HK40079734A - Corneal inlay design and methods of correcting vision - Google Patents

Description

Corneal inlay design and method of correcting vision

Cross reference to related applications

This application claims priority to U.S. provisional application 62/881,124 entitled "corneal inlay design and method of correcting vision" filed on 31/7/2019. The entire contents of the above application are hereby incorporated by reference in their entirety.

Technical Field

The described invention relates generally to medical devices and more particularly to corneal inlays.

Background

Component of the eye

The eye is the organ that responds to light and pressure and achieves visual perception. Fig. 1 is an illustration of the human eye (alaboutvision. com/resources/anatomy. htm, 3 months visit in 2019). The anatomy of the eye includes the conjunctiva, iris, lens, pupil, cornea, sclera, ciliary body, vitreous body, anterior chamber, choroid, retina, macula, optic nerve, and optic disc. The conjunctiva is a transparent film that covers a portion of the anterior surface of the eye and the inner surface of the eyelids. The iris is a thin circular structure made up of connective tissue and muscles that surround the pupil and regulate the amount of light directed to the retina. The retina is a light-sensitive film on which light is focused. It consists of several layers, including a layer containing specialized cells called photoreceptors. The photoreceptor cells take the light focused by the cornea and crystalline lens (transparent biconvex structure) and convert it into chemical and neural signals, which are transmitted through the optic nerve to the visual center in the brain. The sclera is dense connective tissue that surrounds the cornea and forms the white part of the eye. The ciliary body connects the iris to the choroid and consists of the ciliary muscle (which changes the curvature of the lens), a series of radial ciliary processes (from which the lens is suspended by ligaments) and the ciliary annulus (which adjoins the choroid). The choroid is the pigmented vascular layer of the eye between the retina and sclera. The vitreous body is a transparent, colorless, semi-solid mass composed of collagen fibrils and hyaluronic acid that fills the posterior chamber of the eye between the lens and the retina. The anterior chamber is the space inside the eye that is filled with aqueous humor between the iris and the innermost surface of the cornea. The macula is an elliptically-shaped pigmented area near the center of the retina. The optic disc is the convex disc at the entry point of the optic nerve on the retina, which lacks visual receptors and thus creates blind spots.

Cornea

The cornea is a clear and transparent layer in the front of the eye. It is the primary refractive surface of the eye. Fig. 2 is a diagram showing a cornea which is avascular and presents the following five layers from anterior (closer to the front) to posterior (closer to the back): epithelium, anterior elastic layer (Bowman's layer), stroma layer, posterior elastic layer (Descemet's membrane), and endothelium.

Epithelium is a layer of cells that can be considered to cover the surface of the cornea. Specifically, the outer part of the cornea is covered by a stratified non-keratinized epithelium (5-6 cell layers, approximately 50 microns thick) with three types of cells: superficial cells, winged cells and basal cells (deepest cell layer). Desmosomes form tight junctions between surface layer cells. Basal cells are the only corneal epithelial cells capable of mitosis; the basement membrane of epithelial cells has a thickness of 40-60 nm and consists of type IV collagen and laminin secreted by basal cells. The epithelial layer is highly sensitive due to the numerous nerve endings and has excellent regenerative capacity. There is a difference between the epithelium of the central cornea and the peripheral cornea. In the central cornea, the epithelium has 5-7 layers, and basal cells are columnar; there were no melanocytes or langerhans cells, and the epithelium was homogeneous to provide a smooth, regular surface. In the peripheral cornea, the epithelium has 7-10 layers, basal cells are cuboidal, melanocytes and langerhans cells are present, and there is a fluctuating extension of the basal layer. (Sridhar, M.S., "Anatomy of corn and annular surface," Indian J. Ophthalmol. (2018) 66(2): 190-.

The pre-elastic layer is unstructured and acellular. The stromal layer is the thickest layer of the cornea and provides most of the strength of the cornea. Most refractive surgery involves the treatment of stromal cells. Specifically, the substantia propria (stroma) forms 90% of the corneal thickness and is composed of corneal cells and extracellular matrix. The fibrils of the matrix cross at a 90 ° angle; these fibrils are types I, III, V and VII collagen.

The posterior elastic layer and endothelium are considered to be the posterior part of the cornea. The rear elastic layer is unstructured and uniform and measures 3-12 microns; it consists of a front banded region and a rear non-banded region; the rear elastic layer is rich in type IV collagen fibers.

The interior of the cornea is covered by a corneal endothelium, which is a single layer of simple cubic and hexagonal cells 5 microns thick with multiple orthogonal collagen arrays between them. The endothelium originates from the neural crest and is used to transport fluid from the anterior chamber to the matrix layers. Since the cornea is avascular, its nutrients are mainly derived from diffusion from the endothelial layer (Duong, H-V.Q. "Eye Global anatomo," https:// emidicine. mediscape.com/artice/1923010-0 overview, 11 months and 9 days updates in 2017). Due to the high concentration of soluble VEGFR-1, it is usually avascular and surrounded by a transitional rim, the limbus, within which the neoendothelial and corneal epithelial stem cells reside. As above.

Region of cornea

The shape of the cornea is aspherical, which means that it deviates slightly from a sphere. Typically, the central cornea is steeper than the periphery by about 3D. (http:// www.aao.org/bcssdsnippdettail. aspxid =65c7bff9-4 fle-47', 7-8585-.

Clinically, the cornea is divided into areas that surround the point of regard (gaze) and merge with each other. A central zone of 1-2 mm fits closely to the spherical surface. Adjacent to the central zone is a side central zone, a 3-4 mm annular ring of 7-8 mm outer diameter, which represents a region that is gradually flattened from the center. The lateral central region and the central region together form a roof region. The central and paracentral zones are primarily responsible for the refractive power of the cornea. Adjacent to the lateral central region is a peripheral region having an outer diameter of about 11 mm. The peripheral zone is also referred to as the transition zone because it is the area of maximum flattening and asphericity of the normal cornea. Adjacent the peripheral zone is the limbus, which has an average outer diameter of 12 mm. As above.

The optical zone is the portion of the cornea that covers the entrance pupil of the iris; due to the Stiles-Crawford effect, it is physiologically limited to about 5.4 mm (it has been shown from the outset that the decrease in brightness as the entrance of the light beam into the eye moves from the center of the pupil to the edge is due to the change in luminous efficiency of radiation as it is obliquely incident on the retina see G. Westheimer, "directive sensitivity of the retinitis: 75 years of Stiles-Crawford effect," Proc. R. Soc. B. (2008) 275 (1653): 2777-86). As above.

The corneal apex is the point of maximum curvature. The corneal vertex is the point at the intersection of the individual's gaze line and the corneal surface.

For good vision, the cornea must be clear, smooth and healthy. If it is scarred, swollen, or damaged, the light is not properly focused into the eye.

Corneal wound healing

The term "wound healing" refers to the process by which the body repairs wounds to any of its tissues, especially wounds that are caused by physical means and have a continuous interruption.

The wound healing response is generally described as having three distinct phases-injury, inflammation, and repair. The injury often results in the destruction of normal tissue structures, initiating a healing response. In general, the body's response to injury is accompanied by an inflammatory response, which is critical to maintaining the health and integrity of the organism. The end phase of wound healing consists of coordinated cellular reorganization (which is guided by scaffold formation rich in fibrin (fibrin that polymerizes to form a "mesh" to form a clot on the wound site), wound contraction, closure, and re-epithelialization.

The response of the anterior segment of the eye to wound healing is very similar to that of non-CNS tissues. Friedlander, M. "fibers and diseases of the eye," J. Clin. invest. (2007) 117(3): 576-86.

Healing of corneal epithelial wounds involves a number of synergistic events including cell migration, proliferation, adhesion and differentiation, with consequent stratification of the cell layers.

In short, corneal epithelial healing is primarily dependent on Limbal Epithelial Stem Cells (LESCs), which are only present in many species, including humans, in the remodeling of the corneoscleral junction and basement membrane. Ljubamov, AV and Saghizadeh, M., "Progress in coronary winding Healing," prog. Retin Eye Res. (2015) 49: 17-45. In response to injury, LESCs undergo several cycles of proliferation and produce numerous transient-amplifying cells (TACS), which appear to constitute the majority of the basal epithelium in the limbus and peripheral cornea. As above. LESCs are thought to migrate into the central cornea, thereafter proliferate rapidly, and eventually differentiate into central corneal epithelial cells. As above. During stromal healing, corneal cells are converted to motile and contractile myofibroblasts primarily due to the activation of the transforming growth factor beta system. As above. Endothelial cells heal primarily by migration and diffusion, with cell proliferation playing a secondary role. As above.

Epithelial wound healing

The kinetics of epithelial wound healing comprise two distinct phases: initial latency and closure phase. The initial latent phase involves cellular and subcellular recombination to trigger migration of epithelial cells at the wound margin. (As above, reference is made to Kuwabara T et al, Sliding of the epithelium in experimental corn wood, invest. Ophthalmol. (1976) 15: 4-14; Crosson, CE et al, Epithelial wind closure in the laboratory corn. A biphasic process. invest. Ophthalmol. Vis. Sci. (1986) 27: 464-. The closed phase comprises several sequential processes, starting from cell migration independent of cell mitosis (see, above, Anderson, SC et al, Rho and Rho-kinase (rock) signalling in adherens and gap junction establishment in cornual Epithelial. invest. ophthalmol. vis. sci. (2002) 43: 978-.

Wound healing factor in epithelial wound healing

When the corneal epithelium is damaged, nucleotides and neuronal factors are released into the extracellular environment to generate a Ca (2+) wave from the wound origin to adjacent cells. (see, Lee, A et al, Hypoxia-induced changes in Ca2+ conjugation and protein phosphorylation amplified in bound chemistry, Am. J. physical. cell. physical. (2014) 306: C972-985)). ATP release induced within one minute after injury leads to mobilization of intracellular calcium following activation of the purinergic receptor P2Y or P2X (supra, reference Weinger, I et al, Tri-nuclear receptors display a critical role in epithelial cell around, Purinerg. Signal (2005) 1: 281-292; Hypoxia-induced changes in Ca2+ mobilization and protein phosphorylation amplification expressed in bound chemistry Am. J. Physiol. cell. physiol. (2014) 306: C972-985). This activation appears to be one of the earliest events in the healing process. (see, Lee, A. et al, Hypoxia-induced changes in Ca2+ conjugation and protein phosphorylation amplification and outlet chemistry Am. J. Physiol. cell. physiol. (2014) 306: C972-985). Recent data show that the effect of P2X7 on wound healing can be mediated by rearrangement of the actin cytoskeleton to enable better migration of epithelial cells (supra).

Toll-like receptors (TLRs) also contribute to early corneal epithelial wound healing by enhancing cell migration and proliferation in vitro and in vivo (supra, reference is made to Eslani, M et al, The role of Toll-like receptor 4 in corneal epithelial wound healing. invest. ophthalmol. vis. sci. (2014) 55: 6108-. TLRs are a family of proteins that play a major role in the innate immune system and regulate inflammation through several pathways, such as nuclear factor κ B (NF- κ B), MAP kinase, and Activator Protein (AP) -1. (see Pearlman, E et al, Toll-like receptors at the cellular surface. Ocul. Surf. (2008) 6: 108-. TLR signaling pathways are activated in response to their ligands, such as pathogen-associated molecular patterns ("PAMPs", for viruses and bacteria) and damage-associated molecular patterns (DAMPs) caused by tissue damage. This results in the production of proinflammatory cytokines, adhesion molecules and proteolytic enzymes during the inflammatory phase of wound healing (see Pearlman, E et al, supra, Toll-like receptors at the cellular surface. Ocuul. Surf. (2008) 6: 108- & 116; Kostaroy, AV et al, Toll-bacterial lipid application enzymes infection expression responses and proteins around health. J. Interferon cellular kinase Res. (2013) 33: 514- & 522) and in enhanced cell migration and proliferation.

During the initial or lag phase of wound healing, several parallel signaling pathways, which may cross-act, are activated to reorganize cellular and subcellular structures to initiate cell migration, the first step in the healing process. These initiation factors include IL-1 and TNF- α (see Wilson SE et al, supra, both molecular-epithelial interactions in the epidermal, protein, Retin. Eye Res. (1999) 18: 293-. In addition, many transcription factors that are activated during The lag phase of wound healing before cells begin to migrate, such as c-fos, c-jun, jun-B and fos-B (supra, cited Oakdale, Y, Expression of fos family and jun family proteins and even family proteins produced parallel corneal apoptosis, Current Eye Res. (1996) 15: 824-containing 832) can also lead to activation of other parallel pathways in The underlying stroma, including IL-1 mediated corneal apoptosis via FAS/FAS ligands (supra, cited Wilson SE et al, molecular-epithelial interactions in The corneal apoptosis, Collection Eye Res. (1999) 18: 293-containing 309, which leads to The first 24 hour continuous thermal pathway after injury, stroma, and information cells, prog, Retin, Eye Res. (2001) 20: 625-. EGFR Transactivation has been shown to enhance intracellular signaling in corneal epithelial wound healing by activating the ERK and PI3K/Akt pathways in the presence of non-EGF ligands such as IGF, insulin and HGF (supra, reference is made to Lyu J, Transactivation of EGFR media constructs-stimulated ERK1/2 activation and enhanced Cell stimulation in human corneal epithelial cells. mol. Vis. 12: 1403-1410; Spix JK et al, Hepatocyte growth factor tissue stimulation of the epidermal growth factor expression. exp. Cell Res. 313: 3319-index 2007: 3325). Hepatocyte Growth Factor (HGF) and Keratinocyte Growth Factor (KGF), as well as Pigment Epithelium Derived Factor (PEDF) signaling during wound healing, are focused on the p38 and/or ERK1/2 pathways; the former mediates cell migration, while the latter induces proliferation. (As above, reference is made to Sharma GD, He J, Bazan HE. p38 and ERK 1/2-coordinated cellular migration and promotion in temporal surrounding Healhealing: evaluation of cross-talk activation beta MAP kinase cassettes J. biol. chem. (2003) 278: 21989-20. host TC et al, PEDF proteins self-repeat of molecular step cell and optimization temporal surrounding beyond Healhealing. Stem cell. (2013) 31: 1775-1784).

Another initial wound healing factor is the release of Matrix Metalloproteinases (MMPs), which trigger a series of processes to break cell-cell and cell-matrix adhesion. This results in the initiation and promotion of cell migration by cross-interactions with integrins and the production of extracellular matrix (ECM) proteins, such as fibronectin, laminin and tenascin, in the wound area, which act as temporary scaffolds for migrating cells (see, above, Tuft SJ et al, nutritional assessment: injections of coronary and health services Br. J. Ophthalmol. (1993) 77: 243-. Release of nuclear nucleotides (e.g., ATP) following epithelial Injury is also implicated as an initial factor in causing rapid activation of purinergic signaling and increased intracellular CA2+ levels, leading to Epidermal Growth Factor Receptor (EGFR) transactivation and Cell migration, and ultimately to epithelial Wound healing involving the corneal nerve (see Weinger I et al, supra, Tri-nuclear receptors plant a critical roll in epithelial Cell wind repair. Puring. Signal. 2005) 1: 281-292; Boucher I. Inj. and nuclear receptors amplification of epithelial growth factor receptor: MMP and HB-dependent tissue. Exp. Eye Rese.2007: 130-141; Yin J, Xu K, Zhang J. A, 120A. 120. J. Cell 120. EGF. Cell J. EGF. III. EGF. Cell J. P. EGF. Cell J. 35, hypoxia-induced changes in Ca2+ conjugation and protein phosphorylation amplification in amplified white chemistry Am. J. physiology. cell. physiology, (2014) 306: C972-985). EGFR and purinergic signaling are also involved in phosphorylation of Paxillin, a focal adhesion associated phosphotyrosine-containing protein that contains many motifs that mediate protein-protein interactions required for cell migration (see Schaller, MD, "Paxillin: a focal adhesion associated adaptor protein," Oncogene (2001) 20: 6459-72) (supra, Kimura K et al, Role of JNK-dependent peptide phosphorylation of Paxillin in hybridization of biochemical epithelial cells. Invest. Ophthalmol. Vis. 2008. 49: 125. 132; Mayo C et al, Regulation by P2X7: epitapestry hybridization and structural organization of the protein-protein interaction of the adhesion promoter protein 4391. 2008. J. Ophthal. Ophtal. J..

Cell migration during wound healing may also involve cross-interactions between growth factors and the ECM. Insulin-like growth factor 1 (IGF 1) was shown to induce cell migration directly through its receptor and by stimulating the expression of the corneal basal membrane component laminin-332, which promotes epithelial cell migration in vitro (see Lee JG, Kay EP. FGF-2-induced surrounding epithelial cell requirements Cdc42 activation and Rho inactivation of the phosphatydisclosunitol 3-kinase pathway. invest. Ophthalmol. Vis. Sci. (2006) 47: 1376-1386). IGF1 receptors may also participate in the cross-reaction with β 1-chain containing integrins important for corneal epithelial cell migration through their recruitment to lipid rafts (see Salani B et al, supra, IGF-I induced radial recovery of integrins β 1 to lipid rafters is caveolin-1 dependent. biochem. Biophys. Res. Commun. 2009 (2009) 380: 489-492) (see Seomun Y, Joo CK. Lumicon induced human epithelial cell migration and integrins expression via ERK1/2 signalling. Biophys. Res. Commun. 2008: 372: 221-225). In summary, a significant cross-interaction in corneal wound healing between several growth factors, and between the growth factors and the extracellular mediators of the process, through transactivation of the signaling pathway, has been revealed. This cross-over highlights the complex nature of epithelial wound healing.

ECM in epithelial wound healing

The corneal epithelium forms its own ECM in the form of a specialized epithelial basement membrane located between the basal epithelial cells and stroma and attached to the underlying collagenous proelastic layer. Which provide structural support and modulate epithelial migration, proliferation, differentiation, adhesion and apoptosis through various receptors (cited above, Azar DT et al, Altered epithelial-based interactions in epithelial cells. Arch. Ophthalmol. (1992) 110: 537-40; Kurpakus MA et al, The roll of The basic membrane in differential expression of fibrous cells. Dev. biol. (1992) 150: 243 and 255; Zieses JD et al, basic membrane assay and differentiation of epithelial cells: animal of tissue cells. Cell and 55. Cell et al, (1996) 14. Llumina. rearview. 35; 75. rearview. Ophtol. 1996), cell-matrix and Cell-Cell interaction along intrinsic output from prog, Retin, Eye Res. (2003) 22: 113-. Like most basement membranes, corneal epithelial basement membranes consist of specialized networks of collagen IV, Laminin, entactin, and perlecan (cited above, Nakayasu K et al, Distribution of types I, II, III, IV and V collagen in normal and keratoronus kernals, Ophthalmic Res. (1986) 18: 1-10; Martin GR, Timpl R, Laminin and other base membrane components, Annu. Cell biol. (1987) 3: 57-85; Ljibroov AV et al, Human kernal base cellulose derivative of The expression of collagen IV collagen and collagen polysaccharide, 1996; found et al, nucleotide polysaccharide, peptide, polysaccharide Et al, Human metabolic core previous surrounding hearing, base membrane, integrin and MMP-10 differential from normal core in organic culture, exp. Eye Res. (2003) 77: 211-; schl titaner-Schrehardt U et al, Characterisation of extracellular matrix components in the lithium epithelial cell component Exp. Eye Res. (2007) 85: 845-60), as well as additional components such as TSP-1, matrilin-2, matrilin-4, CV, XCII, and XCIII collagen and Fibronectin (FN) (supra, reference Kabosova A et al, Compositional differences between beta and adult human epidermal fibers, invest. Ophthalmol. Vis. Sci.2007) 48: 4989 4999; U.S. Pat. No. 85: 845-60, Characterisation of extracellular matrix compositions in the lithium epithelial cell composition. Exp. Eye Res. (2007); Dietrrich-Ntoukas T et al, synthetic analysis of the base membrane composition of the human membrane epitope and ammoniatic membrane epitope. Cornea. (2012) 31: 564-.

Immune system intervention in epithelial wound healing

Immune system cells, such as neutrophils, play an important role in corneal epithelial wound healing, possibly due to their ability to release growth factors that affect the epithelium (Li Z et al, Lymphocytic function-associated antigen-1-dependent inhibition of corneal wound healing. Am. J. Pathol. (2006) 169: 1590. sup. 600; Li Z et al, Platlet response to corneal abnormality diagnosis for approach for infection and infection-inflammation. invest. Ophthalmol. Vis. Sci. (2006) 47: 4794. sup. 4802).

