ~80% in the visible region (between 400 and 600 nm). Native cornea is reported to be 87% transparent and in general. The hydrogels recorded a transmittance of ~80%, which is good. Swelling Profile

[0285] The swelling behavior of hydrogels prepared using biopolymers is mainly determined by the properties of the polymer chains, such as their molecular weight, degree of cross-linking, and chemical composition. When hydrogels prepared using biopolymers come into contact with water or biological fluids, they absorb and retain the liquid, leading to an increase in their volume and mass. The swelling degree was measured gravimetrically. The HA-MA-Gel-MA hydrogel fabricated using Ru / SPS recorded a weight-based swelling of 8.40±2.1% and a volumetric swelling of 9.79±3.7% (FIG. 3C). The HA-MA / Gel-SH hydrogels demonstrated a maximum of 50 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 15.28 ± 2.56% and 9.16 ± 2.2% in weight and volumetric swelling, respectively, attained within the first 30 min (FIGS. 7A-7B). Degradation Study

[0286] Any biomaterials used for corneal defects undergoes hydrolysis by matrix degrading enzymes produced by corneal cells. Hence, the biomaterial has to be biodegradable in order to maintain cell growth and tissue regeneration. Degradation behavior of the hydrogels was examined for an extended time period of 28 days and the results are presented for samples with enzyme cocktail and another with no enzyme treatment. The HA-MA-Gel-MA hydrogels showed a total of 47% degradation in the presence of the enzyme cocktail and 38% degradation in the absence of the enzyme cocktail (Figure 3d). The HA-MA / Gel-SH hydrogels showed weight-based degradation of 6.45 ± 1.53% (1X PBS) and 30.88 ± 2.23% (1X PBS + enzymes). Compressive Modulus

[0287] The compression strength of hydrogels is an important mechanical property for tissue engineering applications, as it determines the ability of the hydrogel to withstand the compressive forces exerted by cells and tissues. In tissue engineering, hydrogels are often used as scaffolds to support the growth and differentiation of cells into functional tissues. It is important to balance the need for mechanical strength with other properties such as biocompatibility, biodegradability, and swelling behavior to ensure that the hydrogel is suitable for the intended tissue engineering application. The HA-MA-Gel-MA formulation recorded a high compressive modulus of 506.36±95.91 kPa (Figure 4a). The compressive modulus of the HA-MA / Gel-SH hydrogel was 346.49 ± 18.76 kPa (Figure 7c). Tensile Strength

[0288] In corneal applications, the tensile strength of hydrogels is vital for maintaining structural integrity against mechanical stresses experienced by the cornea during eye movements and external pressure. It is also important for surgical handling, ensuring the hydrogel can withstand manipulation without tearing. Long-term stability is another consideration, where appropriate tensile strength helps the hydrogel retain its shape and mechanical properties over time. Ensuring adequate tensile strength in hydrogels is essential for their successful use in corneal applications, promoting structural integrity, surgical feasibility, long-term stability, and optical clarity for improved corneal function and vision. The HA-MA / Gel-MA formulation recorded a tensile strength of 52.36±8.03kPa (Figure 4b). Adhesion strength 51 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117

[0289] To ensure the integration of the hydrogel with the underlying tissue, their adhesion with a biological tissue was determined via adhesion strength analysis. Adhesion of the hydrogel to the surrounding host tissue is essential to prevent premature detaching. The HA-MA / Gel-SH hydrogels demonstrated an adhesion strength of 54.17 ± 6.31 kPa to the porcine skin (Figure 5e of the previous application). Tear and Puncture resistance

[0290] The puncture strength of a biomaterial-based hydrogel refers to its ability to withstand mechanical stress or pressure applied to it in a puncture test. This property is important for the use of hydrogels in various biomedical applications such as tissue engineering, drug delivery, wound healing, and implantable devices. The puncture strength of a hydrogel depends on the crosslinking density and the concentrations of the polymers. Drag strength, on the other hand, refers to the gel’s ability to resist deformation or breaking when subjected to shear forces during the suturing process. This property is important for the use of corneal lenticules. During suturing, the designed lenticules may be subjected to shear forces as the needle is inserted and pulled through the tissue. Therefore, puncture and drag strength are important mechanical properties that must be considered when selecting a biomaterial for use in suturing applications. The results as depicted in FIG. 4C show that the puncture strength decreased with increasing puncture speeds. The puncture strength of the HA-MA-Gel-MA hydrogel was 1117.70±262.85kPa at 1mm / min speeds, which reduced to 499.07±50.44kPa at 200mm / min (FIG. 4C). A drag strength of 39.60±3.06kPa was recorded at 1mm / min speeds and the suture could easily pass through the hydrogel, without causing any break or visual damage to the hydrogel (FIG. 4D). Suturing through a hydrogel can be challenging due to the soft and slippery nature of the material. Puncture strength and drag strength are two important parameters that evaluate the performance of sutures in hydrogels. Refractive index

[0291] The refractive index of the HA-MA-Gel-MA lenticule was found to be in the range of 1.3360 to 1.3363. The refractive index of the human cornea is reported to be in the range from 1.335 to 1.4391 over the visible spectrum which suggests the refractive index of the lenticules are within the range of human native cornea. EXAMPLE 4 - Optometry 52 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 Anterior Segment OCT Imaging

[0292] Anterior segment Optical Coherence Tomography (AS-OST) scan of the lenticule was performed using an OCT device (Optovue, Avanti RTVUE-XR). For imaging the lenticule, it was held using sterile forceps and the scan was taken from the center. For human volunteer, scans were centerd on the pupil and taken along the horizontal axis. The images were processed and analysed using an in-built software. Pentacam Imaging Protocol

[0293] Pentacam (Oculus), a rotating scheimpflug camera was used to understand corneal biomechanics (Densitometry and Corneal Curvature). The lenticule was held using sterile forceps and the scan was taken from the center. For human volunteer, scans were centerd on the pupil and taken along the horizontal and vertical axis. The program located the corneal apex, analysed a 12- mm-diameter area around it and expressed the output in grayscale units (GSU). The GSU scale defines a minimum light scatter of 0 (maximum transparency) and maximum light scatter of 100 (minimum transparency). Results

[0294] Optical coherence tomography (OCT) imaging of the cornea mimetic lenticule, indicated smooth cornea surface with central thickness of 323μm and complete transparency as evident from the raster scans where no hyper-reflectivity was evident (FIGS.5B-5C). Transparency was further validated from densitometry map obtained from the Pentacam. The lenticule transmitted visible light like the human cornea, as the central corneal opacity score was near normal (0-2mm, central cornea score: Lenticule 18.6 and native human cornea 16.5; 2-6mm, Mid Peripheral score: Lenticule 17 and native human cornea 14.8; and 6-10mm, Peripheral Score: Lenticule 13.2 and native human cornea 17.7) (FIG. 5A).

[0295] Apart from maintaining the desired thickness and clarity, the corneal curvature was evaluated and measured using keratometry values. The normal keratometry value of native cornea is 44D, whereas the keratometry value of the lenticule designed is 36D, which is close to the healthy cornea (Figure 5d). The basic ophthalmic measurement proves that the designed lenticule is comparable to native human cornea. EXAMPLE 5 - Cell-Material interaction: Biocompatibility with corneal cells 53 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 Human corneal stromal cell encapsulation