The primary function of the corneal epithelium is to protect the interior of the eye by acting as a physical and chemical barrier against infection by virtue of the tight junctions and maintaining the integrity and visual clarity of the cornea. As above. Injured, damaged or infected epithelial cells secrete the cytokine IL-1 α, which is stored in epithelial cells and released when the cell membrane is damaged by external injury. As above. Secreted IL-1 α can cause an increase in corneal immune infiltration to cause neovascularization, which can lead to vision loss. As above. However, IL-1RN, an IL-1 α antagonist, prevents leukocyte invasion of the cornea and inhibits neovascularization, which may help to preserve vision (cite Stapleton WM et al, Topical interleukin-1 receptor anti-inflammatory inhibition cell attenuation into the cornea. Exp. Eye Res. (2008) 86: 753-757). In animal models, corneal epithelial trauma induces an acute inflammatory response in The limbal vessels to result in The accumulation of leukocytes and neutrophils (cited above in Li SD, Huang L. Non-viral super oxidant to viral gene delivery. J. Control release. (2007) 123: 181-183; Yamagami S et al, CCR5 promoter receptors recovery of MHC II-Positive Langerhans cells in The motor skin epithelial cells (2005) 46: 634-7 SD), and dendritic cells, macrophages and lymphocytes migration (cited above in Y et al, chemokine 7 cells derived genes coding-183-gradient Control. (2007) 13. tissue release. J. 2007; N J. transport J. 2007: 13-32. g. J. gradient freeze. 123, dendritic cell-epithelial display a specific factor for cornual epithelial wind-repair, Am. J. Pathol. (2011) 179: 2243-53) into the stroma and the wounded epithelium. There is evidence that the innate inflammatory response is essential for corneal epithelial wound healing and nerve recovery (supra, cite Li Z et al, Lymphocytic function-associated antigen-1-dependent inhibition of corneal wound healing. Am. J. Pathol. (2006) 169: 1590. sup. 600; Li SD, Huang L. Non-visual is superior to visual gene delivery. J. Control Release. (2007) 123: 181. sup. 183; 2011; Gao N et al, pending cell-epithelial tissue is a dependent factor for corneal epithelial wound healing. J. Pathol. Am. J. sup. 179: 2243-53). Platelets also accumulate in the limbus and migrate to the stroma in response to injured epithelium, which is required for efficient re-epithelialization by cell adhesion molecules such as P-selectin (supra, Li Z et al, plate response to cornual interaction for access to and efficacy of re-epithelialization. invest. Ophthalmol. Vis. Sci. (2006) 47: 4794. 4802; Lam FW et al, plate enhancement of nuclear transduction pathology via P-selection in ligand-1. Am. J physiology. Heart. physiology. 300: H468-H475).

Epithelial Basement Membrane (BM) in corneal wound healing

Several studies have demonstrated The importance of Epithelial BM in Corneal wound healing (Torricelli, AAM et al, The Corneal Epithelial Membrane: Structure, Function and Disease, Invest. Ophthalmol. Vis. Sci. (2013) 54: 6390-. For example, Pal-Ghosh and co-workers have demonstrated that Removal of epithelial BM enhances many wound healing processes in the cornea, including corneal apoptosis and neural death (supra, cite Pal-Ghosh S, et al, Removal of the base membrane industries communicating with health, Exp Eye Res. (2011) 93: 927-. Corneal surgery, injury, or infection often causes the appearance of stromal myofibroblasts associated with persistent corneal haze (haze) (Torricelli AA et al, Transmission Electron microscopy analysis of epithelial base membrane repair in corneal corneas with haze. Invest Ophthalmol Vis Sci. (2013) 54: 4026-. The development of haze is due to reduced transparency of the cells themselves and the production of disordered extracellular matrix components by Stromal cells (see, supra, Jester JV et al, transformed growth factor (beta) -mediated cornual myoblast differentiation acquisition and differentiation assessment, Invest Ophthalmol Vis Sci (1999) 40: 1959-. Singh et al reported that a properly functioning epithelial BM critically regulates myofibroblast development by its barrier function that prevents epithelial TGF- β 1 and platelet-derived growth factor (PDGF) from penetrating into the stroma at a sufficient level (sufficient to drive myofibroblast development and maintain viability once mature myofibroblasts are generated). (As above, reference is made to Singh V et al, structural fiber-bone ground-derived cell interfaces: indications for myofibror depletion in the corn. Exp Eye Res. (2012) 98: 1-8). This hypothesis suggests that stromal surface irregularities following photorefractive keratectomy (PRK) or other corneal injury lead to structural and functional defects in the regenerated epithelial BM that increase and prolong the penetration of epithelial TGF- β 1 and PDGF into the anterior corneal stroma to promote myofibroblast development from keratocyte-derived or bone marrow-derived precursor cells (cited above in Singh V et al, Effect of TGFbeta and PDGF-B blockade on cornual myoblast definition in Exp Eye res. (2011) 93: 810-.

The working hypothesis is that significant mature myofibroblast production and resultant disturbance of extracellular matrix secretion in the prematria of significantly damaged corneas interferes with the corneal cellular contribution of key components to BM (e.g., type VII collagen), which results in defective epithelial BM regeneration. As above. Only when epithelial BM finally regenerates, which may take years in some turbid corneas, and epithelial-derived TGF-beta 1 levels decrease, myofibroblasts undergo apoptosis and the corneocytes reabsorb disordered extracellular matrix and thereby restore transparency (cited above in Singh V et al, Molecular fiber-borne-sequential cells: injections for myoblast depletion in the cornea Eye-Eye Res. (2012) 98: 1-8; Fini ME, Stramer BM. How the corneal skin eyes: nuclear-specific regenerative Molecular tissue: nuclear-biological affinity after tissue culture scientific tissues: Cornea et al, 2005: S2-S11; Stramer et al, Molecular tissue culture: 4246: Molecular fibers: 4246). Thus, epithelial BM may function as a corneal regulatory structure that limits fibrotic responses in the stroma by regulating the availability of epithelial-derived TGF- β 1, PDGF and possibly other growth factors and extracellular matrix components to stromal cells (including myofibroblast precursors). As above. It also modulates the level of epithelial regulators of motility, proliferation and differentiation produced by stromal cells that migrate in the opposite direction through the BM, such as Keratinocyte Growth Factor (KGF) (see Wilson SE et al, Hepatocyte growth factor, keratinococyte growth factor, the ir receptors, fibroblast growth factor receptor-2, and the cells of the corn. Invest Ophthalmol Vis. Sci. (1993) 34: 2544-. Thus, the corneal epithelial BM can modulate epithelial-stromal and stromal-epithelial interactions by regulating the movement of cytokines and growth factors from one cell layer to another.

Latvala et al observed that the Distribution of α 6 and β 4 integrins adjacent to the BM changes during healing of epithelial wounds following epithelial abrasion in rabbit corneas (above, cite Latvala T, et al, Distribution of alpha 6 and beta 4 integrins swelling epithelial adsorption in the rabbit cornea. Acta Ophthalmol Scand. (1996) 74: 21-25). Stepp et al have demonstrated that epithelialization of small wounds is accompanied by an increase in α 6 β 4 integrin (supra, cited Stepp MA et al, Changes in beta 4 integrin expression and localization in vivo in response to coronary epithelial in J jour. Invest Ophthalmol Vis. Sci. (1996) 37: 1593. sup. open 1601). Epithelial Cell migration is also affected by the distribution of laminin and collagen IV during corneal wound healing and BM regeneration (as above, reference is made to Fujikawa LS et al, basic membrane components in the clinical laboratory weights: immunological procedures and ultrastructural students. J Cell biol. (1984) 98: 128-. Thus, α 3(IV) and α 4(IV) collagen chains may be important for healthy corneal epithelium. As above. After injury, BM remodels to include α 1(IV) and α 2(IV) collagens, recapitulating corneal epithelial expression during development. As above.

Corneal stromal wound healing

Stromal remodeling occurs after direct damage to The stroma and its cells (e.g., photorefractive keratectomy (PRK) and LASIK (for myopia correction)) and after death of Stromal cells (corneal cells) caused by damage or removal of The corneal epithelium by various physical or chemical factors (see, above, Nakayasu K. structural changes from corneal in corneal section J. Ophthalmol. (1988) 32: 113. 125; Szerenyi KD et al, Keratocyst loss and rearrangement of anti-corneal tissue from ocular tissue in-ocular modification, Arch. Ophthalmol. (1994) 112: 973. 976; Wilson et al, epidermal injury in tissue repair: 20. injection and repair. 20. injection of corneal tissue in-tissue in and repair. 2. injection, stroma, and inventory cells, prog, Retin, Eye Res. (2001) 20: 625-637; wilson SE et al, Apoptosis in the initiation, modulation and termination of the coronary winding and closing response, exp. Eye Res. (2007) 85: 305-. This damage triggers the release of inflammatory cytokines from epithelial cells and/or tears (cited above in Maycock NJ, Marshall J. Genomics of corneal outgoing health: a review of the performance. Acta Ophthalmol. (2014) 92: e 170-84), mainly IL-1 (alpha and beta), which causes rapid apoptosis by the Fas/Fas ligand system and subsequent necrosis of mainly anterior corneal cells. These cells preferentially die directly beneath the epithelial wound, but not beyond their margins. Subsequent matrix remodeling and subsequent recruitment of these cells from regions adjacent to the depleted region (see Zieske JD et al, supra, Activation of the epidermal growth factor receptor during the epidermal growth promotion of Invest. Ophthalmol. Vis. Sci. (2000) 41: 1346-1355) also constitute the wound healing process, and may result in fibrotic changes, particularly if The epithelial basement membrane is initially damaged (see Stramer BM et al, supra; Molecular mechanisms controlling The fibrous reprocess in core: immunological for surgery animals. invest. Ophthalmol. Vis. Sci. (2003) 44: 4237; Fini ME, Stramer BM. How The fibrous tissues in heart animals: study-scientific for surgery animals. Cornea. (2005) 24(Suppl 1: S2-S11; West-Mays, Dwivedi DJ.. surgery animals: coronary tissue culture. simulation J. 16238). This is a classical example of how stromal-epithelial interactions influence the wound healing process through paracrine mediators. As above.

In the early stages of wound repair, dormant corneocytes at the wound margin change their properties to be activated into fibroblasts. These cells enter The Cell cycle and acquire The migratory properties necessary for The re-proliferation and wound closure (cite, West-Mays JA, Dwivedi DJ. The keratocyte: corneal linear Cell with variable repair viruses, int. J. biochem. Cell biol. (2006) 38: 1625-1631). In culture, this transformation is mediated by some (fibroblast growth factor 2 (FGF-2) and PDGF-AB, TGF- β) growth factors, while other growth factors (IL-1, IGF-1) only provide mitogenic activity (see above, Jester JV, Ho-Chang J. Modulation of cultured mammalian growth factors/cytokines control in vitro control and expression matrix control. Exp. Eye Res. (2003) 77: 581-592; Chen J et al, Rho-mediated regulation of TGF- β 1-and FGF-2-induced activation of mammalian growth sequences. est. Vis. Op. 2009) 3670). These cells reshape their actin cytoskeleton to obtain stress fibers and change their morphology from star to elongated (see, supra, Jester JV, Ho-Chang J. Modulation of cut cornual committed cell phenotype by growth factors/cytokines control in vitro and vitro formation control. exp. Eye Res. (2003) 77: 581. 592). Fibroblasts down-regulate The expression of differentiated Corneal Cell proteins, such as Corneal crystallins (transketolase and aldehyde dehydrogenase 1A 1) and keratan sulfate proteoglycans, and begin to produce proteases (mainly MMPs) required for remodeling The wound ECM (see, supra, Fini ME. Keratocytes and fibrous phenotypes in The regenerative cornea. prog. Reg. Eye Res. (1999) 18: 529. 551; Jester JV et al, cardiac tissue surrounding and healing in regenerative surgery: The role of The cornea of The Eye of The patient, prog. Eye Res. (1999) 18: 311. 356; Carlson EC 2006, expressed KSPG expressing Corneal cells of The cornea cells of The patient, Yeast et al, (2003: western. Biophys. J. 11. 103. Biophys. J. 11. 103. hydrolysate J. DJ.. yeast. wo 10. wo).

After they reach the wound bed, fibroblasts begin to express alpha-smooth muscle actin (alpha-SMA) and desmin, up-regulate the expression of vimentin (supra, reference Chaurasia SS et al, "Dynamics of the expression of the epidermal membrane vision and the expression of the lipid depletion tissue in the" exp. Eye Res. (2009) 89: 590-59), and become highly motile and contractile myofibroblasts needed to remodel wound ECM and contract wounds. They also deposit transient ECM rich in fibronectin and some other proteins including tenascin-C and collagen type III (cited above in Tervo K et al, Expression of tenascin and cellular fibrosis in the scaffold and heart of the tissue and antibody inhibitor key therapy. immunological study of the world and leather dynamics. Invest. Ophthalmol. Vis. Sci. (1991) 32: 2912. 2918; Fini ME. Keratocyte and fibre peptides in the repaving heart of the protein production. Retin. Eye Res (1999) 18: 529. 551). Myofibroblasts generate contractile force to close the wound gap, and the Expression of α -SMA is directly related to corneal wound contraction (supra, cite Jester JV et al, Expression of alpha-smooth muscle (α -SM) act in dual corneal wound healing magnetic health, invest, Ophthalmol. Vis. Sci. (1995) 36: 809 819). When the wound is not truly contracted, as in the case of PRK or light therapeutic keratotomy (PTK), the appearance of myofibroblasts is delayed and they begin to accumulate only at the latest four weeks after an irregular PTK (as above, quoted to Barbosa FL et al, cardiac myoblast generation from bone raw-derived cells. exp. Eye res. (2010) 91: 92-96).

It is generally accepted that myofibroblast transformation is triggered by transforming growth factor beta (TGF-. beta.) in vivo, which has been confirmed by a number of in vitro studies (supra, citation Jester JV et al, central structural ground and Healing in reactive supply: the role of myofibrases, prog. Retin. Eye Res. (1999) 18: 311-. Recent studies have also suggested a potent mitogenic PDGF (AA and BB) in this process, where the combination of TGF- β and PDGF is more potent than either factor alone (as above, reference is made to Kaur H et al, Central Stroma PDGF block and myoblast definition. Exp. Eye. Res. (2009) 88: 960. 965; Singh V et al, transformation growth factor β and planar-driven growth factor modification of myoblast definition in vitro PDG. Exp. Eye. Res. (2014) 120: 152. 160). Only TGF-. beta.1 and TGF-. beta.2 are active in this process, as TGF-. beta.3 does not convert fibroblasts into myofibroblasts (as above, reference is made to Karamichos D et al, reverse of fibrosis by TGF-. beta.3 in a 3D in vitro model. exp. Eye Res. (2014) 124: 31-36). After wound healing was complete, myofibroblasts apparently stopped expressing α -SMA. Their fate in vivo is not yet fully understood, although the appearance of myofibroblasts is recognized as an essential component of stromal wound healing, the number of myofibroblasts in the corneal stroma after PRK varies widely among Mouse strains (supra, refer to Singh V et al, Mouse strain variation in SMA (+) myoblast reduction after skin input in jet re. (2013) 115: 27-30). Some data indicate that after epithelial debridement of mouse cornea, re-proliferation of corneal cells occurs without the appearance of myofibroblasts (see, supra, Matsuba M et al, Localization of thrombospondin-1 and myofibrasts degradation in tissue outlet repeat. Exp. Eye Res. (2011) 93: 534-.

Immune cells in matrix healing

Corneal injury in animal models causes an Inflammatory Response by immune system Cells including monocytes/macrophages, T Cells, Polymorphonuclear (PMN) leukocytes and Natural Killer (NK) Cells (see, above, Gan L et al, Effect of leucocytes on coronary Cells promotion and ground healing. invest. Optimol. Vis. Sci. (1999) 40: 575. 581; WilSE et al, The Corneal outgoing healing Response: cyto. mediated interaction of The Epithelial, strain and inflammation Cells, protein production. Eye Res. (2001) 20: 2004. 625. 637; Wilson et al, RANK, KL, G, M-CSF expression strain and growth healing. expression reaction J. 10. expression K. infiltration of The Corneal Cells, K. expression, K, KL, G, and M-CSF expression strain, and growth promotion, K. infiltration, K. expression, K, M-CSF, expression, K1, expression Macro deletion copies corner following height after transformation in micro-PLoS one. (2013) 8: e 61799). These infiltrating Cells are usually defined by staining with CD11b, although better characterization of these Cells is provided in some studies (Wilson SE et al, supra; The cornual white chemistry Response: cytokine mediated interaction of The epilayer, stream, and in-flight Cells. Reg. Eye Res. (2001) 20: 625-637; Liu Q et al, NK Cells modulation The imaging reaction adsorption and The recovery Support wool theory. J. Pathol. 181: 201452-462; Li S et al, macro tissue complex white chemistry sample treated sample culture reaction 619: PLoo. 3). Immune cells can be transferred from The limbal region to The damaged cornea or from circulation (see Wilson SE et al, supra; The corneal tissue mediated interaction of The epitilium, strain, and inflammation cells. prog. Regin. Eye Res. (2001) 20: 625-. The primary attractive signal to these cells may be monocyte chemoattractant protein-1 (MCP-1), a cytokine secreted by activated fibroblasts and triggered by IL-1 or TNF- α (Wilson SE et al, supra; cell kinase mediated interaction of The epithelial, strain, and inflammatory cells. prog. Retin. Eye Res. 2001) 20: 625-. Another factor required for neutrophil influx after injury was identified as the matrix proteoglycan Lumican (supra, cited Hayashi Y et al, Lumican is required for neutral invasion and swelling associated with J. Cell Sci. (2010) 123: 2987. sup. 2995). It is unclear what is the magnitude, pool and origin of infiltrating cells, and the kinetics of the immune response to corneal injury in humans.

The function of immune cells infiltrating the damaged cornea may be diverse. They can clear away The remnants of apoptotic corneal cells and protect The cornea from possible infection (see Wilson SE et al, supra: The corneal mediated interaction of The epithelial, strain, and inflammatory cells. prog. Retin. Eye Res. (2001) 20: 625-637). Some of these cells can become myofibroblasts (cited above, Barbosa FL et al, nuclear myoblast generation from bone marrow-derived cells. exp. Eye res. (2010) 91: 92-96) and thus participate in wound contraction. Recent studies have also suggested that immune cells are directly involved in wound healing. Blocking PMNs from entering the cornea after PRK in rabbits by fucoidan, an inhibitor of leukocyte adhesion to the vascular endothelium, delays wound healing (see, above, Gan L et al, efficiency of leucocytes on coronary cellular promotion and wind healing. invest. Ophthalmol. Vis. Sci. (1999) 40: 575-581). Functional blockade of NK Cells following Epithelial Abrasion and Corneal cell loss inhibits healing and nerve regeneration (supra, cite Liu Q et al, NK cell modulation the Inflammatory Response to neural Epithelial ablation and the therapeutic Support 1 wooden Healing. J. Pathol. 2012) 181: 452-. Macrophage depletion impairs wound healing after autologous corneal transplantation, with a concomitant decrease in wound myofibroblasts (supra, reference is made to Li S et al, Macrophage deletion impropars coronary outgoing healing after autografting in mice. PLoS one. (2013) 8: e 61799). These studies underscore the importance of local and systemic immunity in corneal wound healing, both epithelial and stromal.

Remodeling of matrix ECM during wound healing

As mentioned above, matrix wound healing is accompanied by several events that may lead to changes in the ECM at the site: the death of corneal cells, the secretion of pro-inflammatory and profibrotic cytokines, including IL-1, TNF- α and MCP-1, the transient emergence of cells that do not normally form a matrix (PMNs, macrophages, myofibroblasts), and the production of ECM-degrading enzymes by activated cells. All of these factors contribute to ECM remodeling, including its degradation, expression of ectopic components (by the temporary formation of matrices of new cell types), and the reassembly of new ECMs to form more or less normal structures (supra, cited Zieske JD et al, Kinetics of metabolic promotion in response to infection described in Exp. Eye Res. (2001)72: 33-39; Torcelili AA, Wil SE. Cellular and extracellular matrix modification of cardiac structural access Exp. Eye Res. (2014) 129: 151-160). Thus, the new ECM formed during wound healing often accumulates proteins that are abnormal in both composition and structure. Over time, these proteins may form local scars which last long (see, supra, Ishizaki M et al Expression of collagen I, smooth muscle alpha-act, and vision in reducing the Expression of alkali-burned and fatty-burned bacteria. invest. Ophthalmol. Vis. Sci. (1993) 34: 3320. 3328; Ishizam M et al, structural fiber area associated with collagen IV in bacteria tissue of alkali-burned and fatty-burned bacteria. curr. Eyer. Res. 1997) 16: 339. medium 348; Maguen E et al, Expression of Extracellular matrix stress from collagen alpha-burned and fatty-burned bacteria. repair. 1997) 16: 339. medium 18; Maguen E et al, Expression of collagen alpha-burned and fatty-burned bacteria strain, Expression of collagen alpha-burned and fatty-burned bacteria, 1997) 16: 1998; Cornus II Expression of collagen IV. Expression strain, Expression of collagen IV. coli II, Expression of collagen II, Expression of alpha-burned bacteria, alpha-burned protein, alpha-expressed protein, expressed in protein, expressed in alpha-expressed in protein, expressed in a protein expressed in Expression of Expression, expressed in protein expressed in Expression, expressed in Expression, expressed in Expression, expressed in (LASIK) Cornea (2002) 21: 95-100; maguen E et al, immunological evaluation of two corner corn buttons with post-LASIK keratectasia. Cornea. (2007) 26: 983-; kato T et al, Expression of type XVIII collagen reducing health of corn induction and keratectomy of invest. Ophthalmol. Vis. Sci. (2003) 44: 78-85; Kamma-Lorger CS et al, Collagen ultra structural changes in organic tubular combustion. exp. Eye Res. (2009) 88: 953-; torricelli AA, Wilson SE. Cellular and extracellular matrix modulation of cornual molecular access. Exp. Eye Res. (2014) 129: 151-. Due to the slow turnover of ECM proteins, there may still be unusual scar components around the healing wound for several years, especially in the cornea of humans (see Latvala T et al, Expression of cellular repair and tenascin in the corneal tissue and tissue effector tissue evaluation: a 12 month study. Br. J. Ophthalmol. 1995: 65-69; Maguen E et al, cellular tissue and matrix metalloproteinase exchange in human tissue repair and tissue repair in situ tissue repair (LASIK) Cornea. 2002) 21: 95-10; Maguen E et al, biological repair of tissue repair and tissue repair of tissue repair, 2008. 9. 11. and 11 tissue repair. 9. 11. 9. the appended drawings of tissue repair and tissue industries, 2008. 11. 3. cortex et al, tissue repair of tissue repair and tissue repair. 2008. 11. 3. the present invention relates to tissue repair of tissue repair and tissue repair industries). These components, which are normally rare or absent in the corneal stroma of adults, include collagen types III, VIII, XIV and XVIII, limbal isoform of collagen type IV, embryonic fibronectin isoform, thrombospondin-1 (TSP-1), tenascin-C, fibrillin-1 and hevin (an ECM-related secreted glycoprotein, a stromal cell protein belonging to the cysteine-rich secreted acidic protein (SPARC) family) (see, supra, Saika S et al, epidermal basal membrane in immobilized-secreted proteins in salts, Immunochastotic tissue, Cornea, (1993) 12: 383; Melles GR et al, Immunochotic analysis of untreated and treated extracellular tissue in tissues, Current research, Eye research, 1995 (1995) (809, III, XVIII, IV, collagen, extracellular tissues, peptide of the family of extracellular proteins), and endothienium Am. J Pathol, (1996) 149: 549-558; ishizaki M et al, structural fibrous materials are associated with a collagen IV in scar tissues of alkali-burned and lacated corn, curr. Eye Res. (1997) 16: 339-; maguen E et al, alternatives of cornual extracellular matrix after multiple reactive products a clinical and immunological chemical study. Cornea, (1997) 16: 675-682; ljublimov AV et al, excellar matrix changes in human cornea after radial keratonomy, exp. Eye Res. (1998) 67: 265-; zieske JD et al, Kinetics of metabolic in response to epidermal hybridization. exp. Eye Res. (2001)72: 33-39; maguen E et al, excellular matrix and matrix metalloprotease changes in human cornea after water compounded laser-assisted in situ keratoiled usage (LASIK) Cornea, (2002) 21: 95-10; maguen E et al, immunological evaluation of two corner buttons with post-LASIK keratectasia. Cornea. (2007) 26: 983-; maguen E et al, alternations of extracellular matrix compositions and proteases in human cornual buttons with INTACS for post-laser in situ kerategoria and kerateconus, Cornea, (2008) 27: 565-; kato T et al, Expression of type XVIII collagen reducing alloying of corn induction and keratectomy in money, invest, Ophthalmol, Vis, Sci, (2003) 44: 78-85; javier JA et al, basic membrane and collagen disposition after laser subepithelial kerateusasis and photorefractive keratection in the leg chip eye, Arch. Ophthalmol. (2006) 124: 703-; matsuba M et al, Localization of thrombospondin-1 and myofibrasts along wind repair. exp. Eye Res. (2011) 93: 534-; chaurasia SS et al, Hevin display a pivot roller in corner near leather. PLoS one. (2013) 8: e 81544; saika S et al, Wakayama symposium: modulation of ground chemistry response in the corneal tissue by osteopontin and tensin-C. Ocul. surf. (2013) 11: 12-15); sullivan, MN, and Sage, EH, Hevin/SCI, a cellular glycoprotein and molecular tissue promoter of the SPARC/BM-40/osteopontin family. Intl.J. biochem. Cell biol. (2004) 38 (6): 991-96).

Signal pathways relating to stromal wound healing

Activation of corneal cells into fibroblasts by FGF-2, TGF-beta and PDGF and their proliferation, EGF, HGF, KGF, PDGF, IL-1 and IGF-I (cited above, Stern ME et al, Effect of planar-driven Growth factor on porous surrounding and chemical Repair (1995) 3: 59-65; Baldwin HC, Marshall J. Growth factor in porous surrounding and chemical Repair function supply: A review. Achthal. mol. Scand. (2002) 80: 238 friendly 247; Jester charum. JV. conversion J. modification of porous surrounding and chemical Repair function supply: 2003: 9; simulation of porous surrounding and chemical Repair J. Growth factor J. modification of porous surrounding and chemical Repair (2003: 7) J. Growth factor J. simulation J. Growth promoter J. propagation of porous surrounding and chemical Repair J. Growth factor J. 3. C. and 9; Growth factor J. 9. simulation of porous surrounding and chemical Repair J. 3. 9; recovery of porous surrounding and chemical Repair J. 3. C. 7. 9; Growth factor J. C. 3. 7. Growth factor J. C. 3. C. 7. C. 7. Growth factor J. and chemical Repair. Growth factor J. 3. 7. C. and chemical Repair. C. 3. Growth factor J. 3. A. 7. recovery of fibrous cell, rho-mediated regulation of TGF-. beta.1-and FGF-2-induced activation of cornual molecular keratocytes. invest. Ophthalmol. Vis. Sci. (2009) 50: 3662-. Although TGF-. beta.is critical for the transformation of fibroblasts into myofibroblasts, it actually inhibits corneal cell proliferation and migration (cited above, in Baldwin HC, Marshall J. Growth factors in corneal outgoing and compressive responsive delivery: A review. acta. Ophthalmol. Scand. (2002) 80: 238-. Stromal cell infiltration after injury was found to be stimulated by cytokines such as MCP-1 and Platelet Activating Factor (PAF) (supra, Wilson SE et al, The coronary outgoing and clinical responding: cytokine mediated interaction of The epilayer, strain, and encapsulating cells. Reg. Eye Res. (2001) 20: 625. 637; Kakazu A et al, Lipoxin A inhibitors platform-activating factor interacting diffusion and membranes coronary outgoing and clinical responding of injection of The strain composition. exp. Eye Res. (2012) 103: 9-16). As described above, TGF-. beta.isoforms 1 and 2 (cited above in Torricelli AA, Wilson SE. Cellular and extracellular matrix modification of cervical structural opportunity. Exp. Eye Res. (2014) 129: 151-160), as well as bone morphogenetic protein 1 (BMP-1) capable of inducing cartilage formation in vivo (cited above in Maleaze F et al, upper regulation of bone morphogenetic protein-1/mmalian toloid and procollagen C-protease enhancement-1 in cervical diagnosis. invest. Ophtalmmol. Vis. Sci. 2014. 55: 6712-6721) may be responsible for the appearance of myofibroblasts, fibroblastic and fibrotic scarring. TGF-. beta.also promotes the deposition of excess ECM in the wound bed, which may lead directly to scar formation, but may also lead to scar formation by stimulating the production of other factors, including Connective Tissue Growth Factor (CTGF) and IGF-I (see above, Izumi K et al, investment of insulin-lipid growth factor-I and insulin-lipid binding protein-3 in cardiac fibrous tissue production complex expressing repair, asset of interest, JNHALIN Vis. Sci. (2006) 47: 591-598; Shi L et al, Activation of K signaling media conditioning growth factor expressing repair, repair expression and repair, and expression in tissue repair, tension and repair, P7: 3217, 9, III, wilson SE. Cellular and extracellular matrix modulation of coronary structural access. Exp. Eye Res. (2014) 129: 151-. Thus, attenuation of TGF- β expression and signaling may provide a means to combat fibrotic changes. For example, topical rosiglitazone, a ligand of the peroxisome proliferator-activated receptor gamma (PPAR- γ), reduces α -SMA expression and scarring in the cat cornea after excimer laser ablation of the anterior matrix without compromising wound healing. In corneal fibroblast cultures, they are also resistant to TGF-. beta.induced myofibroblast transformation (Huxlin KR et al, cited supra, clinical migratory zone is an effective anti-differentiation agent in the corn. PLoS one. (2013) 8: e 70785). Similar effects are observed with Neutralizing antibodies to TGF-. beta.s (see above, M Brother-Pedersen T et al, neutral antibody to TGF. beta. modifications bacterial bud discovery PRK. curr. Eye Res. (1998) 17: 736-747). Inhibition of JNK signaling inhibits TGF- β induced CTGF expression and scarring in penetrating corneal wounds (supra, cite Shi L et al, Activation of JNK signaling mediators connection tissue expression and scar formation in corneal wound PLoS one. (2012) 7: e 32128). The mechanistic targets of Rapamycin (mTOR) and inhibitors of p38MAP kinase signaling can significantly reduce alpha-SMA and collagenase expression in corneal cells and damaged cornea (see Jung JC et al, supra, connective collagen-1 synthesis through MAPK pathway mediated, in part, BY endogenesis IL-1 alpha along fibrous tissue in cellular tissue J. Cell biochem. 2007) 102: 453;. Huh MI et al, Distribution of TGF-beta-oligosaccharides and signaling in fibrous tissue in cellular tissue J. Cell biochem. 2009) 108: 476-19-. Blocking VEGF by the neutralizing antibody Bevacizumab also inhibits TGF- β expression and improves corneal transparency in alkali-burned corneas (see Lee SH et al, supra, Bevacizumab acceleratees cornea outgoing and healing by inhibiting TGF- β 2 expression in alkali-burned cornea Rep. (2009) 42: 800-.

Corneal endothelial wound healing

Endothelial healing studies have been less common because the corneal endothelial layer is relatively inaccessible. This process occurs primarily as a consequence of surgery for various burns (see above, Zhao B et al, An interventional in coronary vascular tissue using An organic tissue model. Cornea. (2009) 28: 541-546.) and endothelial cells intended to replace dysfunction (Descemet's strip corneal endothelial grafting, DSEK) or with a posterior elastic layer (Descemet's membrane graft; DMEK) or (Delcemet's membrane graft; DMEK) (see above, Meller GR et al, Descemet vascular graft; DMEK-corneal graft; DMEK-200. J.P.E.; gradient WO 24; Spectrum WO-32; Spectrum et al, Descemet's graft; DMEK.P.E.; DMEK.P.P.P.E.; 3: 35; Spectrum; 3. P.E.; 3: 35; Spectrum; Delphin 3. 20. E. coli; Spectrum; Descemet. 20. coli, 3. E. coli, 3; Spectrum; Descemet., 3. E. coli, 3. E. A, patterns of coronary end conjugation and coronary clearance after a chess membrane end keystroke for a fungi end keystroke, Am. J. Ophthalmol, (2011) 152: 543-. The wound healing process of the corneal endothelium has certain properties. In many tissues, this process requires cell proliferation as the primary mechanism for reducing and remodeling the wound bed. However, Corneal endothelial cells, especially human Corneal endothelial cells, have a very low proliferation rate (supra, reference is made to Mimura T et al, Corneal endothelial regeneration and tissue engineering. prog. recovery. Eye Res. (2013) 35: 1-17). It is generally believed that the corneal endothelium closes the wound space primarily by migration and increased cell spreading. These two processes are separable pharmacologically and their relative contributions may vary depending on the nature of the wound (see, above, Joyce NC et al, In vitro pharmacological section of biochemical analysis and characterization of responses. invest. Ophthalmol. Vis. Sci. (1990) 31: 1816. incorporated 1826; Ichijima H et al, action parameter organization and reporting of electronic winding In the scientific of the tissue company: compare 2803. 28012; Golgi SR. cytokine diagnosis and characterization of injection. invest. Ophthalmol. Vis. 1994. 34: 2803. 28012; Gene SR.. cytokine diagnosis and characterization of reaction. 12. III. repair. echo. III. repair. 1. experiment of simulation. expression. simulation. III. simulation. 1. injection. production. III. production. III. 1. injection. repair. production. III. production. III. 1. injection. production of the same. Some data indicate that Cell division remains very low during healing (see, above, Lee JG, Kay EP. FGF-2-induced bottom healing in cornual endolamel cells requisites Cdc42 activation and Rho inactivation of the phosphorichallinosol 3-kinase pathway. invest. Ophthalmol. Vis. Sci. (2006) 47: 1376-one 1386), although this view is challenged by the fact that the healing corneal endothelial cells are mainly amitotic and consequently form binuclear cells (see, above, Landshman N et al, Cell division in the healing of the cornual endol of the tissue of Arch. 1804: 1808).

Endothelial wound healing is associated with the transient acquisition of fibroblast morphology and actin stress fibers by migrating cells, consistent with Endothelial-mesenchymal transition (EnMT) (see Lee HT et al, supra, FGF-2 induced by Endothelial in-1 beta through the action of phosphatogenic lipolysis 3-kinase mediators in biochemical transduction in biochemical end cells J. biol. chem. (2004) 279: 32325. 32332; Miyamoto T et al, Endothelial in-vitro transduction in biochemical end cells 2010. 29(Suppl 1S 52-56). In the frostbite model, EnMT occurs as myofibroblasts at the front of migration, where the cells lose zonulin ZO-1 and begin to express α -SMA (see Petroll WM et al, supra, ZO-1 reorganisation and myoblast transformation of corneal end cells after taste in the culture in the cat. Exp. Eye Res. (1997) 64: 257-. Inducers of EnMT and fibrotic changes in the Endothelial layer include FGF-2, which may be derived from PMNs that migrate to the cornea during epithelial and stromal wound healing (see, Lee HT et al, supra), FGF-2 induced by interfacial in-1 beta through the action of phosphatogenic 3-kinase enzymes in intestinal Endothelial cells J. biol. chem. (2004) 279: 32325. 32332) or IL-1 beta (see, Lee JG et al, Endothelial transformation in corneal Endothelial cells J. expressed by IL-1 beta. induced FGF-2 in Endothelial cells Exp. Eye. 95: 35-beta. and TGF-16. TGF-9. incorporated in Endothelial cells J. biological cells J. 22. 14). Since EnMT may cause fibrotic complications of healing, such as the formation of a fibrous membrane behind the cornea (described above In Ichijima H et al, In vivo capacitive microscopical students of endogenous wind healing In a corneal cornea. Cornea. (1993) 12: 369-. These include inhibiting the expression of Connexin 43 (cited above, Nakano Y et al, Connexin 43 knock down access computers around and help building up Inhibition mechanisms sensory transfer after reactor intrinsic Inhibition in vivo. invest. Ophthalmol. Vis. Sci. (2008) 49: 93-104) and TGF-. beta.type I receptor (cited above, Okumura N et al, Inhibition of TGF-. beta.signalling enables human intrinsic Inhibition expression in vitro for use in regenerating medium one. PLoS. (2013) 8: e 58000). The latter technique also promotes endothelial cell proliferation in culture.

The migration and spreading of corneal endothelial cells during wound healing is stimulated by a number of factors. The ECM proteins fibronectin and TSP-1 have been shown to promote Cell migration (see, supra, Munjal ID et al, thrombosis: biosynthesis, distribution, and change associated with surrounding repair in surrounding endothium. Eur. J. Cell biol. (1990) 52: 252. Ophthalmol (1994) 4: 202. 210; Blanco-Mezzita JT et al, Role of surrounding and surrounding by surrounding expressing in surrounding fashion. Eur. J. Ophthalmol. 1994; Blanco-Mezzita JT et al, Role of surrounding and surrounding groups. Invest. Vis. 20154). Growth factors known to promote endothelial migration and wound healing include EGF, FGF-2, IL-1. beta., PDGF-BB, TGF-. beta.2 and VEGF, whereas IGF-I and IGF-II are ineffective and IL-4 reduces migration (see Joyce NC et al, In vitro pharmacological section of coronary endothelial hybridization and proliferation; invest. Ophthalmol. Vis. Sci. (1990) 31: 1816-cells 1826; Raphael B et al, Enhanced healing of coronary endothelial tissue side group growth. invest. Ophthalmol. Vis. Sci. (1993) 34: 5-cells 2312; Sol JB, Lag BJ. influence tissue growth factor of wound healing. cells, see H. cells 23035; see J. 12. cells of coronary tissue culture and growth factors; 1993: 10-cells) 944; hoppenreijs VP et al, Effects of planar-driven ground factor on the adjacent ground help of human corn, invest, Ophthalmol, Vis, Sci, (1994) 35: 150-; hopplerijs VP et al, Corneal endothienium and growth factors, Surv Ophthalmol. (1996) 41: 155-164; bednarz J et al, influx of vascular endothelial growth factor on bone coronary arterial cells in a wind-healing model, Ger. J. Ophthalmol. (1996) 5: 127-31; sabatier P et al, Effects of human recombinant basic fiber winding factor on end of human output in organic culture of human corn J. Fr. Ophtalmol. (1996) 19: 200- "207; Thalmann-Goetsch A et al, synthetic study on the effects of differential growth factors on the simulation of bone cornmeal end cells with magnetic near health. Rieck PW et al, Intracellular signaling pathway of FGF-2-modified communicating cell migration in video, exp. Eye Res. (2001) 73: 639-; imanishi J et al, Growth factors: opportunity in around health and residence of transparency of the core. Prog Retin Eye Res. (2000) 19: 113-129; baldwin HC, Marshall J. Growth factors in communicating outgoing and alloying reactive supply: A review. acta. Ophthalmol. Scand. (2002) 80: 238-247; lee JG, Heur M, Interleukin-1. beta. enhancement cell migration through AP-1 and NF-. kappa.B path-dependent FGF2 expression in human cornual end cells. biol. cell. (2013) 105: 175-; lee JG, Heur M. Interleukin-1. beta. -induced Wnt5a enhancement of human cardiac analysis of the expression of Cdc42 and RhoA. mol. Cell biol. (2014) 34: 3535-.

The signaling pathways downstream of these factors important for wound healing are diverse. Prostaglandin E2 acting through the cAMP pathway, ERK1/2 and P38MAP kinases have been shown to be involved in endothelial migration and wound healing (as above, refer to journal NC, Meklir B. PGE2: a media of coronary end adjacent around repair in vitro. Am. J. physiology. (1994) 266: C269-275; Sumioka T et al, inhibition effect of blocking TGF-. beta./small signal on adjacent-induced repair of coronary end addition. mol. Vis. (2008) 14: 2272. J. 2281; Chen et al, ERK1/2 activation repair of the treating process of coronary end adjacent around repair. TGF-. beta. (111. J. Et 3) 19. J. TGF 19. J. III. 2. III. TGF 11. J. III. 2. III. 2. III. TGF. III. P. III. P. III. A. III. A. III. A. B. A. B. A. B. A. B. A. B. A. B. FGF-2 stimulates migration via several pathways, including P38, PI3K/Akt and the protein kinase C/phospholipase A2 (see, above, Rieck PW et al, Intracellular signaling pathway of FGF-2-modulated conjugated extracellular cell migration in vitro. Exp. Eye Res. (2001) 73: 639. 650; L Lee HT et al, FGF-2 induced by Intracellular transduction-1 beta. of heparin 3-kinase mediated transformation in Intracellular transduction cells J. Biol. 2004. 323232279. T. J. Biol. expression of TGF-11. J. Bion. 32. Et 32. J. Bion. Et 32. J. TGF. Et 32. J. expression of extracellular kinase. J. Et 32. TGF. Et 32. of J. TGF-11. TGF. III. 11. Et 32. J. Et 32. of J. Et 32. TGF. Et 32. of J. Et 32. TGF. Et 32. of J. TGF-D.). IL-1. beta. is produced by inducing FGF-2 (supra, Lee JG et al, endogenous media transformation mediated by IL-1. beta. -induced FGF-2 in cornual endovertical cells. exp. Eye Res. (2012) 95: 35-39) and inducing Cdc42 and Wnt5a which inactivates RhoA (supra, eLe JG, Kay EP. FGF-2-induced bound lipids in cornual endovertical cells. expression Cdc42 activation and Rhoactivation thereof through reaction of said photochemical catalyst 3-kinetic cells. Invhtable page. expression. Ophthalmol. Vis. Sci. (47: 6. JK.G 1386; Lee.g. 1381. beta. -expression cell 120. interpositional cells. F-1. G-19) and expressing cell 19. beta. -cell 19. 12. F. 12. beta. -expression of Lee JG et al, Engineer. III, heur M, Interleukin-1 beta-induced Wnt5a enhanced human cardiac inflammatory Cell migration of Cdc42 and RhoA, mol, Cell biol. (2014) 34: 3535-3545) to stimulate migration. In endothelial cells, interleukin-1 β directly and indirectly stimulates cell migration.

Surgical correction of corneal injury

The diseased cornea can be replaced by clear, healthy corneal surgery from a human donor (corneal transplant) by a variety of methods.

Light-therapeutic keratotomy ("PTK") is a laser eye surgery used to treat corneal dystrophy, corneal scarring, and some corneal infections. The surgeon uses a laser to microscopically remove a thin layer of diseased corneal tissue to enable new tissue to grow on a smooth surface.

Performing Deep Anterior Lamellar Keratoplasty (DALK) or partial thickness corneal transplantation if the anterior and middle layers of the cornea are damaged; only the anterior and middle layers of the cornea are removed, while the endothelial layer remains in place. The healing time after DALK is shorter than after a complete corneal transplant. The risk of rejection of a new cornea is also less. DALK is commonly used to treat keratoconus or corneal ectasia.

If both the anterior corneal layer and the interior corneal layer are damaged, a Penetrating Keratoplasty (PK) or full-thickness corneal transplant is performed to remove and replace the damaged cornea. The recovery period for PK is longer than for other types of corneal transplants. Complete recovery of vision after PK may take 1 year or more. The risk of corneal rejection for PK is slightly higher than for other types of corneal transplants.