[0296] The isolation of human corneal stromal cells (hCSCs) from donor cadaveric tissues (obtained from Daryaganj, New Delhi), was carried out by dissecting the limbal ring from the cadaveric human corneal rim and digested via collagenase (200U / μL) for 16h. The pellet obtained after centrifuging this digested solution resulted in 1 million hCSCs which were cultured in advanced DMEM / F12 medium containing fetal bovine serum (FBS) (2%), recombinant epidermal growth factor (10ng / mL), Insulin Transferrin Selenium (1%) and penicillin-streptomycin (1%). These hCSCs were used for encapsulation studies in the 3rd passage. A seeding density of 1 million cells / mL of hydrogel was followed while fabricating the hydrogels. The cell suspension was mixed with the pre-gel solution, dropped on to a sterile glass slide, covered with a sterile coverslip and then photo-crosslinked. Thereafter, the hCSCs encapsulated hydrogels were submerged in the complete culture media and incubated at 37°C and 5% CO2, followed by complete media change on every 3rdday. At predetermined time points (Day 1, 7, 14, 21), the hydrogels samples were removed from culture for viability and biomarker studies. Cell viability

[0297] For viability assessment, media comprising of calcein acetoxymethyl (calcein‐AM, 0.2 μg / mL C3099) (Invitrogen, Paisley, UK), ethidium homodimer (EthD-1, 2.5 μg / mL, E3599,) (Invitrogen, Paisley, UK) and Hoechst 33342 (Sigma, 1:500) prepared in the MEM media, was added to the samples and incubated for 20 min at 37°C. The samples were then observed under a confocal microscope (Nikon LSCM C2) to identify the distribution of live cells and dead cells. Biomarker analysis

[0298] For biomarker studies, the hCSCs encapsulated hydrogel samples recovered at different time points were washed with PBS and fixed with 10% formalin solution. The samples were then washed using 1X PBS followed by incubation in permeabilization buffer (0.2% Triton X in 1X PBS) for 10min. Then 1X PBS was used to rinse the samples twice for 5min each. Thereafter, the hydrogels were incubated in blocking buffer (5% BSA solution prepared in 1X PBS) for 60min at room temperature. A cocktail of primary anti‐CD90 (BD550402) and anti‐alpha smooth muscle actin (α‐SMA) antibody (Abcam, ab32575) was prepared in the 1:100 dilution prepared in 1% BSA, and samples were incubated at 4°C overnight. Next day, the samples were washed with 1X PBS thrice for 5min each after discarding the primary antibody solution, followed by addition of the secondary antibodies (Goat anti-mouse conjugated with Alexa Fluor 594 and anti-rabbit with Alexa Fluor 488; Thermo Fisher Scientific) (1:200 dilution in 1% BSA) which was then incubated 54 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 at room temperature for 1h. Subsequently, the samples were washed thrice with 1X PBS and Vectashield antifade mounting medium containing DAPI was added. The samples were then imaged under a confocal microscope (Nikon LSCM C2) to evaluate the phenotype of the cells encapsulated in the hydrogels. Cells epithelization study on lenticules

[0299] Human cornea limbal epithelial cells (HCLE cells; obtained from USA) were cultured in complete culture media (Keratinocyte-serum free media (KSFM), supplemented with bovine pituitary extract and 0.2ng / mL Epidermal Growth factor (EGF)). The phase contrast images (FIG. 6C) were acquired in a time dependent manner to evaluate the biocompatibility of the lenticule. Results

[0300] The cell viability study (FIGS. 6A-6C) revealed a viability of ~98% ensuring the cytocompatibility of the lenticule, with minimal dead cells in the later time points.