In some ocular conditions, the endothelium, the innermost layer of the cornea, is damaged. Corneal endothelial transplantation is a surgical procedure that replaces this layer of the cornea with healthy donor tissue. It is known as a partial graft because only the endothelium is replaced. Examples of types of corneal implants include DSEK (or DSAEK) -post-elastic layer peel (Automated) corneal implant Descemet's striping (Automated) Endothelial Keratoplast, and DMEK-post-elastic layer corneal implant (Descemet's Membrane Endothelial Keratoplast). Each procedure removes damaged cells from the posterior elastic layer (Descemet's membrane) by removing the damaged corneal layer through a small incision and placing new tissue in place. The majority of the cornea is intact.

Optical system of eye

The focus of the eye contracts the ciliary muscle to reduce the tension or stress transmitted to the lens through the zonules. This results in an increase in the convexity of the lens and thus in an increase in the optical power of the eye. The term "accommodation" refers to increasing the thickness and convexity of the lens of the eye in response to contraction of the ciliary muscle to focus an image of an external object on the retina. The term "accommodative amplitude" refers to the difference in refractive index of the eye at rest and at full accommodation.

The refractive power of the human eye is measured in diopters, which is a unit of measure of the optical power of the lens and is equal to the reciprocal of the focal length in meters. In humans, the total refractive power (optical power) of the relaxed eye is about 60 diopters. The cornea accounts for approximately 2/3 diopters of power (i.e., 40 diopters), while the lens accounts for the remainder of power 1/3 (i.e., 20 diopters). (Najjar, Dany MD., "Clinical Optics and reference," https:// web. archive. org/web/20080323035251/http:// www.eyeweb.org/Optics. htm).

Emmetropia refers to the eye without visual defects. It is such a visual state: wherein distant objects at infinity are in sharp focus on the eye lens in a neutral or relaxed state. Emmetropia does not require vision correction.

Visual abnormality of human eye

Abnormalities in the human eye can lead to visual disorders such as myopia (nearsightedness), hyperopia (farsightedness), astigmatism and presbyopia.

Myopia (or nearsightedness) occurs when a human eye is too long relative to the focusing power of the cornea and lens of the eye. This focuses the light at a point in front of the retina, rather than directly on its surface. Hyperopia (or hyperopia) occurs when light rays entering the eye are focused behind the retina rather than directly on it. Astigmatism is a vision condition that causes blurred vision, and occurs when the cornea is irregularly shaped. This prevents the light rays from being correctly focused on the retina.

As seen in fig. 3, presbyopia is generally characterized by a reduced ability of the eye to increase its power to focus on near objects due to, for example, loss of elasticity of the lens which occurs over time. Ophthalmic instruments and/or surgery (e.g., contact lenses, intraocular lenses, LASIK, inlays) can be used to address presbyopia using three common approaches. With a single vision prescription, the dioptric power of one eye is adjusted to focus on distant objects and the power of the other eye is adjusted to focus on near objects. Appropriate eyes are used to clearly view the relevant object. In the next two approaches, multifocal or bifocal optics are used to provide the ability to focus both distant and near objects in one eye at the same time. One common multifocal design includes a central zone of higher refractive power to focus near objects, surrounded by a peripheral zone of lower power required to focus distant objects. In a modified single vision prescription, the refractive power of one eye is adjusted to focus distant objects, and in the other eye, a multifocal optical design is introduced through the corneal inlay. Thus, the subject obtains the refractive power necessary to view distant objects from both eyes, while the near power zone (near power zone) of the multifocal eye provides the power necessary to view near objects. In a bilateral multifocal prescription, multifocal optical designs are introduced in both eyes. Thus, both eyes contribute to distance and near vision.

Corneal inlay structure and function

Various devices and methods have been developed in an attempt to provide vision correction.

Excimer Laser in situ keratomileusis ("LASIK") is a type of refractive Laser eye surgery in which a Laser is used to reshape a portion of the cornea after a previously cut corneal flap has been lifted.

Corneal inlays are implants that are surgically embedded into the cornea beneath a portion of the corneal tissue. It may be placed by, for example, cutting a corneal flap in the cornea and placing the inlay under the flap. A flap is formed by making an incision in corneal tissue and separating the corneal tissue from the underlying stroma, with a segment that remains attached, functioning like a hinge. The corneal inlay may also be placed within a pocket (i.e., a capsular cavity) formed in the cornea. The corneal inlay may alter the refractive power of the cornea as follows: establishing an optical interface between the cornea and the implant by changing the shape of the anterior surface of the cornea, by having a different refractive index than the cornea (i.e., the intrinsic power); or both. The cornea is the most refractive optical element of the eye, and thus altering the shape of the anterior surface of the cornea can be a particularly useful method for correcting vision disorders caused by refractive errors.

Cornea mosaic surgery (cornea Inlay Procedures)

Regardless of the vision correction procedure and/or the implanted device, it is important to understand the natural response of the cornea to the procedure to understand how the cornea will attempt to reduce or minimize the effects of the vision correction procedure.

In a simple biomechanical model ("Watsky model") proposed by Watsky optics and Visual Science, vol.26, pp. 240-243 (1985), it is assumed that the anterior corneal surface radius of curvature is equal to the thickness of the layered corneal material (i.e., flap) between the anterior corneal surface and the anterior surface of the corneal inlay plus the radius of curvature of the anterior surface of the inlay. An overview of the clinical outcome or design methodology of an implanted inlay generally discusses relatively thick inlays (e.g., greater than 200 microns thick) for which the Watsky simple biomechanical response model has some effectiveness, as the physical dimensions of the inlay dominate the biomechanical response of the cornea and determine the major anterior surface changes.

However, when the inlay is relatively small and thin, the material properties of the cornea significantly affect the changes that occur in the anterior surface of the cornea. Petrol et al reported that implantation of an inlay resulted in thinning of the central corneal epithelium covering the inlay. "structural assessment of the cardiac response to the cardiac insertion and laser in situ tissue with flash creation using IntraLase," J.

Huang et al report thickening of the central epithelium after myopic ablation and thickening of the peripheral epithelium and thinning of the central epithelium after hyperopic ablation. "physical Model of Surface Smoothing After Laser reflective Surface," American Journal of Ophthallography, 3.2003, page 267- "is a comprehensive Model of Surface Smoothing After Laser reflective Surface. The Huang's theory does not address the correction of presbyopia, nor does it accurately predict the changes in the anterior surface that create the near-central portion of the cornea for near vision while enabling far vision in the corneal region surrounding the near-central portion. Furthermore, Huang reports removal of corneal tissue by ablation, rather than adding material to the cornea, such as an intracorneal inlay.

It is understood that the corneal response to a presbyopic correction using, for example, a corneal inlay can compensate for this response when performing surgery on the cornea.

Corneal opacity

Corneal implants can cause a cloudy or opaque appearance to the cornea, which can lead to blurred or glare vision by clouding the cornea or by altering the focusing power of the eye. The effect of this corneal haze on a patient's vision depends on the severity of the haze and its location in the cornea. While steroid eye drops are commonly used to treat corneal haze, corneal implants are commonly removed in cases where steroid eye drops are ineffective.

The present disclosure provides a corneal implant device designed to treat presbyopia and other vision conditions using a corneal inlay. Said invention comprises microdroplet molding (droplet molding) with high water content, which can reduce/eliminate the risk of developing corneal haze in patients. Furthermore, the invention can reduce the hospital visits and reduce the patient expenses.

Summary of The Invention

According to one aspect, the invention provides a method of treating presbyopia, comprising placing in the cornea of a mammalian subject a high water content corneal inlay device comprising a thickness, diameter, flat or quasi-flat bottom and a dome or microdroplet shaped top that forms a contact angle with the bottom, wherein the corneal inlay device is effective, when placed in the cornea, to: changing the shape of the anterior surface of the cornea, and increasing the ability of the eye to increase its power to focus on near objects, while reducing the risk of developing corneal haze compared to controls. According to one embodiment, a corneal inlay device is placed by cutting a corneal flap in the cornea and placing the inlay under the flap. According to another embodiment, the corneal inlay device is placed by placing the inlay device within a pocket formed in the cornea. According to another embodiment, the corneal inlay device is placed at a depth of about 100 microns to about 200 microns (inclusive) in the cornea. According to another embodiment, the placement of the corneal inlay device is at a depth of about 130 microns to about 160 microns (including endpoints) in the cornea. According to another embodiment, the contact angle is between 1 ° and 180 °. According to another embodiment, the corneal inlay has a thickness of at least 25 microns, at least 26 microns, at least 27 microns, at least 28 microns, at least 29 microns, at least 30 microns, at least 31 microns, at least 32 microns, at least 33 microns, at least 34 microns, at least 35 microns, at least 36 microns, at least 37 microns, at least 38 microns, at least 39 microns, at least 40 microns, at least 41 microns, at least 42 microns, at least 43 microns, at least 44 microns, at least 45 microns, at least 46 microns, at least 47 microns, at least 48 microns, at least 49 microns, at least 50 microns, at least 51 microns, at least 52 microns, at least 53 microns, at least 54 microns, at least 55 microns, at least 56 microns, at least 57 microns, at least 58 microns, at least 59 microns to 60 microns. According to another embodiment, the corneal inlay has a thickness of at least 32 microns, at least 33 microns, at least 34 microns, at least 35 microns, at least 36 microns, at least 37 microns, at least 38 microns, at least 39 microns, at least 40 microns, at least 41 microns, at least 42 microns, at least 43 microns, at least 44 microns, at least 45 microns, at least 46 microns, at least 47 microns, at least 48 microns, at least 49 microns to 50 microns. According to another embodiment, the corneal inlay device has a diameter of at least 1mm, at least 1.1 mm, at least 1.2 mm, at least 1.3 mm, at least 1.4 mm, at least 1.5 mm, at least 1.6 mm, at least 1.7 mm, at least 1.8 mm, at least 1.9 mm, at least 2.0 mm, at least 2.1 mm, at least 2.2 mm, at least 2.3 mm, at least 2.4 mm, at least 2.5mm, at least 2.6 mm, at least 2.7 mm, at least 2.8 mm, at least 2.9 mm, or at least 3.0 mm. According to another embodiment, a corneal inlay device comprises water, a hydrophilic polymer, and a protein. According to another embodiment, the protein is an isolated protein, a recombinant protein, a synthetic protein or a peptidomimetic. According to another embodiment, the hydrophilic polymer comprises polyethylene glycol ("PEG"), poly (2-Methacryloyloxyethyl Phosphorylcholine) (MPC), or both. According to another embodiment, the corneal inlay has a water content of at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%. According to another embodiment, the corneal inlay device is optically transparent, biocompatible, permeable, and refractive.

The invention also provides for the use of a corneal inlay device having a high water content for treating presbyopia in a mammalian subject, the corneal device comprising a thickness, diameter, flat or quasi-flat base and a dome or microdroplet shaped top that forms a contact angle with the base, wherein the inlay device, when placed in the cornea, is effective to alter the shape of the anterior surface of the cornea and improve the eye's ability to increase its power to focus on near objects while reducing the risk of developing corneal haze compared to a control. According to one embodiment, the corneal inlay device is placed by cutting a corneal flap in the cornea and placing the inlay under the flap. According to another embodiment, the corneal inlay device is placed by placing the inlay device within a pocket formed in the cornea. According to one embodiment, the placement of the corneal inlay device is at a depth of about 100 microns to about 200 microns (including endpoints) in the cornea. According to one embodiment, the placement of the corneal inlay device is at a depth of about 130 microns to about 160 microns (including endpoints) in the cornea. According to one embodiment, the contact angle is between 1 ° and 180 °. According to one embodiment, the corneal inlay has a thickness of at least 25 microns, at least 26 microns, at least 27 microns, at least 28 microns, at least 29 microns, at least 30 microns, at least 31 microns, at least 32 microns, at least 33 microns, at least 34 microns, at least 35 microns, at least 36 microns, at least 37 microns, at least 38 microns, at least 39 microns, at least 40 microns, at least 41 microns, at least 42 microns, at least 43 microns, at least 44 microns, at least 45 microns, at least 46 microns, at least 47 microns, at least 48 microns, at least 49 microns, at least 50 microns, at least 51 microns, at least 52 microns, at least 53 microns, at least 54 microns, at least 55 microns, at least 56 microns, at least 57 microns, at least 58 microns, at least 59 microns to 60 microns. According to one embodiment, the corneal inlay has a thickness of 32 microns to 50 microns (inclusive), i.e., at least 32 microns, at least 33 microns, at least 34 microns, at least 35 microns, at least 36 microns, at least 37 microns, at least 38 microns, at least 39 microns, at least 40 microns, at least 41 microns, at least 42 microns, at least 43 microns, at least 44 microns, at least 45 microns, at least 46 microns, at least 47 microns, at least 48 microns, at least 49 microns, or 50 microns. According to one embodiment, the corneal inlay device has a diameter of at least 1mm, at least 1.1 mm, at least 1.2 mm, at least 1.3 mm, at least 1.4 mm, at least 1.5 mm, at least 1.6 mm, at least 1.7 mm, at least 1.8 mm, at least 1.9 mm, at least 2.0 mm, at least 2.1 mm, at least 2.2 mm, at least 2.3 mm, at least 2.4 mm, at least 2.5mm, at least 2.6 mm, at least 2.7 mm, at least 2.8 mm, at least 2.9 mm, or at least 3.0 mm. According to one embodiment, a corneal inlay device comprises water, a hydrophilic polymer, and a protein. According to another embodiment, the protein is an isolated protein, a recombinant protein, a synthetic protein or a peptidomimetic. According to one embodiment, the hydrophilic polymer comprises polyethylene glycol ("PEG"), poly (2-Methacryloyloxyethyl Phosphorylcholine) (MPC), or both. According to one embodiment, the water content of the corneal inlay is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%. According to one embodiment, the corneal inlay device is optically transparent, biocompatible, permeable, and refractive.

These and other advantages of the present invention will become apparent to those of ordinary skill in the art by reference to the following detailed description and accompanying drawings.

Like reference numerals designate like or similar parts throughout the various views of the drawings.

Brief Description of Drawings

FIG. 1 shows a diagrammatic view of a human eye; (from alamoutvision. com/resources/anatomy. htm, 3 month 2019 visit);

FIG. 2 shows a diagrammatic view of five layers of the cornea;

FIG. 3 shows a diagrammatic view of the presbyopia effect of a human eye;

figure 4 shows an exemplary embodiment of a corneal inlay device of the present disclosure;

FIGS. 5A, 5B and 5C show the top of a droplet of corneal inlay forming a contact angle with the bottom of the corneal inlay;

FIG. 6 is a diagram showing a corneal inlay of the present disclosure implanted in a cornea;

figure 7 shows an example of how a corneal inlay may provide near vision to a subject's eye while maintaining some distance vision, according to one embodiment of the present disclosure;

fig. 8 is a graph showing the change in the elevation of the anterior surface of the cornea and the corresponding induced added power.

Figure 9 is a diagram showing pre-operative optical coherence tomography ("OCT") and post-operative OCT, including exemplary locations of corneal inlays of the present disclosure;

figure 10 is a graph showing the refractive effect of water content on inlay refractive index and intrinsic power.

Detailed Description

Glossary of words and phrases

Anatomical terms

When referring to an animal, which typically has a head and mouth at one end and an anus and tail at the other end, the cephalic end (head end) is called the cranial end (cranial end) and the caudal end (tail end) is called the caudal end (caudal end). Within the head itself, the rostral (rostral) side refers to the direction towards the tip of the nose and the caudal (caudal) side refers to the caudal direction. The normally upward facing, gravity-remote surface or side of the animal's body is the dorsal side; the opposite side, typically the side closest to the ground when walking, swimming or flying with all legs, is the ventral side. On a limb or other appendage, the point closer to the subject is the "proximal" and the point further away is the "distal". Three basic reference planes are used in animal anatomy. The "sagittal" plane divides the body into left and right parts. The "median sagittal" plane is midline, i.e., it passes through a midline structure, such as the spine, and all other sagittal planes are parallel thereto. The "coronal" plane divides the body into the back and the abdomen. The "transverse" plane divides the body into the head and tail.

When referring to humans, it is always assumed that the body is described upright and its parts. The body part closer to the cephalic end is "superior" (corresponding to the cranium of the animal) and the body part further away is "inferior" (corresponding to the cauda of the animal). An object near the front of the body is called "anterior" (corresponding to the ventral side of the animal); the object near the back of the body is called the "posteroir" (corresponding to the dorsal side of the animal). The transverse, axial or horizontal plane is the X-Y plane parallel to the ground, which separates the upper/head portion from the lower/foot portion. The coronal or frontal plane is the Y-Z plane perpendicular to the ground, which separates the anterior and posterior. The sagittal plane is the X-Z plane perpendicular to the ground and coronal planes, which separates the left and right. The median sagittal plane is the particular sagittal plane that is just in the middle of the body.

Structures near the midline are called medial (medial), and structures near the lateral aspect of the animal are called lateral (lateral). Thus, the medial structures are closer to the midsagittal plane, and the lateral structures are further from the midsagittal plane. The structure of the body midline is the median (mean). For example, the tip of the nose of a human subject is on the midline.

The term "ipsilateral" as used herein means on the same side, the term "contralateral" as used herein means on the other side, and "bilateral" as used herein means on both sides. Structures near the center of the body are proximal or central, while more distal structures are distal or peripheral. For example, the hand is distal to the arm and the shoulder is proximal.

The term "biocompatible" as used herein means not causing clinically relevant tissue irritation, damage, toxic response or immune response to human tissue based on clinical risk/benefit assessment.

The term "collagen" as used herein refers to a natural, chemically synthesized or synthetic glycine and proline rich protein which is a major component of extracellular matrix and connective tissue in vivo.

The term "contact angle" as used herein refers to the angle that a liquid establishes with a solid surface or the capillary wall of a porous material when the two materials are in contact. It depends on the nature of the solid and liquid, the interaction and repulsion forces between the liquid and solid, and the three-phase interface properties (gas, liquid and solid). The balance of cohesive forces (i.e., hydrogen bonding and van der waals forces) between similar molecules, such as liquid molecules, and adhesive forces (i.e., mechanical and electrostatic forces) between dissimilar molecules, such as liquid and solid molecules, will determine the contact angle established in the solid and liquid interface. Contact angle is a common method of measuring the wettability of a surface or material. https// chem. library. org/Bookshelves/Physical _ and _ Theoretical _ Chemistry _ Textbook _ Maps/supplementary _ Modules (Physical _ and _ Theoretical _ Chemistry)/Physical _ Properties _ of _ Matter/State _ of _ Matter/Properties _ of _ Liquirids/Contact _ Angles, 5/17/19 access).

The term "corneal apex (corneal apex)" as used herein refers to the point of maximum curvature.

The term "corneal vertex" as used herein refers to a point located at the intersection of an individual's gaze line and the corneal surface.

The term "curvature" as used herein refers to the degree of curvature of a continuous curved line without corners.

The term "demold" as used herein refers to the process of removing a mold from a pattern or removing a casting from a mold. The process may be, for example, by mechanical means, by hand, by using compressed air, etc.

The term "elasticity" as used herein refers to a measure of the deformation of an object when a force is applied. An object that is very elastic like rubber has a high elasticity and is easily stretched.

The term "focal length" of a lens as used herein refers to the distance that the lens focuses parallel rays of light. Given its diopter, the focal length of the lens can be calculated by the following equation: focal length in mm = 1000/diopter.

The term "hydrogel" as used herein refers to a substance that produces a solid, semi-solid, pseudoplastic or plastic structure, which contains the aqueous components necessary to produce a gel-like or jelly-like substance.

The term "hydrophilic" as used herein refers to a material or substance that has an affinity for polar substances such as water.

The term "refractive index" as used herein refers to a measure of the extent to which a substance/medium slows the light wave passing through it. The value of which determines the degree to which light is refracted (bent) as it enters or leaves the substance/medium. Which is the ratio of the speed of light in vacuum to its speed in a substance or medium.

The term "isolated" as used herein refers to a material, such as, but not limited to, a nucleic acid, peptide, polypeptide, or protein, which is: (1) to a large extent free or substantially free of components with which it is normally associated or with which it interacts when found in its naturally occurring environment. The term "substantially free" or "substantially free" is used herein to mean substantially free or substantially free, or more than about 95% free, more than about 96% free, more than about 97% free, more than about 98% free, or more than about 99% free. The isolated material optionally comprises a material not found with the material in its natural environment; or (2) the material has been altered synthetically (non-naturally) by deliberate human intervention.

The term "matrix" as used herein refers to a three-dimensional network of fibers that contain voids (or "pores") at the intersections of the woven fibers. Structural parameters of the pores, including pore size, porosity, pore interconnectivity/tortuosity, and surface area, can affect how substances (e.g., fluids, solutes) move into and out of the matrix.

The term "miosis" as used herein refers to an excessive constriction (narrowing) of the pupil. In miosis, the diameter of the pupil is less than 2 millimeters (mm).

The term "permeable" as used herein refers to allowing substances, such as oxygen, glucose, water and ions, to pass through a membrane or other structure.

The term "protein" is used herein to refer to a large, complex molecule or polypeptide consisting of amino acids. The amino acid sequence in a protein depends on the base sequence in the nucleic acid sequence encoding the protein.

The term "peptide" as used herein refers to a molecule of two or more amino acids chemically linked together. Peptide may refer to a polypeptide, protein or peptidomimetic.

The term "peptidomimetic" refers to a small protein-like chain designed to mimic or mimic a peptide. The peptidomimetic may comprise a non-peptide structural element capable of mimicking (meaning mimicking) or antagonizing (meaning neutralizing or counteracting) one or more biological effects of the native parent peptide.

The terms "polypeptide" and "protein" are used herein in their broadest sense to refer to a series of subunit amino acids, amino acid analogs, or peptidomimetics. Unless otherwise noted, subunits are linked by peptide bonds. The polypeptides described herein may be chemically synthesized or recombinantly expressed. The polypeptide of the invention is chemically synthesized. Synthetic polypeptides prepared using well-known techniques of solid phase, liquid phase, or peptide condensation techniques, or any combination thereof, may comprise natural and unnatural amino acids. The amino acids used for peptide synthesis can be either standard Boc (N-. alpha. -amino protected N-. alpha. -t-butyloxycarbonyl) amino acid resins using standard deprotection, neutralization, coupling and washing procedures of the original solid phase method of Merrifield (1963, J. Am. chem. Soc. 85: 2149-2154) or the base-labile N-. alpha. -amino protected 9-fluorenylmethoxycarbonyl (Fmoc) amino acids described at the earliest by Carpino and Han (1972, J. org. chem. 37: 3403-3409). Both Fmoc and Boc N- α -amino protected amino acids are available from Sigma, Cambridge Research Biochemical or other chemical companies familiar to those skilled in the art. In addition, polypeptides can be synthesized using other N- α -protecting groups familiar to those skilled in the art. Solid Phase peptide Synthesis can be performed by methods familiar to those skilled in the art and described, for example, in Stewart and Young, 1984, Solid Phase Synthesis, second edition, Pierce Chemical Co., Rockford, Ill.; fields and Noble, 1990, int. J. Pept. Protein Res. 35: 161-. The polypeptides of the invention may comprise D-amino acids (which are resistant to L-amino acid specific proteases in vivo), combinations of D-and L-amino acids, and various "designer" amino acids (e.g., beta-methyl amino acids, C-alpha-methyl amino acids, N-alpha-methyl amino acids, and the like) to provide specific properties. Synthetic amino acids include ornithine for lysine, norleucine for leucine or isoleucine. In addition, the polypeptide may have a peptidomimetic bond, e.g.Ester linkage to produce peptides with novel properties. For example, a peptide comprising a reduced peptide bond, i.e., R, can be generated ¹ -CH ₂ -NH-R ² Wherein R is ₁ And R ₂ Is an amino acid residue or sequence. The reduced peptide bond may be introduced as a dipeptide subunit. Such polypeptides will be resistant to protease activity and have an extended half-life in vivo. Thus, these terms also apply to amino acid polymers in which one or more amino acid residues are artificial chemical analogues of the corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers. When incorporated into a protein, the protein can react specifically with antibodies directed against the same protein (immobilized to), but consisting entirely of naturally occurring amino acids. The terms "polypeptide", "peptide" and "protein" also include modifications, including but not limited to glycosylation, lipid attachment, sulfation, gamma-carboxylation of glutamic acid residues, hydroxylation and ADP-ribosylation. It is to be appreciated that, as is well known and as described above, polypeptides may not be completely linear. For example, polypeptides may be branched due to ubiquitination, and they may be cyclic, with or without branching, typically due to post-translational events, including natural processing events and events resulting from non-naturally occurring manual manipulations. Cyclic, branched and branched cyclic (branched) polypeptides may be synthesized by non-translational natural processes, as well as by entirely synthetic methods.

The term "polymer" as used herein refers to any of a variety of chemical compounds made from smaller identical molecules (referred to as monomers) that are linked together. The polymers generally have a high molecular weight. Two different monomers a and B are incorporated into the polymer chain in a statistical manner to give a copolymer. In the limit, the single monomers may alternate regularly in the chain, and these are called alternating copolymers. The monomers can be combined in a more regular manner-by end-to-end addition connecting an extended linear sequence of one monomer to a linear sequence of another monomer to produce a block copolymer, or by linking the chains of B at points on the backbone of a to form a branched structure known as a graft copolymer.

The term "recombinant DNA" refers to a DNA molecule formed by laboratory methods whereby DNA fragments from different sources are joined to produce a new genetic combination.

The term "recombinant protein" as used herein refers to a protein encoded by recombinant DNA that has been cloned into a system that supports gene expression and messenger RNA translation within a living cell. To produce a human recombinant protein, for example, the relevant gene is isolated, cloned into an expression vector, and expressed in an expression system. Exemplary expression systems include prokaryotes, such as bacteria, and eukaryotes, such as cultured yeast, insect cells, plant and mammalian cells.

The term "refraction" as used herein refers to the deflection of light from one medium into another medium of different optical density; when entering the optically thinner medium from the optically denser medium, the light rays deviate from a line perpendicular to the surface of the refractive medium. When entering the optically denser medium from the optically thinner medium, it bends towards this perpendicular line. The term "refraction" also refers to the determination of the nature and extent of refractive error in the eye and the act of correcting it.

As used herein, the "refractive power" of a lens refers to the reciprocal of its focal length in meters, or D =1/f, where D is the refractive power in diopters and f is the focal length in meters.

The term "RGD motif as used herein refers to the binding motif of arginyl glycyl aspartate, fibronectin and cell adhesion molecules, which can serve as cell adhesion sites for extracellular matrix, cell surface proteins and integrins.

The term "shape" as used herein refers to the property (quality of a discrete object or body) of an independent object or body having an outer surface or contour of a particular form or contour.

The terms "subject" or "individual" or "patient" are used interchangeably to refer to a member of an animal species of mammalian origin, including but not limited to mice, rats, cats, goats, sheep, horses, hamsters, ferrets, pigs, dogs, guinea pigs, rabbits, and primates, such as monkeys, apes, or humans.

The term "surface tension" as used herein refers to the property of a liquid to resist an external force due to the cohesive nature of its molecules. Due to the high molecular concentration of the liquid compared to the low molecular concentration of the gas, the attractive forces exerted by the liquid molecules below the surface to the liquid molecules at the surface-air interface create an inward pulling force or internal pressure that tends to impede the flow of the liquid.

The term "thickness" as used herein refers to a measurement from top to bottom, or between opposing surfaces in a direction perpendicular to the length and width.

The term "viscosity" as used herein refers to the property of a fluid to resist forces tending to cause the fluid to flow. Viscosity is a measure of the resistance to fluid flow. The resistance is caused by intermolecular friction applied when the fluid layers attempt to slide over each other. The viscosity can be of two types: dynamic (or absolute) viscosity and kinematic viscosity. Absolute viscosity or absolute viscosity coefficient is a measure of internal resistance. Dynamic (or absolute) viscosity is the tangential force per unit area required to move one horizontal plane relative to another at a unit velocity while remaining separated by a unit distance by a fluid. Dynamic viscosity is typically expressed in poise (P) or centipoise (cP), with 1 poise =1 g/cm ² And 1 cP = 0.01P. Kinematic viscosity is the ratio of absolute or dynamic viscosity to density. Kinematic viscosities are often expressed in stokes (St) or centistokes (cSt), where 1 St = 10-4 m ² (ii)/s, and 1 cSt = 0.01 St.

The term "wetting" as used herein refers to the ability of a liquid deposited on a solid (or liquid) substrate to spread out or form a boundary surface with the solid state. Which is determined by measuring the contact angle formed by a liquid in contact with a solid or liquid. The smaller the contact angle or surface tension, the greater the wetting tendency.

Unless expressly stated to the contrary, the terms "wt%" or "weight percent" or "wt/wt%" of a component refer to the ratio of the weight of the component, expressed as a percentage, to the total weight of the composition in which the component is included.

The term "young's modulus" as used herein refers to a measure of elasticity, equal to the ratio of stress applied to a substance to strain produced. The term "stress" as used herein refers to a measure of the force exerted on an object over an area. The term "strain" as used herein refers to the change in length divided by the original length of the object. The change in length is proportional to the force exerted on it and depends on the substance from which the object is made. The change in length is proportional to the original length and inversely proportional to the cross-sectional area. Fracture is caused by strain exerted on the object such that the object deforms (changes shape) beyond its elastic limit and fractures.

The present disclosure relates to corneal inlay devices, methods of insertion (insertion means), and methods of construction (constraint means) as discussed in detail below in connection with figures 4-10.

Figure 4 is a diagram showing one example of a corneal inlay 10 of the present disclosure. The corneal inlay 10 includes a thickness 12 and a diameter 14. It may have a droplet shape comprising a flat or quasi-flat bottom and a dome or more or less spherical droplet-shaped top. The corneal inlay 10 is biocompatible with the eye. The corneal inlay 10 comprises a diameter that is less than the diameter of the pupil and is capable of correcting presbyopia while reducing or eliminating the risk of patient formation of corneal haze. To provide near vision, the corneal inlay 10 may be centrally implanted into the cornea to introduce an "effect" zone on the anterior surface of the cornea that is smaller than the optical zone of the cornea, where the "effect" zone is the area of the anterior surface of the cornea affected by the corneal inlay 10. The implanted corneal inlay 10 increases the curvature of the anterior surface of the cornea in the "effect" zone, thereby increasing the refractive power of the cornea in the "effect" zone. Since the corneal inlay 10 is smaller than the diameter of the pupil, light from distant objects bypasses the inlay and is refracted through the corneal region peripheral to the "effect" zone to create an image of the distant object on the retina. This will be discussed in further detail below.

In exemplary embodiments, the diameter 14 of the corneal inlay 10 can be 1 millimeter ("mm") to 3 mm (including endpoints), i.e., at least 1mm, at least 1.1 mm, at least 1.2 mm, at least 1.3 mm, at least 1.4 mm, at least 1.5 mm, at least 1.6 mm, at least 1.7 mm, at least 1.8 mm, at least 1.9 mm, at least 2.0 mm, at least 2.1 mm, at least 2.2 mm, at least 2.3 mm, at least 2.4 mm, at least 2.5mm, at least 2.6 mm, at least 2.7 mm, at least 2.8 mm, at least 2.9 mm, or at least 3.0 mm. According to some embodiments, the diameter 14 is at least 1.0 mm. According to some embodiments, the diameter 14 is at least 1.1 mm. According to some embodiments, the diameter 14 is at least 1.2 mm. According to some embodiments, the diameter 14 is at least 1.3 mm. According to some embodiments, the diameter 14 is at least 1.4 mm. According to some embodiments, the diameter 14 is at least 1.5 mm. According to some embodiments, the diameter 14 is at least 1.6 mm. According to some embodiments, the diameter 14 is at least 1.7 mm. According to some embodiments, the diameter 14 is at least 1.8 mm. According to some embodiments, the diameter 14 is at least 1.9 mm. According to some embodiments, the diameter 14 is at least 2.0 mm. According to some embodiments, the diameter 14 is at least 2.1 mm. According to some embodiments, the diameter 14 is at least 2.2 mm. According to some embodiments, the diameter 14 is at least 2.3 mm. According to some embodiments, the diameter 14 is at least 2.4 mm. According to some embodiments, the diameter 14 is at least 2.5 mm. According to some embodiments, the diameter 14 is at least 2.6 mm. According to some embodiments, the diameter 14 is at least 2.7 mm. According to some embodiments, the diameter 14 is at least 2.8 mm. According to some embodiments, the diameter 14 is at least 2.9 mm. According to some embodiments, the diameter 14 is at least 3.0 mm.

In an exemplary embodiment, corneal inlay 10 can have a thickness 12 in the range of 25 to 60 microns (including endpoints), i.e., at least 25 microns, at least 26 microns, at least 27 microns, at least 28 microns, at least 29 microns, at least 30 microns, at least 31 microns, at least 32 microns, at least 33 microns, at least 34 microns, at least 35 microns, at least 36 microns, at least 37 microns, at least 38 microns, at least 39 microns, at least 40 microns, at least 41 microns, at least 42 microns, at least 43 microns, at least 44 microns, at least 45 microns, at least 46 microns, at least 47 microns, at least 48 microns, at least 49 microns, at least 50 microns, at least 51 microns, at least 52 microns, at least 53 microns, at least 54 microns, at least 55 microns, at least 56 microns, at least 57 microns, at least 58 microns, at least 59 microns, or 60 microns. According to some embodiments, the thickness 12 of corneal inlay 10 can be from 32 microns to 50 microns (including endpoints), i.e., at least 32 microns, at least 33 microns, at least 34 microns, at least 35 microns, at least 36 microns, at least 37 microns, at least 38 microns, at least 39 microns, at least 40 microns, at least 41 microns, at least 42 microns, at least 43 microns, at least 44 microns, at least 45 microns, at least 46 microns, at least 47 microns, at least 48 microns, at least 49 microns, or 50 microns.

Figures 5A-5C show the top of a droplet of corneal inlay 10 forming a contact angle 16 with the bottom of corneal inlay 10. High contact angles yield low surface energies, while low contact angles yield high surface energies. According to some embodiments, the contact angle 16 is at least 1 °. According to some embodiments, the contact angle 16 is at least 2 °. According to some embodiments, the contact angle 16 is at least 3 °. According to some embodiments, the contact angle 16 is at least 4 °. According to some embodiments, the contact angle 16 is at least 5 °. According to some embodiments, the contact angle 16 is at least 6 °. According to some embodiments, the contact angle 16 is at least 7 °. According to some embodiments, the contact angle 16 is at least 8 °. According to some embodiments, the contact angle 16 is at least 9 °. According to some embodiments, the contact angle 16 is at least 10 °. According to some embodiments, the contact angle 16 is at least 11 °. According to some embodiments, the contact angle 16 is at least 12 °. According to some embodiments, the contact angle 16 is at least 13 °. According to some embodiments, the contact angle 16 is at least 14 °. According to some embodiments, the contact angle 16 is at least 15 °. According to some embodiments, the contact angle 16 is at least 16 °. According to some embodiments, the contact angle 16 is at least 17 °. According to some embodiments, the contact angle 16 is at least 18 °. According to some embodiments, the contact angle 16 is at least 19 °. According to some embodiments, the contact angle 16 is at least 20 °. According to some embodiments, the contact angle 16 is at least 21 °. According to some embodiments, the contact angle 16 is at least 22 °. According to some embodiments, the contact angle 16 is at least 23 °. According to some embodiments, the contact angle 16 is at least 24 °. According to some embodiments, the contact angle 16 is at least 25 °. According to some embodiments, the contact angle 16 is at least 26 °. According to some embodiments, the contact angle 16 is at least 27 °. According to some embodiments, the contact angle 16 is at least 28 °. According to some embodiments, the contact angle 16 is at least 29 °. According to some embodiments, the contact angle 16 is at least 30 °. According to some embodiments, the contact angle 16 is at least 31 °. According to some embodiments, the contact angle 16 is at least 32 °. According to some embodiments, the contact angle 16 is at least 33 °. According to some embodiments, the contact angle 16 is at least 34 °. According to some embodiments, the contact angle 16 is at least 35 °. According to some embodiments, the contact angle 16 is at least 36 °. According to some embodiments, the contact angle 16 is at least 37 °. According to some embodiments, the contact angle 16 is at least 38 °. According to some embodiments, the contact angle 16 is at least 39 °. According to some embodiments, the contact angle 16 is at least 40 °. According to some embodiments, the contact angle 16 is at least 41 °. According to some embodiments, the contact angle 16 is at least 42 °. According to some embodiments, the contact angle 16 is at least 43 °. According to some embodiments, the contact angle 16 is at least 44 °. According to some embodiments, the contact angle 16 is at least 45 °. According to some embodiments, the contact angle 16 is at least 46 °. According to some embodiments, the contact angle 16 is at least 47 °. According to some embodiments, the contact angle 16 is at least 48 °. According to some embodiments, the contact angle 16 is at least 49 °. According to some embodiments, the contact angle 16 is at least 50 °. According to some embodiments, the contact angle 16 is at least 51 °. According to some embodiments, the contact angle 16 is at least 52 °. According to some embodiments, the contact angle 16 is at least 53 °. According to some embodiments, the contact angle 16 is at least 54 °. According to some embodiments, the contact angle 16 is at least 55 °. According to some embodiments, the contact angle 16 is at least 56 °. According to some embodiments, the contact angle 16 is at least 57 °. According to some embodiments, the contact angle 16 is at least 58 °. According to some embodiments, the contact angle 16 is at least 59 °. According to some embodiments, the contact angle 16 is at least 60 °. According to some embodiments, the contact angle 16 is at least 61 °. According to some embodiments, the contact angle 16 is at least 62 °. According to some embodiments, the contact angle 16 is at least 63 °. According to some embodiments, the contact angle 16 is at least 64 °. According to some embodiments, the contact angle 16 is at least 65 °. According to some embodiments, the contact angle 16 is at least 66 °. According to some embodiments, the contact angle 16 is at least 67 °. According to some embodiments, the contact angle 16 is at least 68 °. According to some embodiments, the contact angle 16 is at least 69 °. According to some embodiments, the contact angle 16 is at least 70 °. According to some embodiments, the contact angle 16 is at least 71 °. According to some embodiments, the contact angle 16 is at least 72 °. According to some embodiments, the contact angle 16 is at least 73 °. According to some embodiments, the contact angle 16 is at least 74 °. According to some embodiments, the contact angle 16 is at least 75 °. According to some embodiments, the contact angle 16 is at least 76 °. According to some embodiments, the contact angle 16 is at least 77 °. According to some embodiments, the contact angle 16 is at least 78 °. According to some embodiments, the contact angle 16 is at least 79 °. According to some embodiments, the contact angle 16 is at least 80 °. According to some embodiments, the contact angle 16 is at least 81 °. According to some embodiments, the contact angle 16 is at least 82 °. According to some embodiments, the contact angle 16 is at least 83 °. According to some embodiments, the contact angle 16 is at least 84 °. According to some embodiments, the contact angle 16 is at least 85 °. According to some embodiments, the contact angle 16 is at least 86 °. According to some embodiments, the contact angle 16 is at least 87 °. According to some embodiments, the contact angle 16 is at least 88 °. According to some embodiments, the contact angle 16 is at least 89 °. According to some embodiments, the contact angle 16 is at least 80 °. According to some embodiments, the contact angle 16 is at least 91 °. According to some embodiments, the contact angle 16 is at least 92 °. According to some embodiments, the contact angle 16 is at least 93 °. According to some embodiments, the contact angle 16 is at least 94 °. According to some embodiments, the contact angle 16 is at least 95 °. According to some embodiments, the contact angle 16 is at least 96 °. According to some embodiments, the contact angle 16 is at least 97 °. According to some embodiments, the contact angle 16 is at least 98 °. According to some embodiments, the contact angle 16 is at least 99 °. According to some embodiments, the contact angle 16 is at least 100 °. According to some embodiments, the contact angle 16 is at least 101 °. According to some embodiments, the contact angle 16 is at least 102 °. According to some embodiments, the contact angle 16 is at least 103 °. According to some embodiments, the contact angle 16 is at least 104 °. According to some embodiments, the contact angle 16 is at least 105 °. According to some embodiments, the contact angle 16 is at least 106 °. According to some embodiments, the contact angle 16 is at least 107 °. According to some embodiments, the contact angle 16 is at least 108 °. According to some embodiments, the contact angle 16 is at least 109 °. According to some embodiments, the contact angle 16 is at least 110 °. According to some embodiments, the contact angle 16 is at least 111 °. According to some embodiments, the contact angle 16 is at least 112 °. According to some embodiments, the contact angle 16 is at least 113 °. According to some embodiments, the contact angle 16 is at least 114 °. According to some embodiments, the contact angle 16 is at least 115 °. According to some embodiments, the contact angle 16 is at least 116 °. According to some embodiments, the contact angle 16 is at least 117 °. According to some embodiments, the contact angle 16 is at least 118 °. According to some embodiments, the contact angle 16 is at least 119 °. According to some embodiments, the contact angle 16 is at least 120 °. According to some embodiments, the contact angle 16 is at least 121 °. According to some embodiments, the contact angle 16 is at least 122 °. According to some embodiments, the contact angle 16 is at least 123 °. According to some embodiments, the contact angle 16 is at least 124 °. According to some embodiments, the contact angle 16 is at least 125 °. According to some embodiments, the contact angle 16 is at least 126 °. According to some embodiments, the contact angle 16 is at least 127 °. According to some embodiments, the contact angle 16 is at least 128 °. According to some embodiments, the contact angle 16 is at least 129 °. According to some embodiments, the contact angle 16 is at least 130 °. According to some embodiments, the contact angle 16 is at least 131 °. According to some embodiments, the contact angle 16 is at least 132 °. According to some embodiments, the contact angle 16 is at least 133 °. According to some embodiments, the contact angle 16 is at least 134 °. According to some embodiments, the contact angle 16 is at least 135 °. According to some embodiments, the contact angle 16 is at least 136 °. According to some embodiments, the contact angle 16 is at least 137 °. According to some embodiments, the contact angle 16 is at least 138 °. According to some embodiments, the contact angle 16 is at least 139 °. According to some embodiments, the contact angle 16 is at least 140 °. According to some embodiments, the contact angle 16 is at least 141 °. According to some embodiments, the contact angle 16 is at least 142 °. According to some embodiments, the contact angle 16 is at least 143 °. According to some embodiments, the contact angle 16 is at least 144 °. According to some embodiments, the contact angle 16 is at least 145 °. According to some embodiments, the contact angle 16 is at least 146 °. According to some embodiments, the contact angle 16 is at least 147 °. According to some embodiments, the contact angle 16 is at least 148 °. According to some embodiments, the contact angle 16 is at least 149 °. According to some embodiments, the contact angle 16 is at least 150 °. According to some embodiments, the contact angle 16 is at least 151 °. According to some embodiments, the contact angle 16 is at least 152 °. According to some embodiments, the contact angle 16 is at least 153 °. According to some embodiments, the contact angle 16 is at least 154 °. According to some embodiments, the contact angle 16 is at least 155 °. According to some embodiments, the contact angle 16 is at least 156 °. According to some embodiments, the contact angle 16 is at least 157 °. According to some embodiments, the contact angle 16 is at least 158 °. According to some embodiments, the contact angle 16 is at least 159 °. According to some embodiments, the contact angle 16 is at least 160 °. According to some embodiments, the contact angle 16 is at least 161 °. According to some embodiments, the contact angle 16 is at least 162 °. According to some embodiments, the contact angle 16 is at least 163 °. According to some embodiments, the contact angle 16 is at least 164 °. According to some embodiments, the contact angle 16 is at least 165 °. According to some embodiments, the contact angle 16 is at least 166 °. According to some embodiments, the contact angle 16 is at least 167 °. According to some embodiments, the contact angle 16 is at least 168 °. According to some embodiments, the contact angle 16 is at least 169 °. According to some embodiments, the contact angle 16 is at least 170 °. According to some embodiments, the contact angle 16 is at least 171 °. According to some embodiments, the contact angle 16 is at least 172 °. According to some embodiments, the contact angle 16 is at least 173 °. According to some embodiments, the contact angle 16 is at least 174 °. According to some embodiments, the contact angle 16 is at least 175 °. According to some embodiments, the contact angle 16 is at least 176 °. According to some embodiments, the contact angle 16 is at least 177 °. According to some embodiments, the contact angle 16 is at least 178 °. According to some embodiments, the contact angle 16 is at least 179 °. According to some embodiments, the contact angle 16 is at least 180 °.