[0301] Post 24h, human corneal limbal epithelial cells were able to attach and maintain its shape on corneal mimetic lenticule. With time, the cells were able to migrate from the peripheral to central region as indicated by the arrow in FIG. 6C. EXAMPLE 6 – Peripheral Zone for Suturable Lenticule Rim

[0302] Various materials were tested for producing a suturable lenticule rim at a peripheral zone of a corneal implant that is amenable for attaching to the eye or cornea via suture. The following composite materials provided advantageous parameters:

[0303] Composite material 1 was a combination of the polymers HA-MA, Gel-MA, HA-CHO, and HA-NHNH2. The polymers of composite material 1 are characterized as follows: the HA-MA had an average molecular weight of 33 kDa and an average degree of substitution of 0.81 mmol / g (~50%), and was present at a concentration of 15 mg / ml; the Gel-MA had an average molecular weight of 175 bloom and an average degree of substitution of 42%, and was present at a concentration of 100 mg / ml; the HA-CHO had an average molecular weight of 250 kDA and an average degree of substitution of 5%, and was present at a concentration of 41 mg / ml; and the HA-NHNH2 had an average molecular weight of 50 kDA and an average degree of substitution of 50%, and was present at a concentration of 8 mg / ml.

[0304] Composite material 2 was a combination of HA-SH and PEGDA. The polymers of composite material 2 are characterized as follows: HA-SH had an average molecular weight of 50 kDa and an average degree of substitution of 50%, and was present at a concentration of 25 mg / ml; 55 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 and PEGDA had an average molecular weight of 50kDa and a saturated average degree of substitution, and was present at a concentration of 25 mg / ml.

[0305] The preparation of the composite material are summarized below in Table 4: Table 4 – Formulations for peripheral zone

[0306] For composite material 1, the crosslinking included an Imine bond (-CH=N) formation between amine groups of HA-NHNH2, as well as between free amine groups present in Gel-MA and aldehyde (HA-CHO). This crosslinking chemistry occurs at room temperature, and started as soon as the polymers were mixed together. Light-based crosslinking was aided by Ru / SPS (photoc-rosslinker) using blue light to cross link HA-MA and Gel-MA.

[0307] For composite material 2, the DMSO crosslinked HA-SH to form –S-S- disulfide bonds. In addition, blue light irradiation in presence of Ru / SPS crosslinked acrylate groups in PEGDA. 56 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 During this light irradiation, another competitive reaction between unreacted HA-SH and PEGDA took place through thiol-ene click chemistry, further strengthening the hydrogels. Table 5 – physical properties of composite materials for Suturable Lenticule RimCertain advantages of embodiments the present disclosure

[0308] Embodiments of present disclosure provides a corneal implant / lenticule that mimics physical properties of human native cornea, made of a composite polymer material fabricated using compression molding with, for example but not limited to, the following advantages: 1. Certain hydrogels of the disclosure recorded a transmittance of ~80% or higher, which is close to native cornea, which is reported to be 87% transparent. A hydrogel with a high transmittance is desirable for corneal applications, as this allows for better visual acuity and minimizes the risk of vision loss. 2. Fast crosslinking times as low as ~1min is clinically relevant as they can reduce the time required for surgical procedures, allowing surgeons to complete procedures more quickly and efficiently, particularly important in emergency situations, where time is of the essence. Faster crosslinking times can also reduce the risk of infection or contamination during surgical procedures. Certain hydrogels of the disclosure that are crosslinked quickly can be used to seal wounds more rapidly, reducing the time that bacteria or other pathogens enter the wound site and cause infection. 3. Swelling behavior of the certain hydrogels of the disclosure in the cylindrical form was measured which showed weight-based swelling of 8.40 ± 2.1% and a volumetric swelling of 9.79 ± 3.7%. Low swelling is beneficial for corneal lenticules to maintain the structural integrity in the wound site. 57 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 4. The refractive index of the lenticule ranges from 1.3360 to 1.3363. The refractive index of the human cornea is reported to range from 1.335 to 1.4391 over the visible spectrum which suggests the refractive index of certain lenticules of the disclosure are within the range of human native cornea. 5. Certain lenticules of the disclosure recorded a high compressive modulus of 506.36 ± 95.91 kPa which complements the swelling degree measurements and is greater than the range of moduli observed in the native cornea (115.3 ± 13.6kPa). 6. Certain lenticules of the disclosure transmitted visible light like the human cornea, as the central corneal opacity score was near normal (0-2mm, central cornea score: Lenticule 18.6 and native human cornea: 16.5; 2-6mm, Mid Peripheral score: Lenticule 17 and native human cornea: 14.8 and 6-10mm, Peripheral Score: Lenticule 13.2 and native human cornea: 17.7). 7. The normal keratometry value of properly shaped native cornea is 44D, whereas the keratometry value of certain lenticules of the disclosure is 36D, which is close to the healthy human cornea. 8. It has been demonstrated that the certain lenticules of the disclosure have the ability to withstand mechanical stress and showed good suturability. The puncture and drag strength were measured as a function of puncture speeds. 9. The method of constructing corneal lenticules using compression molding method of the present disclosure is straight-forward, easy to adopt, user-friendly and low-cost technique. The method also allows for production of lenticules at the point of care, thus obviating a need for storage. 10. The compression molded lenticules of the present disclosure can be mass-produced (high throughput) while maintaining consistency in their structure and functionality. Their properties also allow convenient and customizable use (trimming or punching the desired portion in the operation theatre) by the surgeons suiting patient specific requirements. 58 322531570

Claims

Attorney Docket No.: PNDM-021 / 01WO 345086-2117 1. A biocompatible, lenticule-shaped corneal implant formed from a first composite material and configured to conform to a curvature of a cornea of a subject, comprising: an outer surface having a convex dome shape; and an inner surface having a concave dome shape, wherein the inner surface comprises at least two indented grooves that are circular and concentric.

2. The corneal implant of claim 1, wherein the at least two grooves are concentric with each other and with the center of inner surface.

3. The corneal implant of claim 1 or claim 2, wherein the at least two circular grooves comprise a higher diameter circular groove and a lower diameter circular groove, and the depth of the higher diameter circular groove is higher than the depth of the lower diameter circular groove.

4. The corneal implant of any one of claims 1-3, wherein the corneal implant has a myopic lenticule shape or a hyperopic lenticule shape, or wherein the thickness of the corneal implant is uniform.

5. The corneal implant of any one of claims 1-4, wherein each of the at least two circular grooves has a diameter of between about 1 mm and about 14 mm.

6. The corneal implant of any one of claims 1-5, wherein each of the at least two circular grooves has a width of between about 20 nm and about 500 nm.

7. The corneal implant of any one of claims 1-6, wherein each of the at least two circular grooves has a depth of between about 20 nm and about 500 nm.

8. The corneal implant of any one of claims 1-7, wherein the first composite material comprises at least one polymer is selected from the group consisting of: a hyaluronic acid; a gelatin; a polyethylene glycol; an alginate; a collagen; a synthetic polypeptide as set forth in SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3; and combinations thereof.

9. The corneal implant of any one of claims 1-8, wherein the first composite material comprises a photoinitiator for cross-linking at least one polymer upon exposure to light.

10. The corneal implant of claim 8 or claim 9, wherein the first composite material comprises a thiolated gelatin (Gel-SH) having an average molecular weight of between 50 kDa and 200 kDa, and with an average degree of substitution of between about 0.1 mmol / g and about 0.9 mmol / g; and a methacrylated hyaluronic acid (HA-MA) having an average 59 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 molecular weight of between 25 kDa and 40 kDa, and with an average degree of substitution of between about 0.7 mmol / g and about 0.9 mmol / g.

11. The corneal implant of claim 10, wherein the Gel-SH is at a concentration of between about 20 mg / ml and about 150 mg / ml; and wherein the HA-MA is at a concentration of between about 20 mg / ml and about 150 mg / ml.

12. The corneal implant of claim 8 or claim 9, wherein the first composite material comprises methacrylated hyaluronic acid (HA-MA) having molecular weight in a range of 5 to 60 kDa and with an average degree of substitution of between about 20 to 75%; and methacrylated gelatin (Gel-MA) having molecular weight in a range of 50 to 1000 kDa and with an average degree of substitution of between about 30 to 99%.