Figure 6 is a diagram showing corneal inlay 10 implanted in cornea 20. The corneal inlay 10 can have a droplet shape with an anterior surface 22 and a posterior surface 24. The corneal inlay 10 may be implanted into the cornea at a depth of 50% or less (about 250 μm or less) of the cornea and placed on a stromal bed 26 of the cornea 20 created by a microkeratome or any other suitable surgical instrument. For example, corneal inlay 10 can be implanted into cornea 20 by cutting a flap 28 in cornea 20, lifting flap 28 to expose the interior of cornea 20, placing corneal inlay 10 on the exposed area of the interior, and repositioning flap 28 on corneal inlay 10. The flap 28 may be cut using a laser (e.g., a femtosecond laser, a mechanical keratome, etc.) or manually by an ophthalmic surgeon. When the flap 28 is cut into the cornea 28, a small piece of corneal tissue remains intact to make the hinge (hinge) of the flap 28 to accurately reposition the flap 28 on the corneal inlay 10. After repositioning the flap 28 on the corneal inlay 10, the cornea 20 heals around the flap 28 and seals the flap 28 back to the uncut peripheral portion of the anterior surface of the cornea. Alternatively, a pocket or well (well) having a sidewall or barrier structure may be cut into the cornea 20 and the corneal inlay 10 inserted between the sidewall or barrier structure through a small opening or "port" in the cornea 20.

The corneal inlay 10 changes the refractive power of the cornea by changing the shape of the anterior surface of the cornea. In FIG. 6, the anterior surface of the pre-operative cornea is indicated by dashed line 30 and the anterior surface of the post-operative cornea resulting from the underlying corneal inlay 10 is indicated by solid line 32.

In some embodiments in which the corneal inlay is positioned under the flap, the inlay 10 is implanted into the cornea to a depth of between about 100 microns and about 200 microns. In some embodiments, the inlay is disposed at a depth of between about 130 microns to about 160 microns. According to some embodiments, the inlay 10 is positioned at a depth of 100 microns. According to some embodiments, the inlay 10 is positioned at a depth of 101 microns. According to some embodiments, the inlay 10 is positioned at a depth of 102 microns. According to some embodiments, the inlay 10 is positioned at a depth of 103 microns. According to some embodiments, the inlay 10 is positioned at a depth of 104 microns. According to some embodiments, inlay 10 is positioned at a depth of 105 microns. According to some embodiments, the inlay 10 is positioned at a depth of 106 microns. According to some embodiments, the inlay 10 is positioned at a depth of 107 microns. According to some embodiments, the inlay 10 is positioned at a depth of 108 microns. According to some embodiments, inlay 10 is positioned at a depth of 109 microns. According to some embodiments, the inlay 10 is positioned at a depth of 110 microns. According to some embodiments, the inlay 10 is positioned at a depth of 111 microns. According to some embodiments, the inlay 10 is positioned at a depth of 112 microns. According to some embodiments, the inlay 10 is positioned at a depth of 113 microns. According to some embodiments, the inlay 10 is positioned at a depth of 114 microns. According to some embodiments, the inlay 10 is positioned at a depth of 115 microns. According to some embodiments, the inlay 10 is positioned at a depth of 116 microns. According to some embodiments, the inlay 10 is positioned at a depth of 117 microns. According to some embodiments, the inlay 10 is positioned at a depth of 118 microns. According to some embodiments, inlay 10 is positioned at a depth of 119 microns. According to some embodiments, the inlay 10 is positioned at a depth of 120 microns. According to some embodiments, inlay 10 is positioned at a depth of 121 microns. According to some embodiments, inlay 10 is positioned at a depth of 122 microns. According to some embodiments, the inlay 10 is positioned at a depth of 123 microns. According to some embodiments, the inlay 10 is positioned at a depth of 124 microns. According to some embodiments, the inlay 10 is positioned at a depth of 125 microns. According to some embodiments, inlay 10 is positioned at a depth of 126 microns. According to some embodiments, the inlay 10 is positioned at a depth of 127 microns. According to some embodiments, the inlay 10 is positioned at a depth of 128 microns. According to some embodiments, the inlay 10 is positioned at a depth of 129 microns. According to some embodiments, the inlay 10 is positioned at a depth of 130 microns. According to some embodiments, the inlay 10 is positioned at a depth of 131 microns. According to some embodiments, inlay 10 is positioned at a depth of 132 microns. According to some embodiments, the inlay 10 is positioned at a depth of 133 microns. According to some embodiments, the inlay 10 is positioned at a depth of 134 microns. According to some embodiments, the inlay 10 is positioned at a depth of 135 microns. According to some embodiments, the inlay 10 is positioned at a depth of 136 microns. According to some embodiments, the inlay 10 is positioned at a depth of 137 microns. According to some embodiments, inlay 10 is positioned at a depth of 138 microns. According to some embodiments, the inlay 10 is positioned at a depth of 139 microns. According to some embodiments, the inlay 10 is positioned at a depth of 140 microns. According to some embodiments, the inlay 10 is positioned at a depth of 141 microns. According to some embodiments, inlay 10 is positioned at a depth of 142 microns. According to some embodiments, the inlay 10 is positioned at a depth of 143 microns. According to some embodiments, the inlay 10 is positioned at a depth of 144 microns. According to some embodiments, inlay 10 is positioned at a depth of 145 microns. According to some embodiments, the inlay 10 is positioned at a depth of 146 microns. According to some embodiments, inlay 10 is positioned at a depth of 147 microns. According to some embodiments, inlay 10 is positioned at a depth of 148 microns. According to some embodiments, inlay 10 is positioned at a depth of 149 microns. According to some embodiments, the inlay 10 is positioned at a depth of 150 microns. According to some embodiments, the inlay 10 is positioned at a depth of 151 microns. According to some embodiments, the inlay 10 is positioned at a depth of 152 microns. According to some embodiments, inlay 10 is positioned at a depth of 153 microns. According to some embodiments, inlay 10 is positioned at a depth of 154 microns. According to some embodiments, the inlay 10 is positioned at a depth of 155 microns. According to some embodiments, inlay 10 is positioned at a depth of 156 microns. According to some embodiments, the inlay 10 is positioned at a depth of 157 microns. According to some embodiments, the inlay 10 is positioned at a depth of 158 microns. According to some embodiments, the inlay 10 is positioned at a depth of 159 microns. According to some embodiments, the inlay 10 is positioned at a depth of 160 microns. According to some embodiments, the inlay 10 is positioned at a depth of 161 microns. According to some embodiments, the inlay 10 is positioned at a depth of 162 microns. According to some embodiments, inlay 10 is positioned at a depth of 163 microns. According to some embodiments, the inlay 10 is positioned at a depth of 164 microns. According to some embodiments, inlay 10 is positioned at a depth of 165 microns. According to some embodiments, the inlay 10 is positioned at a depth of 166 microns. According to some embodiments, the inlay 10 is positioned at a depth of 167 microns. According to some embodiments, the inlay 10 is positioned at a depth of 168 microns. According to some embodiments, the inlay 10 is positioned at a depth of 169 microns. According to some embodiments, the inlay 10 is positioned at a depth of 170 microns. According to some embodiments, inlay 10 is positioned at a depth of 171 microns. According to some embodiments, the inlay 10 is positioned at a depth of 172 microns. According to some embodiments, the inlay 10 is positioned at a depth of 173 microns. According to some embodiments, inlay 10 is positioned at a depth of 174 microns. According to some embodiments, inlay 10 is positioned at a depth of 175 microns. According to some embodiments, the inlay 10 is positioned at a depth of 176 microns. According to some embodiments, the inlay 10 is positioned at a depth of 177 microns. According to some embodiments, inlay 10 is positioned at a depth of 178 microns. According to some embodiments, the inlay 10 is positioned at a depth of 179 microns. According to some embodiments, the inlay 10 is positioned at a depth of 180 microns. According to some embodiments, the inlay 10 is positioned at a depth of 181 microns. According to some embodiments, the inlay 10 is positioned at a depth of 182 microns. According to some embodiments, the inlay 10 is positioned at a depth of 183 microns. According to some embodiments, the inlay 10 is positioned at a depth of 184 microns. According to some embodiments, the inlay 10 is positioned at a depth of 185 microns. According to some embodiments, the inlay 10 is positioned at a depth of 186 microns. According to some embodiments, the inlay 10 is positioned at a depth of 187 microns. According to some embodiments, the inlay 10 is positioned at a depth of 188 microns. According to some embodiments, the inlay 10 is positioned at a depth of 189 microns. According to some embodiments, inlay 10 is positioned at a depth of 190 microns. According to some embodiments, the inlay 10 is positioned at a depth of 191 microns. According to some embodiments, the inlay 10 is positioned at a depth of 192 microns. According to some embodiments, the inlay 10 is positioned at a depth of 193 microns. According to some embodiments, the inlay 10 is positioned at a depth of 194 microns. According to some embodiments, inlay 10 is positioned at a depth of 195 microns. According to some embodiments, the inlay 10 is positioned at a depth of 196 microns. According to some embodiments, the inlay 10 is positioned at a depth of 197 microns. According to some embodiments, the inlay 10 is positioned at a depth of 198 microns. According to some embodiments, the inlay 10 is positioned at a depth of 199 microns. According to some embodiments, the inlay 10 is positioned at a depth of 200 microns. According to some embodiments, the corneal depth for the pocket may be greater than the depth for the flap. According to some exemplary embodiments, a thicker inlay may be required to achieve refractive correction since the corneal depth for the pocket is greater than the depth for the flap.

The elastic (young) modulus of the corneal inlay 10 can be, for example, 0.18 megapascals ("MPa") with a tolerance of ± 0.06 MPa. However, in some embodiments, the modulus of elasticity of the corneal inlay 10 may exceed tolerances. According to some embodiments, the corneal inlay 10 can have an elastic modulus of at least 0.05 MPa. According to some embodiments, the corneal inlay 10 may have an elastic modulus of at least 0.06 MPa. According to some embodiments, the corneal inlay 10 can have an elastic modulus of at least 0.07 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 may be at least 0.08 MPa. According to some embodiments, the corneal inlay 10 can have an elastic modulus of at least 0.09 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 may be at least 0.10 MPa. According to some embodiments, the corneal inlay 10 can have an elastic modulus of at least 0.11 MPa. According to some embodiments, the corneal inlay 10 can have an elastic modulus of at least 0.12 MPa. According to some embodiments, the corneal inlay 10 can have an elastic modulus of at least 0.13 MPa. According to some embodiments, the corneal inlay 10 can have an elastic modulus of at least 0.14 MPa. According to some embodiments, the corneal inlay 10 can have an elastic modulus of at least 0.15 MPa. According to some embodiments, the corneal inlay 10 may have an elastic modulus of at least 0.16 MPa. According to some embodiments, the corneal inlay 10 can have an elastic modulus of at least 0.17 MPa. According to some embodiments, the corneal inlay 10 may have an elastic modulus of at least 0.18 MPa. According to some embodiments, the corneal inlay 10 may have an elastic modulus of at least 0.19 MPa. According to some embodiments, the corneal inlay 10 can have an elastic modulus of at least 0.20 MPa. According to some embodiments, the elastic modulus of corneal inlay 10 may be at least 0.21 MPa. According to some embodiments, the corneal inlay 10 can have an elastic modulus of at least 0.22 MPa. According to some embodiments, the corneal inlay 10 can have an elastic modulus of at least 0.23 MPa. According to some embodiments, the corneal inlay 10 can have an elastic modulus of at least 0.24 MPa. According to some embodiments, the corneal inlay 10 can have an elastic modulus of at least 0.25 MPa. According to some embodiments, the corneal inlay 10 can have an elastic modulus of at least 0.26 MPa. According to some embodiments, the corneal inlay 10 can have an elastic modulus of at least 0.27 MPa. According to some embodiments, the corneal inlay 10 can have an elastic modulus of at least 0.28 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 may be at least 0.29 MPa. According to some embodiments, the corneal inlay 10 can have an elastic modulus of at least 0.30 MPa.

The corneal inlay 10 can have an elongation to break of 58.30% with a tolerance of + -4.49%. However, in some embodiments, the elongation to break of the corneal inlay 10 can exceed tolerances. According to some embodiments, the elongation at break of the corneal inlay 10 may be at least 48%. According to some embodiments, the elongation at break of the corneal inlay 10 may be at least 49%. According to some embodiments, the elongation at break of corneal inlay 10 may be at least 50%. According to some embodiments, the elongation at break of corneal inlay 10 may be at least 21%. According to some embodiments, the elongation at break of the corneal inlay 10 may be at least 52%. According to some embodiments, the corneal inlay 10 can have an elongation at break of at least 53%. According to some embodiments, the elongation at break of the corneal inlay 10 may be at least 54%. According to some embodiments, the elongation at break of corneal inlay 10 may be at least 55%. According to some embodiments, the elongation at break of corneal inlay 10 may be at least 56%. According to some embodiments, the corneal inlay 10 may have an elongation at break of at least 57%. According to some embodiments, the elongation at break of corneal inlay 10 may be at least 58%. According to some embodiments, the elongation at break of corneal inlay 10 may be at least 59%. According to some embodiments, the elongation at break of the corneal inlay 10 may be at least 60%. According to some embodiments, the corneal inlay 10 may have an elongation at break of at least 61%. According to some embodiments, the corneal inlay 10 may have an elongation at break of at least 62%. According to some embodiments, the elongation at break of the corneal inlay 10 may be at least 63%. According to some embodiments, the corneal inlay 10 may have an elongation at break of at least 64%. According to some embodiments, the corneal inlay 10 may have an elongation at break of at least 65%. According to some embodiments, the elongation at break of corneal inlay 10 may be at least 66%. According to some embodiments, the elongation at break of the corneal inlay 10 may be at least 67%. According to some embodiments, the elongation at break of the corneal inlay 10 may be at least 68%. According to some embodiments, the corneal inlay 10 may have an elongation at break of at least 69%. According to some embodiments, the elongation at break of the corneal inlay 10 may be at least 70%.

The tensile strength (meaning the breaking strength of the material under tension) of the corneal inlay 10 can be 0.07 MPa with a tolerance of ± 0.02 MPa. In some embodiments, the tensile strength of the corneal inlay can exceed a tolerance. According to some embodiments, the tensile strength of the corneal inlay 10 may be at least 0.01 MPa. According to some embodiments, the tensile strength of the corneal inlay 10 may be at least 0.02 MPa. According to some embodiments, the tensile strength of corneal inlay 10 may be at least 0.03 MPa. According to some embodiments, the tensile strength of the corneal inlay 10 may be at least 0.04 MPa. According to some embodiments, the tensile strength of corneal inlay 10 may be at least 0.05 MPa. According to some embodiments, the tensile strength of corneal inlay 10 may be at least 0.06 MPa. According to some embodiments, the tensile strength of corneal inlay 10 may be at least 0.07 MPa. According to some embodiments, the tensile strength of the corneal inlay 10 may be at least 0.08 MPa. According to some embodiments, the corneal inlay 10 can have a tensile strength of at least 0.09 MPa. According to some embodiments, the tensile strength of corneal inlay 10 may be at least 0.10 MPa. According to some embodiments, the tensile strength of corneal inlay 10 may be at least 0.11 MPa. According to some embodiments, the tensile strength of the corneal inlay 10 may be at least 0.12 MPa. According to some embodiments, the tensile strength of corneal inlay 10 may be at least 0.13 MPa. According to some embodiments, the corneal inlay 10 can have a tensile strength of at least 0.14 MPa. According to some embodiments, the corneal inlay 10 can have a tensile strength of at least 0.15 Mpa.

The corneal inlay 10 can have a backscattering (meaning that the radiation or particles are turned through an angle of 180 °) of 0.90% with a tolerance of ± 0.17%. However, in some embodiments, the backscattering of the corneal inlay 10 can exceed tolerances. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.65%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.66%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.67%. According to some embodiments, the corneal inlay 10 may have a backscatter of at least 0.68%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.69%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.70%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.71%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.72%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.73%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.74%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.75%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.76%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.77%. According to some embodiments, the corneal inlay 10 may have a backscatter of at least 0.78%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.79%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.80%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.81%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.82%. According to some embodiments, the corneal inlay 10 may have a backscatter of at least 0.83%. According to some embodiments, the corneal inlay 10 may have a backscatter of at least 0.84%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.85%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.86%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.87%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.88%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.89%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.90%. According to some embodiments, the corneal inlay 10 may have a backscatter of at least 0.91%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.92%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.93%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.94%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.95%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.96%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.97%. According to some embodiments, the corneal inlay 10 may have a backscatter of at least 0.98%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 0.99%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 1.00%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 1.01%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 1.02%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 1.03%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 1.04%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 1.05%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 1.06%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 1.07%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 1.08%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 1.09%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 1.10%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 1.11%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 1.12%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 1.13%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 1.14%. According to some embodiments, the corneal inlay 10 may have a backscattering of at least 1.15%.

The corneal inlay 10 can have a light transmission (meaning the penetrating motion of the electromagnetic waves) of 92.4% with a tolerance of ± 0.95%. In some embodiments, the modulus of elasticity of the corneal inlay 10 can exceed tolerances. According to some embodiments, the corneal inlay 10 can have a light transmittance of at least 85.0%. According to some embodiments, the corneal inlay 10 may have a light transmittance of at least 86.0%. According to some embodiments, the corneal inlay 10 can have a light transmittance of at least 87.0%. According to some embodiments, the corneal inlay 10 can have a light transmittance of at least 88.0%. According to some embodiments, the corneal inlay 10 can have a light transmittance of at least 89.0%. According to some embodiments, the corneal inlay 10 can have a light transmittance of at least 90.0%. According to some embodiments, the corneal inlay 10 can have a light transmittance of at least 91.0%. According to some embodiments, the corneal inlay 10 can have a light transmittance of at least 92.0%. According to some embodiments, the corneal inlay 10 can have a light transmittance of at least 93.0%. According to some embodiments, the corneal inlay 10 may have a light transmittance of at least 94.0%. According to some embodiments, the corneal inlay 10 may have a light transmittance of at least 95.0%. According to some embodiments, the corneal inlay 10 may have a light transmittance of at least 96.0%. According to some embodiments, the corneal inlay 10 may have a light transmittance of at least 97.0%. According to some embodiments, the corneal inlay 10 can have a light transmittance of at least 98.0%. According to some embodiments, the corneal inlay 10 may have a light transmittance of at least 99.0%. According to some embodiments, the corneal inlay 10 can have a light transmittance of 100.0%.

The morphology (meaning form) of the corneal inlay 10 may be a fibrous network with nanopores. According to some embodiments, the nanopores of the corneal inlay 10 can have a diameter of at least 0.1 μm. According to some embodiments, the nanopores of the corneal inlay 10 may have a diameter of at least 0.2 μm. According to some embodiments, the nanopores of the corneal inlay 10 may have a diameter of at least 0.3 μm. According to some embodiments, the nanopores of the corneal inlay 10 may have a diameter of at least 0.4 μm. According to some embodiments, the nanopores of the corneal inlay 10 may have a diameter of at least 0.5 μm. According to some embodiments, the nanopores of the corneal inlay 10 may have a diameter of at least 0.6 μm. According to some embodiments, the nanopores of the corneal inlay 10 may have a diameter of at least 0.7 μm. According to some embodiments, the nanopores of the corneal inlay 10 may have a diameter of at least 0.8 μm. According to some embodiments, the nanopores of the corneal inlay 10 may have a diameter of at least 0.9 μm. According to some embodiments, the nanopores of the corneal inlay 10 may have a diameter of at least 1.0 μm. According to some embodiments, the nanopores may have a diameter of about 0.4 μm. According to some embodiments, the corneal inlay 10 can be stored at a temperature of about 2 ℃ to about 6 ℃, i.e., about 2 ℃, 2.5 ℃,3 ℃, 3.5 ℃, 4 ℃, 4.5 ℃,5 ℃, 5.5 ℃,6 ℃.