13. The corneal implant of claim 12, wherein the HA-MA is at a concentration of between about 20 mg / ml and about 70 mg / ml; and the Gel-MA is at a concentration of between about 20 mg / ml and about 220 mg / ml.

14. The corneal implant of claim 8 or claim 9, wherein the first composite material is an elastomeric hydrogel comprising: (a) a synthetic polypeptide as set forth in SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3, (b) a photoinitiator for cross linking the synthetic polypeptide, and (c) a catalyst.

15. The corneal implant of any one of claims 1-14, wherein the first composite material further comprises a therapeutic agent selected from exosomes and liposomes.

16. A biocompatible corneal implant comprising: a central body formed from a first composite material and having a dome shape comprising an inner surface configured to conform to a curvature of a cornea of a subject; and a peripheral zone contacting, is at least partially coextensive with, or fully surrounds an outer rim of the central body, wherein the peripheral zone comprises a second composite material is characterized by: a higher tensile strength compared to the first composite material; a higher puncture resistance compared to the first composite material, a lower elastic modulus compared to the first composite material, or a combination thereof.

17. The corneal implant of claim 16, wherein the first composite material and the second composite material are a same cross-linkable material, and the first composite material is characterized by a higher degree of cross-linking compared to the second composite material. 60 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 18. The corneal implant of claim 16 or claim 17, wherein the first composite material and the second composite material are different composite materials.

19. The corneal implant of claim 18, wherein the second composite material comprises a methacrylated gelatin (Gel-MA) and a Hyaluronic acid-Aldehyde (HA-CHO).

20. The corneal implant of claim 19, wherein the Gel-MA has an average molecular weight of between about 100 bloom and about 250 bloom and an average degree of substitution of between about 30% and about 50%.

21. The corneal implant of claim 19 or claim 20, wherein HA-CHO has an average molecular weight of between about 200 kDa and about 300 kDa and an average degree of substitution of between about 2% and about 10%.

22. The corneal implant of any one of claims 19-21, wherein the Gel-MA and the HA-CHO are comprised in the second composite material at a weight ratio (Gel-MA:HA-CHO) of between about 100:15 and about 100:

50.

23. The corneal implant of any one of claims 19-21, wherein the second composite material further comprises a methacrylated Hyaluronic acid (HA-MA), a Hyaluronic acid- Hydrazide (HA-NHNH2), or a combination thereof.

24. The corneal implant of claim 23, wherein the HA-NHNH2 has an average molecular weight of between about 30 kDa and about 70 kDa and an average degree of substitution of between about 40% and about 60%.

25. The corneal implant of claim 23, wherein the HA-MA has an average molecular weight of between about 25 kDa and about 40 kDa and an average degree of substitution of between about 0.7 mmol / g and about 0.9 mmol / g.

26. The corneal implant of any one of claims 23-25, wherein the second composite material comprises the HA-MA, and the Gel-MA and the HA-MA are at a weight ratio (Gel- MA:HA-MA) of between about 100:10 and about 100:

20.

27. The corneal implant of any one of claims 19-26, wherein the second composite material comprises the HA-NHNH2, and the Gel-MA and the HA-NHNH2 are at a weight ratio (Gel-MA:HA-NHNH2) of between about 100:2 and about 100:

10.

28. The corneal implant of any one of claims 19-26, wherein the second composite material further comprises a combination of ruthenium(II) tris(bipyridyl) chloride and sodium persulphate (SPS) as a photoinitiator. 61 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 29. The corneal implant of claim 18, wherein the second composite material comprises a thiolated hyaluronic acid (HA-SH) and a poly(ethylene glycol) diacrylate (PEGDA).

30. The corneal implant of claim 29, wherein the HA-SH has an average molecular weight of between about 30 kDa and about 70 kDa and an average degree of substitution of between about 40% and about 60%.