Presbyopia inlay (Presbyyopic inlay)

According to some embodiments, the corneal inlay 10 has a diameter that is smaller than the diameter of the pupil for correcting presbyopia. In some embodiments, the corneal inlay 10 (e.g., 1mm to 3 mm in diameter) is centrally implanted into the cornea to introduce an "effect" zone on the anterior surface of the cornea that is smaller than the optical zone of the cornea used to provide near vision. Here, the "effect" zone is the region of the anterior surface of the cornea affected by the corneal inlay 10. The implanted corneal inlay 10 increases the curvature of the anterior surface of the cornea in the "effect" zone, thereby increasing the refractive power of the cornea in the "effect" zone. Distance vision is provided by the corneal region that is peripheral to the "effect" zone.

Presbyopia is characterized by a decrease in the ability of the eye to increase its power to focus on near objects due to the loss of elasticity of the lens that occurs with age. Typically, presbyopic patients require presbyopic glasses to provide near vision.

Figure 7 shows an example of how the corneal inlay 10 can provide near vision to a subject's eye while maintaining some distance vision, according to one embodiment of the present invention. The eye 40 includes a cornea 42, a pupil 44, a lens 46, and a retina 48. In this example, corneal inlay 10 (not shown) is centrally implanted into cornea 42 to create a small diameter "effect" zone 50. The corneal inlay 10 has a diameter that is smaller than the pupil 44 such that the resulting "effect" zone 50 has a diameter that is smaller than the optical zone of the cornea 42. The "effect" zone 50 provides near vision by increasing the curvature of the anterior surface of the cornea and thus increasing the refractive power within the "effect" zone 50. The corneal region 52 peripheral to the "effect" zone provides distance vision.

To increase the refractive power in the "effect" zone 50, the corneal inlay 10 has a higher curvature than the anterior corneal surface prior to implantation to increase the curvature of the anterior corneal surface in the "effect" zone 50. The corneal inlay 10 may have a refractive index that is higher than the refractive index (n) of the cornea _Cornea = 1.376) to further increase the refractive power within the "effect" zone 50. Thus, the increase in refractive power within the "effect" zone 50 can be attributed to the change in the corneal anterior surface induced by the corneal inlay 10 or a combination of the change in the corneal anterior surface and the refractive index of the corneal inlay 10. For early presbyopia (e.g., about 45 to 55 years of age), near vision typically requires at least 1 diopter. For full presbyopia (e.g., about 60 years of age or older), 2 to 3 extra diopters are required.

One advantage of the corneal inlay 10 is that when focused on a near object 54, the pupil naturally becomes smaller (e.g., a near miosis) to make the corneal inlay effect more effective. Further enhancement of the corneal inlay effect can be achieved by increasing the illumination of nearby objects (e.g., turning on the reading light).

As shown in FIG. 7, since the inlay is smaller than the diameter of the pupil 44, light rays 56 from the distant object 58 bypass the inlay and refract with the corneal region peripheral to the "effect" zone to create an image of the distant object on the retina 48. This is particularly true for larger pupils. At night, when distance vision is most important, the pupil naturally becomes larger, thereby lessening the inlay effect and maximizing distance vision.

The subject's natural distance vision is only in focus when the subject is emmetropic (i.e., no glasses are required to obtain distance vision). Many subjects are ametropic and require myopic or hyperopic refractive correction. In particular, for myopes, distance vision correction may be provided by myopic Laser in Situ Keratomileusis ("LASIK"), Laser Epithelial Keratomileusis ("LASEK"), Photorefractive Keratectomy ("PRK"), or other similar refractive corneal surgeries. After the distance vision correction procedure is completed, the corneal inlay 10 may be implanted into the cornea to provide near vision. Since LASIK requires the creation of a flap, the corneal inlay 10 can be inserted at the same time as the LASIK procedure. The corneal inlay 10 can also be embedded into the cornea after LASIK surgery because the flap can be reopened. Thus, the corneal inlay 10 may be used in conjunction with other refractive procedures, such as LASIK for correcting myopia or hyperopia.

Figure 8 is a graph of corneal anterior surface height (microns) (y-axis) vs. radius (millimeters) (x-axis) from the center of the inlay. The graph shows the change in corneal anterior surface height (microns) and the corresponding induced add power (e.g., diopters).

Figure 9 is a graph showing pre-operative optical coherence tomography ("OCT") and post-operative OCT. In post-operative OCT, an exemplary location 70 of corneal inlay 10 is shown.

Material chemistry of inlays

According to some embodiments, the inlay material comprises a biopolymer. According to some embodiments, the biopolymer is a synthetic self-assembling biopolymer. According to some embodiments, the biopolymer is a naturally occurring biopolymer. Exemplary naturally occurring biopolymers include, but are not limited to, protein polymers, collagen, polysaccharides, and photopolymerizable compounds. Exemplary protein polymers synthesized from self-assembled protein polymers include, for example, fibroin, elastin, collagen and combinations thereof. According to some embodiments, the synthetic self-assembling biopolymer is synthetic collagen. According to some embodiments, the collagen is a collagen mimetic peptide. The term "mimetic" as used herein refers to a chemical that contains a chemical moiety that mimics the function of a peptide. For example, if a peptide contains two functionally active charged chemical moieties, a mimetic places the two charged chemical moieties in a spatially oriented and constrained structure to retain charged electrochemical functions in three dimensions.

According to some embodiments, the inlay material comprises a synthetic polymeric material. According to some embodiments, the synthetic material is an optically transparent material. According to some embodiments, the synthetic material is a biocompatible material. According to some embodiments, the synthetic material is a hydrophilic material. According to some embodiments, the synthetic material is a low molecular weight nutrient permeable material to maintain corneal health. According to some embodiments, the synthetic material is a refractive material. According to some embodiments, the synthetic material is optically transparent, biocompatible, hydrophilic, permeable, and refractive.

Exemplary biocompatible, biodegradable polymers include, but are not limited to, polylactide, polyglycolide, poly (lactide-co-glycolide); poly (lactic acid); poly (glycolic acid); poly (lactic-co-glycolic acid); poly (caprolactone); poly (ortho esters); polyanhydrides; poly (phosphazenes); polyhydroxyalkanoates; poly (hydroxybutyrate); a polycarbonate; a tyrosine polycarbonate; a polyamide; a polyester amide; a polyester; poly (dioxanone); poly (alkylene alkylate)); polyethers (such as polyethylene glycol PEG and polyethylene oxide PEO); polyvinylpyrrolidone or PVP; a polyurethane; a polyether ester; a polyacetal; polycyanoacrylates; poly (oxyethylene)/poly (oxypropylene) copolymers; polyacetals, polyketals; polyphosphate ester; (phosphorus-containing) polymers; polyphosphates (polyphosphasters); polyhydroxyvalerate; a polyalkylene oxalate; polyalkylene succinates; or poly (maleic acid). The water-soluble biocompatible polymer poly (2-methacryloyloxyethyl phosphorylcholine) (PMPC) is a zwitterionic polymer that is capable of forming a more compact conformation in aqueous solution than poly (ethylene glycol) (PEG).

Exemplary non-degradable biocompatible polymers include, but are not limited to, polysiloxanes, polyvinyl alcohol, and polyimides.

Exemplary copolymers include hydroxyethyl methacrylate and methyl methacrylate, and hydroxyethyl methacrylate copolymerized with polyvinylpyrrolidone (PVP to improve water retention) or Ethylene Glycol Dimethacrylate (EGDM). Nexofilcon A (Bausch & Lomb) is a hydrophilic copolymer of 2-hydroxyethyl methacrylate and N-vinyl pyrrolidone.

Exemplary block polymers comprising blocks of hydrophilic biocompatible polymers or biopolymers or biodegradable polymers include polyethers, including polyethylene glycol PEG; polyethylene oxide PEO; polypropylene oxide PPO, perfluoropolyether (PFPE), and block copolymers consisting of combinations thereof.

According to some embodiments, the hydrophilic polymer comprises a hydrogel polymer. Hydrogels are water-swollen crosslinked polymeric structures made by polymerization of one or more monomers or by association of bonds, such as hydrogen bonds, and strong van der waals interactions between chains, which exist in a state between a rigid solid and a liquid. Hydrogels are formed when high molecular weight polymers or high polymer concentrations are included in the formulation. Hydrogels generally comprise various polymers. Exemplary polymers include acrylic acid, acrylamide, and 2-hydroxyethyl methacrylate (HEMA). For example, high molecular weight crosslinked poly (acrylic acid) is commercially available as Carbopol @ (B.F./Goodrich Chemical Co., Cleveland, OH). Polyethylene glycol diacrylate (PEGDA 400) is a long chain hydrophilic crosslinking monomer. Methacryloyloxyethyl Phosphorylcholine (MPC) containing a phosphorylcholine group in the side chain is a monomer that mimics the phospholipid polar groups contained in cell membranes. Polyoxamers available as Pluronic (BASF-Wyandotte, USA) are thermosetting polymers formed of a central hydrophobic moiety (polyoxypropylene) surrounded by a hydrophilic moiety (ethylene oxide). (4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholine hydrochloride (DMTMM) or N-3- (dimethylaminopropyl) -N '-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide (EDC/NHS) can be used to synthesize hyaluronic acid derivatives see D' Ester, M. et al, Carbohydrate Polymers (2014) 108: 239-, PJ et al Soft Matter (2012) 8: 10409-.

According to some embodiments, the first polymer and the second polymer comprise one or more different non-repeating units, such as end groups, or non-repeating units in the polymer backbone. According to some embodiments, the first polymer and the second polymer comprise one or more different end groups. For example, the first polymer may have end groups that are more polar than one or more end groups of the second polymer. According to some such embodiments, the first polymer present alone is more hydrophilic relative to the second polymer (having less polar end groups). According to some such embodiments, the first polymer comprises one or more carboxylic acid end groups and the second polymer comprises one or more ester end groups.

According to some embodiments, the inlay material comprises a polymer matrix.

According to some embodiments, the inlay material comprises a uv blocker.

The corneal inlay 10 may have properties similar to a natural cornea and may be made of a hydrogel or other transparent biocompatible material. To increase the optical power of the inlay, the inlay may be made of a material with a higher refractive index than the cornea, e.g., > 1.376.

Materials that may be used to make corneal inlay 10 include, but are not limited to, self-assembling peptide hydrogels containing one or more non-protein amino acids (e.g., Thota, CK et al, sci. rep. 6: 31167; doi: 10.1038/srep31167 (2016)), collagen mimetic peptides coupled to polyethylene glycol ("PEG") ("CMP"), lipofilcon a (high water (> 50% water) non-ionic hydrogel polymers), poly (2-hydroxyethyl methacrylate) (PolyHEMA), polysulfone, silicone hydrogel polymers, water, and the like.

According to some embodiments, the composition of corneal inlay 10 comprises water and CMP coupled to PEG. According to some embodiments, the composition of corneal inlay 10 comprises water, one or more hydrophilic polymers (e.g., PEG, MPC), and mammalian collagen.

According to some embodiments, the water content may be 80% to 99%. According to some embodiments, the water content is at least 80%. According to some embodiments, the water content is at least 81%. According to some embodiments, the water content is at least 82%. According to some embodiments, the water content is at least 83%. According to some embodiments, the water content is at least 84%. According to some embodiments, the water content is at least 85%. According to some embodiments, the water content is at least 86%. According to some embodiments, the water content is at least 87%. According to some embodiments, the water content is at least 88%. According to some embodiments, the water content is at least 89%. According to some embodiments, the water content is at least 90%. According to some embodiments, the water content is at least 91%. According to some embodiments, the water content is at least 92%. According to some embodiments, the water content is at least 93%. According to some embodiments, the water content is at least 94%. According to some embodiments, the water content is at least 95%. According to some embodiments, the water content is at least 96%. According to some embodiments, the water content is at least 97%. According to some embodiments, the water content is at least 98%. According to some embodiments, the water content is at least 99%. According to some embodiments, the water content is, for example, at least 90%.

Figure 10 is a graph showing the refractive effect of water content on inlay refractive index and intrinsic power. As can be seen, as the percentage of water increases, the intrinsic power increases, while the inlay refractive index decreases as the percentage of water increases.

Manufacture of

According to some embodiments, the reusable mold comprises a first mold half comprising a first mold surface in contact with a polymerizable and/or crosslinkable silicone-containing inlay-forming composition and a second mold half comprising a second mold surface in contact with the inlay-forming composition. The first and second mold halves may be configured to engage each other to form a cavity between the first and second mold surfaces. The cavity may define the shape of the inlay to be molded.

According to some embodiments, the polymer may be injected into the mold, and the corneal inlay then polymerized by a method appropriate to the particular polymer used, for example by chemical means, by sequential crosslinking using precursors of the crosslinking agent, by thermal means, or by photopolymerization. After polymerization, the inlay can be removed from the mold (demolded), washed and stored in a preservative-containing buffer until use.

According to some embodiments, the corneal inlay is cast as a flat, thin disc. According to some embodiments, the manufactured inlay is cast into a hemispherical dome. According to some embodiments, the manufactured inlay is cast into a spherical lens.

Where a range of values is provided, it is understood that each intervening value, in the unit of lower limit 1/10, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention unless the context clearly dictates otherwise. The upper and lower limits of these smaller ranges, which may independently be included in the smaller ranges, are also encompassed within the invention, subject to any specifically excluded limit in the stated range. If a stated range includes one or both of the limits, ranges that do not include either or both of those included limits are also included in the invention.

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 invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the exemplary methods and materials have been described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

It must be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application and are each incorporated by reference herein in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.

Examples

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is ° c, and pressure is at or near atmospheric.

Example 1 evaluation of corneal haze (non-GLP) after corneal implantation of various inlay materials in New Zealand white rabbits

BackgroundThe study was designed to assess corneal haze in rabbits following corneal implantation of various inlay materials. Such information is only available from in vivo systems treated with inlay material. Rabbits are a standard species for ocular studies based on historical data and FDA requirements. New Zealand white rabbits (NZW), considered as a preferred and best model for evaluating study endpoints, have proven useful in ophthalmic studies. Their ocular anatomy and physiology are similar to humans, and their eyes have similar metabolic pathways.

A. Suggested duration of study 5-6 months

B. Design of experiments

1. Test system

Species:Oryctolagus cuiculus

new Zealand white rabbit

Sex male (all the same sex)

Body weight approximately 3.5 to 4.5 kg at study initiation

Number 16

Identification method based on SOP ear tag and cage tag

Minimum acclimation (minimum acclimation) 5 days

2. Specialized animal feeding and/or leasing

(a) Fasting without

(b) Restraint animals were manually restrained according to SOP to facilitate examination

(c) Housing animals were housed separately before and during the study to reduce the likelihood of eye damage from the cage partner.

C. Test article

Test article

Abbreviations

Description of the invention

ID No.

Manufacturer(s)

(Storage)

Expiration or retest periods

1

PEG

Polyethylene glycol (PEG); 82% water Content (c); (diameter: -2.5mm inlay Body, thickness: -40 micron)

1386B

Ferentis

At room temperature

N/A

2

MPC

2-Methacryloyloxyethylphosphorus An acid choline polymer; 82% water content An amount; (a disc with a diameter of-2.5 mm, diameter of 40 microns

1385A

Ferentis

Storing at 2-8 deg.C

N/A

3

PEG-(CMP-RGD)-MPC

2-methylpropenes with RGD motif Glue of acyloxy ethyl phosphorylcholine A protomimetic peptide; 80% water content; (straight) Disc with diameter of 2.5mm, thickness: to 36 micron)

1444A

Ferrentis

Storing at 2-8 deg.C

N/A

4

PC-MPC

Porcine collagen/2-methacryloyloxy Ylethyl phosphorylcholine (PC-MPC) A polymer; 80% water content; (straight) Disc with diameter of 2.5mm, thickness: to 40 micron)

1442B

Ferentis

Storing at 2-8 deg.C

N/A

5

FIB-PEG-CMP-MPC

Fibronectin-polyethylene glycol-collagen Mimetic peptide-2-methacryloyloxy Ethyl phosphorylcholine; 80% water content An amount; (diameter: -2.5mm circle Dish, thickness of 32 micron)

1441

Ferrentis

Cold storage at 2-8 deg.C

N/A

6.

Biotrue

22% Nesofilcon a; 78% water Content (c); (diameter: -2.5mm circle Disc thickness of 45-micron'

TBD

Optics Medical

Storing at 2-8 deg.C

N/A

7 control system Article 1

PC-MPC

Porcine collagen/2-methacryloyloxy Ylethyl phosphorylcholine (PC-MPC) A polymer; 90% water content; (straight line) Disc with diameter of 2.5mm, thickness: to 40 micron)

1366B

Ferrentis

Storing at 2-8 deg.C

N/A

8 control system Article 2

Raindrop inlays

A Raindrop-near vision inlay; 78% water content; (diameter:. about. 2.0 mm inlay with a thickness of 34-34 mm Micron meter)

003450

Revision Optics

At room temperature

2021-01-16

Details of test article application

Examination before treatment

Before the study, each animal will receive an ophthalmic examination (slit-lamp biomicroscopy and indirect ophthalmoscopy) by the study chief or assistant chief. Ocular findings were scored according to the modified McDonald-shandduck scoring system (appendix a). The acceptance criteria in the study was a score of "0" for all variables.

Anaesthesia

Animals were anesthetized by IM injection of a mixture containing ketamine (up to about 50 mg/kg), glycopyrronium bromide (0.01 mg/kg, IM), and xylazine (up to about 10 mg/kg). Altemezole hydrochloride (up to 1 mg/kg) can be used as a reversal agent. One to two drops of topical proparacaine hydrochloride anesthetic (0.5%) were applied to the eyes of the animals prior to the injection procedure. Additional local ocular anesthetic administration may be used during surgery, if desired.

Surgical procedure for removal of an instant membrane

Since the nictitating membrane or the third eyelid was able to push out the test article, each rabbit removed the nictitating membrane from both eyes before placing the membrane. Since the human does not have a transitory membrane, the removal of these membranes provides a model that more closely mimics the human eye. The transient films were removed at least 10 days prior to application of the test article.

Animals were anesthetized as described above. Both eyes of each rabbit were cleaned with bitonal iodine (betadine) and then rinsed with Balanced Salt Solution (BSS). One to two drops of topical proparacaine hydrochloride anesthetic (0.5%) were applied to the nictitating membrane of each eye of the animal prior to the surgical procedure.

The instant membrane is grasped by a pair of forceps and gently grasped at its base by a pair of hemostats. After approximately 1 to 2 minutes of clamping, the clamps were removed and the instant membrane was cut with scissors along the clamping line according to SOP ASI-112. The area can be blotted dry and dosed with topical gentamicin (0.3%) and neodectron (1 to 2 drops). The contralateral eye was subjected to the same procedure to remove its nictitating membrane. Triple antibiotic ointment was applied topically once immediately after removal of the nictitating membrane. Rabbit post-operative recovery is described in SOP ASI-079, ASI-057 and ASI-102 (if catheter placement is required). Buprenorphine (0.02 to 0.05 mg/kg, IM/SC) may be injected once after removal of the nictitating membrane, if deemed necessary by the attending veterinarian. Any analgesic treatment will be equally administered to all study animals.

On the next day after surgery, animals were examined to ensure no postoperative complications. Animals received triple antibiotic ointment for up to 3 days post-operatively. Additional buprenorphine may be administered (this may be more than once) if deemed necessary by the attending veterinarian. In the event of a postoperative complication, the appropriate course of action for the research executive and/or veterinary personnel with respect to maintaining the health and welfare of the animal will be consulted. The eyes were allowed to heal for at least 10 days before the test article was applied as described below.

Surgical procedure for applying test articles

The test articles were implanted into the cornea of both eyes of all study animals on day 0 according to the study design in table 1. The implantation procedure will be performed by the designated surgeon. The laser, microkeratome, and surgical supplies will be provided by the host.

Animals were anesthetized as described above. Eyes were cleaned with iodine and then rinsed with BSS.

A flap or a prosthetic pocket is cut in each cornea using a laser or microkeratome. The type of surgery is noted in the study data.

The appropriate inlay for each eye is inserted into a valve or prosthetic capsular bag. The inserts were stained with 25% fluorescein (provided by the host) to facilitate visualization during the implantation procedure.

Following the surgical procedure, animals were recovered from anesthesia according to ASC SOP.

Analgesics (e.g., buprenorphine [0.01 to 0.05 mg/kg, IM/SC ]), antibiotics (e.g., triple antibiotic ointment or 0.3% tobramycin drops), and prednisolone as an anti-inflammatory therapy are administered on days 1-3 post-surgical procedure if deemed necessary by the attending physician and/or veterinarian. The analgesic, anti-inflammatory and/or antibiotic regimen may be extended or otherwise modified as desired based on the judgment of the investigator and/or attending veterinarian. Any such processing will be recorded in the raw data.

Safety precaution measures

The test articles were operated using standard laboratory safety procedures. In particular, gloves and lab coats, as well as appropriate animal feeding garments, are worn in preparation and application of the dose.

TABLE 1 study design

OD is right eye; OS left eye

The type of operation (laser flap, laser pseudocapsular bag or microkeratome flap) can be changed according to the judgment of the host

Indirect ophthalmoscopy during reading and writing only for baselines

Optional extension to monthly exams on some or all animals after day 180 (+ -4) according to host judgment increase #

α in the case of corneal lesions, animals can be euthanized and tissue collected earlier.

In vivo Observations of key study parameters (In-Life Observations) and summary of measurements are shown In appendix A.

Body weight

Animals were weighed before application of the test article and termination.

General health observations

Animals were observed once daily in their cages throughout the study period. Changes in the general appearance and behavior of each animal were observed. Any anomalous observations will be reported to the study director.

General health observations were made and recorded starting on day 0 and continuing daily throughout the study. Health observations include assessment of ocular abnormalities such as secretions, swelling, or congestion.

Slit lamp inspection

Slit lamp examinations were performed at baseline prior to application of the test article, and at days 7, 30 (+ -2), 60 (+ -2), 90 (+ -4), 120 (+ -4), 150 (+ -4), and 180 (+ -4) after application of the test article.

Additional monthly checks after day 180 (+ -4) may be added as an optional extension, at the discretion of the sponsor.

Slit lamp examinations will be performed by study chief or chief deputy and only the eye observation variables of the modified McDonald-shandduck scoring system (appendix a) related to corneal opacity/opaqueness are evaluated. The severity of corneal haze/opacity ("cornea") and the area ("surface area of affected cornea") were evaluated.

In addition, the examination included a score for corneal haze according to the study-specific scoring system (study-specific scoring system) presented in appendix B.

OCT imaging

Optical Coherence Tomography (OCT) images were taken at baseline and at day 14(± 1) and day 90(± 4) or before termination. More OCT time points can be added at the discretion of the sponsor.

OCT will be used to analyze corneal cross-section, device placement and geometry. An image is taken to capture any ocular abnormalities noted at the time of imaging. OCT examinations will be performed by the research master. All captured original images will be provided to the host.

The animal can be anesthetized as described above for OCT imaging.

Calculation and statistical analysis

The data will be presented in tabular form and no calculations or statistical analysis will be performed on the data collected during the life of the study.

Termination program (Terminal Procedures)

Premature death/unscheduled sacrifice

If the animals died in the study, the time of death was estimated and recorded as closely as possible. Animals can be subjected to necropsy; if so, a necropsy is performed as soon as possible. If necropsy could not be performed immediately, animals were refrigerated (not frozen) to minimize tissue autolysis. After discussion with the host, animals that terminated prematurely can be necropsied and marked for major organ findings.

If the animal dies as defined by SOP ASI-023 Care and Use of Animals, it is euthanized as described below, which complies with the animal humanity policy of ASC. An animal will be considered an indication of a moribund condition if it has any of the following signs: dysambulation that prevents the animal from accessing food or water, excessive weight loss and wasting (> 20%), lack of physical or mental alertness, difficulty breathing, or inability to remain upright. Animals with other less severe clinical signs will be treated (antibiotics or analgesics, fluids, etc.) or euthanized after discussion with the attending veterinarian and research director. Any surrogate endpoints (e.g., death, allowing the diseased animal to remain untreated and alive (i.e., moribund endpoints), etc.) must be justified in the study documentation.

Blood or other samples may be collected and analyzed as appropriate (e.g., with respect to clinical pathology parameters) to help reveal the cause of the discomfort/morbidity, if possible. Necropsy can be performed on all animals sacrificed outside the schedule. If so, necropsy was performed immediately, or if not, the animals were refrigerated to minimize autolysis and necropsy was performed no later than 12 hours after death. All the organizations listed in this scheme are saved.

The specific ocular endpoints (oculars) that must be treated and/or euthanized are:

eye infection

Ocular hemorrhage and congestion

Visual impairment manifested as abnormal behaviour, pain and/or distress in animals

Loss of ocular integrity

Corneal damage.

In the case of death or euthanasia of the animals during the study, termination procedures were performed according to SOP.

Death by peace and happiness

After completion of the final examination on day 90 (+ -4), animals were euthanized by intravenous injection of a commercial barbiturate-based euthanization solution (approximately 150 mg/kg to effect). If there is evidence of corneal damage, it is possible to euthanize the animal and collect the tissue earlier. At the discretion of the host, the day 90(± 4) euthanasia may be extended under weekly checks. The Euthanasia operation will be performed in accordance with the 2013 American Veteriary Medical Association (AVMA) Guidelines on Euthanasia.

Tissue collection tissue was collected according to the following method.

Method 1

Immediately after euthanasia, the anterior chamber of the eye was perfused with 2% Paraformaldehyde (PFA)/Phosphate Buffered Saline (PBS), pH 7.4 for 4 minutes to fix the cornea. Perfusion was performed using a hand-held syringe using a push-pull technique (two needles, one to push in PFA and one to pull out aqueous humor). Slow push/pull will serve to maintain the internal pressure of the eye and avoid damaging the cornea. After perfusion, the eyes were harvested. The cornea plus 1-2 mm of limbal tissue was removed using a scalpel to pierce and bend the corneal scissors. The remaining eyes will be discarded.

The excised cornea was placed in a refrigerated container containing 2% PFA. The container was sealed to prevent leakage or evaporation and immediately placed on wet ice until refrigerated storage at 2-8 ℃.

Samples collected by this method will be shipped on cold packs (on cold packs) by overnight transport (overnight shift) within 2 days of collection (to ensure that samples are received within 3 days of collection) to the host-designated laboratory.

Method 2

Eyes were harvested immediately after euthanasia. After trimming the excess tissue, the entire eyeball was placed in Davidson's solution. If desired, gauze pads should be used to keep the eyes submerged for consistent fixation. The eyes were placed in Davidson's solution for 48 hours. The eyes were then removed from the solution and placed in 70% ethanol.

Samples collected by this method were transported in 70% ethanol solution to a host designated laboratory.

A total of 32 corneas were collected.

Appendix A. improved MeDonald-Shadduek scoring system

(T, McDonald and J.A. Shadduck, "Eye understanding," in Advances in model society, edited by German society, F. Marzulli and H.I. Maibach, page 579-

And (4) checking:

the following were observed using a slit lamp:

pupillary response

Conjunctival secretions

Conjunctival congestion

Swelling of conjunctiva

Cornea

The surface area of the cornea affected

Corneal nebula

Room water flash

Aqueous humor cells

Iris Involvement (Iris invasion)

The lens.

The following were observed using an indirect ophthalmoscope:

glass glitter (Vitreous sparkle)

Vitreous body cells

Vitreous hemorrhage

Retinal detachment

Retinal hemorrhage

Choroidal/retinal inflammation.

Animals were prepared for observation by dilating their pupils using one of the three solutions. Generally two drops of an ophthalmic formulation of atropine, tropicamide or phenylephrine are sufficient. The selection of dilators is generally outlined in the study protocol. Wait until the pupil of the animal appears to dilate. It may take up to 60 minutes to achieve pupil dilation.

Pupillary response-any occlusion (block) or blunting response in the pupillary region is examined. Scoring will be performed as follows:

0= normal pupillary response

1= dull or incomplete pupillary response

2= no pupillary response

3= no pupillary response due to pharmacological block.

Conjunctival secretions-secretions are defined as white-grey deposits from the eye. Scoring will be performed as follows:

0= normal. No secretion.

1= secretions above normal and present inside the eye but not on the eyelids or eyelid hair.

2= large secretions, easily observed and collected on the eyelids and eyelid hair.

3= secretions have flowed through the eyelid to substantially moisturize hair on the skin surrounding the eye.

Conjunctival congestion causes the blood vessels of the eye to enlarge. Scoring will be performed as follows:

0= normal. May appear pale to pink with no perilimbal hyperemia (perilimbal injections) (except at the 12:00 and 6:00 positions), and vessels of the eyelid and bulbar conjunctiva are readily visible.

1= flushing, reddish color is primarily confined to the palpebral conjunctiva with some pericorneal hyperemia (perillbamal injection), but primarily to the lower and upper parts of the eye, 4:00 to 7:00 and 11:00 to 1:00 positions.

2= bright red color of the palpebral conjunctiva with perilimbal hyperemia (perilimbal injection) covering at least 75% of the periphery of the perilimbal area.

3= dark deep red (beefy red color), redness of both bulbar and palpebral conjunctiva, and also pronounced pericorneal redness (perilimbal observation) and petechiae in the conjunctiva. The petechiae point is usually mainly along the nictitating membrane and the upper palpebral conjunctiva.

Swelling of the conjunctiva (meaning swelling of the conjunctiva). Scoring will be performed as follows:

0= normal or no swelling of conjunctival tissue

1= swelling above normal, with no lid eversion (easily discernable by noting that the upper and lower eyelids are positioned as in a normal eye); swelling usually begins in the lower cul-de-sac near the inner canthus.

2= swelling, dislocation of normal approximation (normal approximation) of the lower and upper eyelids; primarily to the upper eyelid, so that in the initial phase, misapproximation of the eyelid begins with partial eversion of the upper eyelid. At this stage, swelling is usually limited to the upper eyelid, with some swelling in the lower cul-de-sac.

3= clear swelling, partial eversion of the upper and lower eyelids was substantially equal. This can be easily observed by looking at the animal frontally and noting the position of the eyelids; if the edge of the eye cannot be reached, eversion has already occurred.

4= eversion of the upper eyelid is evident, while eversion of the lower eyelid is less evident. It is difficult to retract the eyelids and observe the perilimbal area.

Cornea any abnormalities of the cornea were examined. Scoring will be performed as follows:

0= normal cornea

1= some loss of transparency. Only the anterior half of the epithelium and/or stroma is affected. The underlying structure is clearly visible, although some haze may be apparent.

2= total thickness of matrix. Under diffuse illumination, the underlying structures are hardly visible (flare, iris, pupil reaction and lens can still be observed).

3= total thickness of the matrix. Under diffuse illumination, the underlying structures are not visible.

Cornea affected surface area examination of the eye for haze in the stromal region. Scoring will be performed as follows:

0= normal

1= 1-25% of turbid area of substrate

2= 26-50% turbid area of substrate

3= 51-75% turbid area of the substrate

4= 76% -100% of the turbid area of the substrate.

Corneal nebula-examination of the vascularization of the cornea. Scoring will be performed as follows:

0= without corneal nebula (vascularization of cornea)

1= vascularization present, but the blood vessels have not yet invaded the entire corneal circumference.

2= the blood vessel has invaded 2 mm or more around the entire corneal surface.

Aqueous flare-up-the disruption of the blood-aqueous barrier. The field size is 1mm x 1mm slit beam. Scoring will be done as follows (based on Jabs DA et al, 2005):

0= none

1= weak

2= medium (clear iris and lens details)

3= significant (blurred iris and lens details)

4= strong (fibrin or plastic aqueous humor).

Aqueous humor cells cell observation in aqueous humor. The field size is 1mm x 1mm slit beam. Scoring will be done as follows (based on Jabs DA et al, 2005):

0= none

0.5= trace (1-5)

1=6-15

2=16-25

3=26-50

4=>50。

Iris Involvement (Iris invasion) the Iris is examined for vascular congestion. Scoring will be performed as follows:

0= normal iris without any vascular congestion.

1= Minimal congestion (Minimal injection) of secondary vessels but not tertiary vessels. Generally uniform, but may have higher strength at the 12:00 to 1:00 or 6:00 positions. If localized to this region, the tertiary vessels must be significantly engorged with blood.

2= Minimal hyperemia of tertiary vessels (Minimal injection) and Minimal to moderate hyperemia of secondary vessels.

3= Moderate hyperemia of secondary and tertiary vessels (Moderate injection), with slight swelling of the iris stroma (the iris surface appears slightly wrinkled, usually mainly around the 3:00 and 9:00 positions).

4= significant hyperemia of secondary and tertiary vessels (Marked injection), with significant swelling of the iris stroma. The iris looks wrinkled; may be accompanied by an anterior chamber hemorrhage (hyphema).

Lens-observation of the lens for any cataract. Scoring will be performed as follows:

0= lens clarity

1= anterior (cortex/sac)

2= kernel

3= posterior (cortical/optical)

4= equator (Equatorial).

Vitreous Flare (vitrous Flare) is the opacity or cloudiness of the Vitreous humor. Scoring will proceed as follows (based on Opremcak EM, 2012):

0= none (nerve fiber layer [ NFL ] is clearly visible)

1= faint (clear optic nerve and vessels, turbid NFL)

2= moderate (optic nerve and vascular opacity)

3= notably (optic nerve only visible)

4= strong (optic nerve not visible).

Vitreous body cell-cell observation in vitreous humor. Scoring will be done as follows (based on Opremcak EM, 2012):

0= trace (0-10)

1=11-20

2=21-30

3=31-100

4=>100。

Vitreous hemorrhage-any hemorrhage of the vitreous was observed. Scoring will be performed as follows:

0= none

1=1-25%

2=26-50%

3=51-75%

4=76-100%。

Retinal detachment during retinal detachment, bleeding from the small retinal blood vessels can obscure the interior of the eye, which is usually filled with vitreous humor. Scoring will be performed as follows:

0= none

1= porogenic (retinal detachment occurs when subretinal fluid accumulates in the potential space between the neurosensory retina and the underlying retinal pigment epithelium).

2= exudative (occurring due to inflammation, injury, or vascular abnormalities causing fluid to accumulate under the retina, without a hole, tear, or rupture).

3= tractional (which occurs when fibrous or fibrovascular tissue caused by injury, inflammation, or neovascularization pulls the sensory retina from the retinal pigment epithelium).

Retinal hemorrhage-abnormal hemorrhage of retinal blood vessels. Scoring will be performed as follows:

0= none

1=1-25%

2=26-50%

3=51-75%

4=76-100%。

Choroidal/retinal inflammation of the retina and/or choroid. Scoring will be performed as follows:

0= none

l = mild

2= medium

3= severe.

Reference documents:

Jabs DA, Nussenblatt RB, Rosenbaum JT, Standardization of Uveitis Nomenclature (SUN) Working Group (2005). Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. American Journal of Ophthalmology 140(3): 509-516.

Opremcak EM (2012). Uveitis: A Clinical Manual for Ocular Inflammation. New York: Springer Science + Business Media.

appendix B corneal opacity score

The haze rating is based on the scale used to grade haze after PRK, Arch, Ophthalmology (1992) (110): 1286-1291:

transparent (grade 0)Diffuse, peripheral, faint haze, (CLEAR CENTER), invisible with a diffuse slit lamp beam, minimally visible with a tilted or slit beam. Does not affect the vision.

Trace amount of turbidity (grade 1)Trace turbidity covers the mid-week (mid-peripheral) and center of the inlay. Difficult to see using diffuse illumination, visible by wide tangential illumination. May be accompanied by myopic wandering, reduced wear point, visual symptoms (glare and halos)

Slight (grade 2)

Medium (grade 3).

While the invention has been described with reference to specific embodiments thereof, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process step or steps, to the objective spirit and scope of the present invention. All such modifications are intended to be within the scope of the appended claims.

Claims (28)

1. A method of treating presbyopia, comprising placing a high water content corneal inlay device in a cornea of a mammalian subject, the corneal inlay device comprising a thickness, diameter, flat or quasi-flat bottom and a dome or microdroplet shaped top that forms a contact angle with the bottom, wherein the corneal inlay device is effective when placed in the cornea to: changing the shape of the anterior surface of the cornea, and increasing the ability of the eye to increase its power to focus on near objects while reducing the risk of developing corneal haze compared to controls.

2. The method of claim 1 wherein the corneal inlay device is placed by cutting a corneal flap in the cornea and placing the inlay under the flap.

3. The method of claim 1 wherein the corneal inlay device is placed by positioning the inlay device within a pocket formed in the cornea.

4. The method of claim 1, wherein the placement of the corneal inlay device is at a depth, including the endpoints, of about 100 microns to about 200 microns in the cornea.

5. The method of claim 1, wherein the placement of the corneal inlay device is at a depth, including the endpoints, of about 130 microns to about 160 microns in the cornea.

6. The method of claim 1, wherein the contact angle is between 1 ° and 180 °.

7. The method of claim 1, wherein the corneal inlay has a thickness of at least 25 microns, at least 26 microns, at least 27 microns, at least 28 microns, at least 29 microns, at least 30 microns, at least 31 microns, at least 32 microns, at least 33 microns, at least 34 microns, at least 35 microns, at least 36 microns, at least 37 microns, at least 38 microns, at least 39 microns, at least 40 microns, at least 41 microns, at least 42 microns, at least 43 microns, at least 44 microns, at least 45 microns, at least 46 microns, at least 47 microns, at least 48 microns, at least 49 microns, at least 50 microns, at least 51 microns, at least 52 microns, at least 53 microns, at least 54 microns, at least 55 microns, at least 56 microns, at least 57 microns, at least 58 microns, at least 59 microns, to 60 microns.

8. The method of claim 5, wherein the corneal inlay has a thickness of at least 32 microns, at least 33 microns, at least 34 microns, at least 35 microns, at least 36 microns, at least 37 microns, at least 38 microns, at least 39 microns, at least 40 microns, at least 41 microns, at least 42 microns, at least 43 microns, at least 44 microns, at least 45 microns, at least 46 microns, at least 47 microns, at least 48 microns, at least 49 microns, to 50 microns.

9. The method of claim 1, wherein the corneal inlay device has a diameter of at least 1mm, at least 1.1 mm, at least 1.2 mm, at least 1.3 mm, at least 1.4 mm, at least 1.5 mm, at least 1.6 mm, at least 1.7 mm, at least 1.8 mm, at least 1.9 mm, at least 2.0 mm, at least 2.1 mm, at least 2.2 mm, at least 2.3 mm, at least 2.4 mm, at least 2.5mm, at least 2.6 mm, at least 2.7 mm, at least 2.8 mm, at least 2.9 mm, or at least 3.0 mm.

10. The method of claim 1 wherein the corneal inlay device comprises water, a hydrophilic polymer, and a protein.

11. The method of claim 10, wherein the protein is an isolated protein, a recombinant protein, a synthetic protein, or a peptidomimetic.

12. The method of claim 10, wherein the hydrophilic polymer comprises polyethylene glycol ("PEG"), poly (2-Methacryloyloxyethyl Phosphorylcholine) (MPC), or both.

13. The method of claim 1 wherein the corneal inlay has a water content of at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%.

14. The method of claim 1, wherein the corneal inlay device is optically transparent, biocompatible, transparent, and refractive.

15. Use of a corneal inlay device having a high water content for treating presbyopia of a mammalian subject, the corneal device comprising a thickness, diameter, flat or similarly flat base and a dome or microdroplet shaped top that forms a contact angle with the base, wherein the inlay device when placed in the cornea is effective to change the shape of the anterior surface of the cornea and to increase the eye's ability to increase its power to focus on a proximal object while reducing the risk of developing corneal haze compared to a control.

16. The use of claim 15 wherein the corneal inlay device is placed by cutting a corneal flap in the cornea and placing the inlay under the flap.

17. The use of claim 15 wherein the corneal inlay device is placed by positioning the inlay device within a pocket formed in the cornea.

18. The use of claim 15, wherein the placement of the corneal inlay device is at a depth, including the endpoints, of about 100 microns to about 200 microns in the cornea.

19. The use of claim 15, wherein the corneal inlay device is placed at a depth, inclusive, of about 130 microns to about 160 microns in the cornea.

20. Use according to claim 15, wherein the contact angle is between 1 ° and 180 °.

21. The use of claim 15, wherein the corneal inlay has a thickness of at least 25 microns, at least 26 microns, at least 27 microns, at least 28 microns, at least 29 microns, at least 30 microns, at least 31 microns, at least 32 microns, at least 33 microns, at least 34 microns, at least 35 microns, at least 36 microns, at least 37 microns, at least 38 microns, at least 39 microns, at least 40 microns, at least 41 microns, at least 42 microns, at least 43 microns, at least 44 microns, at least 45 microns, at least 46 microns, at least 47 microns, at least 48 microns, at least 49 microns, at least 50 microns, at least 51 microns, at least 52 microns, at least 53 microns, at least 54 microns, at least 55 microns, at least 56 microns, at least 57 microns, at least 58 microns, at least 59 microns, to 60 microns.

22. The use of claim 15, wherein the corneal inlay has a thickness of 32 microns to 50 microns, inclusive, of at least 32 microns, at least 33 microns, at least 34 microns, at least 35 microns, at least 36 microns, at least 37 microns, at least 38 microns, at least 39 microns, at least 40 microns, at least 41 microns, at least 42 microns, at least 43 microns, at least 44 microns, at least 45 microns, at least 46 microns, at least 47 microns, at least 48 microns, at least 49 microns, or 50 microns.

23. The use of claim 15, wherein the corneal inlay device has a diameter of at least 1mm, at least 1.1 mm, at least 1.2 mm, at least 1.3 mm, at least 1.4 mm, at least 1.5 mm, at least 1.6 mm, at least 1.7 mm, at least 1.8 mm, at least 1.9 mm, at least 2.0 mm, at least 2.1 mm, at least 2.2 mm, at least 2.3 mm, at least 2.4 mm, at least 2.5mm, at least 2.6 mm, at least 2.7 mm, at least 2.8 mm, at least 2.9 mm, or at least 3.0 mm.

24. The use of claim 15, wherein the corneal inlay device comprises water, a hydrophilic polymer, and a protein.

25. The use of claim 24, wherein the protein is an isolated protein, a recombinant protein, a synthetic protein, or a peptidomimetic.

26. The use of claim 24, wherein the hydrophilic polymer comprises polyethylene glycol ("PEG"), poly (2-Methacryloyloxyethyl Phosphorylcholine) (MPC), or both.

27. The use of claim 15, wherein the corneal inlay has a water content of at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%.

28. The use of claim 15, wherein said corneal inlay device is optically clear, biocompatible, permeable, and refractive.