31. The corneal implant of claim 29 or claim 30, wherein the PEGDA has an average molecular weight of between about 3 kDa and about 5 kDa and an average degree of substitution of at least 60% 32. The corneal implant of any one of claims 29-31, wherein the second composite material further comprises a combination of ruthenium(II) tris(bipyridyl) chloride and sodium persulphate (SPS) as a photoinitiator and dimethyl sulfoxide (DMSO) as a crosslinker.

33. The corneal implant of any one of claims 29-32, wherein the HA-SH and the PEGDA are comprised in the second composite material at a weight ratio (HA-SH:PEGDA) of between about 1:2 and about 2:

1.

34. The corneal implant of any one of claims 16-33, wherein the first composite material comprised at least one polymer is selected from the group consisting of: a hyaluronic acid; a gelatin; a polyethylene glycol; an alginate; a collagen; a synthetic polypeptide as set forth in SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3; and combinations thereof.

35. The corneal implant of any one of claims 16-34, wherein the first composite material comprises a photoinitiator for cross-linking at least one polymer upon exposure to light.

36. The corneal implant of claim 16, wherein the first composite material comprises a thiolated gelatin (Gel-SH) having an average molecular weight of between 50 kDa and 200 kDa, and with an average degree of substitution of between about 0.1 mmol / g and about 0.9 mmol / g; and a methacrylated hyaluronic acid (HA-MA) having an average molecular weight of between 25 kDa and 40 kDa, and with an average degree of substitution of between about 0.7 mmol / g and about 0.9 mmol / g.

37. The corneal implant of claim 36, wherein the Gel-SH is at a concentration of between about 20 mg / ml and about 150 mg / ml; and wherein the HA-MA is at a concentration of between about 20 mg / ml and about 150 mg / ml.

38. The corneal implant of claim 16, wherein the first composite material comprises methacrylated hyaluronic acid (HA-MA) having molecular weight in a range of 5 to 60 kDa and with an average degree of substitution of between about 20 to 75%; and 62 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 methacrylated gelatin (Gel-MA) having molecular weight in a range of 50 to 1000 kDa and with an average degree of substitution of between about 30 to 99%.

39. The corneal implant of claim 38, wherein the HA-MA is at a concentration of between about 20 mg / ml and about 70 mg / ml; and the Gel-MA is at a concentration of between about 20 mg / ml and about 220 mg / ml.

40. The corneal implant of claim 16, wherein the first composite material is an elastomeric hydrogel comprising: (a) a synthetic polypeptide as set forth in SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3, (b) a photoinitiator for cross linking the synthetic polypeptide, and (c) a catalyst.

41. The corneal implant of any one of claims 16-40, wherein the first composite material further comprises a therapeutic agent selected from exosomes and liposomes.

42. The corneal implant of any one of claims 16-41, wherein the implant has a diameter ranging from 2mm to 15mm.

43. The corneal implant of any one of claims 16-42, wherein the implant has a height ranging from 0.05mm to 5mm.

44. The corneal implant of any one of claims 16-43, wherein the implant has a thickness in the range of 50- 300 μm.

45. A molding apparatus for manufacturing a lenticule-shaped corneal implant, the molding apparatus comprising: a base having a concave dome-shaped cavity configured to receive a cross-linkable composite material; a top configured to be placed on the base and comprising a convex dome-shaped elevation surface shaped and dimensioned so that a lenticule-shaped gap is formed between the cavity and the elevation surface when the top is situated on the base, and the cross- linkable composite material situated in the concave dome-shaped cavity would be formed having a shape corresponding to the lenticule-shaped gap; a light source configured to emit light; and a light-transmitting surface positioned to allow passage of the light from the light source through a light-transmitting surface to the concave cavity for crosslinking of the cross-linkable composite material.

46. The molding apparatus of claim 45, wherein the top is formed of a transparent material, and the light-transmitting surface is the convex elevation surface. 63 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 47. The molding apparatus of claim 45, wherein the base is formed of a transparent material, and the light-transmitting surface is the concave cavity.

48. The molding apparatus of any one of claims 45-47, wherein the lenticule-shaped gap has a myopic lenticule shape or a hyperopic lenticule shape, or wherein the height between the concave cavity and the convex elevation surface is uniform.

49. The molding apparatus of any one of claims 45-48, wherein the convex dome-shaped elevation surface comprises at least two circular ridges that are concentric with each other and the center of the convex dome-shaped elevation surface, such that the corneal implant formed in the gap would comprise at least two circular grooves on a concave surface of the corneal implant corresponding to the at least two circular ridges.

50. The molding apparatus of claim 49, wherein each of the at least two circular ridges has a diameter of between about 1 mm and about 14 mm.

51. The molding apparatus of claim 49 or claim 50, wherein each of the at least two circular ridges has a width of between about 20 nm and about 500 nm.

52. The molding apparatus of any one of claims 49-51, wherein each of the at least two circular ridges has a height of between about 20 nm and about 500 nm.

53. The molding apparatus of claim 49, wherein the at least two concentric ridges do not contact the concave dome-shaped cavity when the top is situated on the base.

54. The molding apparatus of claim 49 or claim 53, wherein the at least two circular ridges comprises a higher diameter circular ridge and a lower diameter circular ridge, and the height of the higher diameter circular ridge is higher than the height of the lower diameter circular ridge.

55. The molding apparatus of any one of claims 45, 46, and 48-54, wherein the top is made of a glass or a transparent acrylic resin and the base is made of a non-transparent acrylic resin or a metal.

56. The molding apparatus of any one of claims 45-55, wherein the distance between the elevation surface and the cavity is in the range of 50-300 μm.

57. The molding apparatus of any one of claims 45-56, wherein the molding apparatus is an injection molding apparatus or compression molding apparatus.

58. A process of preparing a corneal implant, comprising: applying a first composite material into the cavity in the molding apparatus of any one of claims 45-57; and 64 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 exposing the first composite material to light for crosslinking of the first composite material, thereby forming the corneal implant.

59. A process of preparing a corneal implant, comprising: applying a first composite material into the cavity in the molding apparatus of any one of claims 45-57; exposing the first composite material to light for crosslinking of the first composite material, thereby forming a central body; applying a second composite material into the cavity in the molding apparatus of claim 45, so that the second composite material is placed on, near, or around the outer rim of the central body; and exposing the second composite material to light for crosslinking of the second composite material, thereby forming the peripheral zone.

60. The process of claim 58 or claim 59, wherein the light is selected from white light (visible light), blue light or green light.

61. The process of claim 59, wherein the first composition material are a same composite material.

62. The process of claim 59, wherein the first composition material are different composite materials.

63. A process of treating a corneal disorder in a subject, said process comprising implanting the corneal implant of any one of claims 1-44 on an implantation site on an eye of the subject.

64. The process of claim 63, wherein the corneal disorder is selected from the group consisting of corneal thinning, advanced keratoconus, corneal degeneration and corneal defects requiring transplant or graft.

65. The process of claim 63 or claim 64, wherein the implanting of the corneal implant comprises applying a surgical adhesive on the inner surface of the corneal implant or the implantation site, following by placing the corneal implant on the implantation site.

66. The process of claim 65, wherein the surgical adhesive is the first composite material in a non-crosslinked state.

67. The process of claim 66, wherein the placing of the implant onto the application site is followed by exposing the first composite material to light to crosslink the first composite material. 65 322531570Attorney Docket No.: PNDM-021 / 01WO 345086-2117 68. The process of claim 63 or claim 64, wherein the implanting of the corneal implant comprises suturing the corneal implant to tissue surrounding the implantation site. 66 322531570

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