WO2022272082A1 - Dispositif médical d'onlay cornéen - Google Patents

Dispositif médical d'onlay cornéen Download PDF

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WO2022272082A1
WO2022272082A1 PCT/US2022/034931 US2022034931W WO2022272082A1 WO 2022272082 A1 WO2022272082 A1 WO 2022272082A1 US 2022034931 W US2022034931 W US 2022034931W WO 2022272082 A1 WO2022272082 A1 WO 2022272082A1
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onlay
comeal
microns
corneal
inclusive
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PCT/US2022/034931
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WO2022272082A8 (fr
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Gabriel N. NJIKANG
Alan Ngoc Le
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Rvo 2.0, Inc, D/B/A Optics Medical
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Publication of WO2022272082A8 publication Critical patent/WO2022272082A8/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/14—Eye parts, e.g. lenses, corneal implants; Implanting instruments specially adapted therefor; Artificial eyes
    • A61F2/145—Corneal inlays, onlays, or lenses for refractive correction
    • A61F2/1451—Inlays or onlays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/26—Mixtures of macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/16—Materials or treatment for tissue regeneration for reconstruction of eye parts, e.g. intraocular lens, cornea

Definitions

  • the described invention relates generally to medical devices, and more particularly to comeal onlays devices.
  • FIG. 1 is an illustration of a human eye.
  • the anatomy of the eye includes a conjunctiva, an iris, a lens, a pupil, a cornea, a sclera, a ciliary body, a vitreous body, an anterior chamber, a choroid, a retina, a macula, an optic nerve, and an optic disc.
  • the conjunctiva is a clear, thin membrane that covers part of the front surface of the eye and the inner surface of the eyelids.
  • the iris is a thin, circular structure made of connective tissue and muscle that surrounds the pupil and regulates the amount of light that strikes the retina.
  • the retina is a light-sensitive membrane on which light rays are focused.
  • Photoreceptors take light focused by the cornea and lens (a transparent, biconvex structure) and convert it into chemical and nervous signals which are transported to visual centers in the brain by way of the optic nerve.
  • the sclera is a 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 ciliary muscle (which alters the curvature of the lens), a series of radial ciliary processes (from which the lens is suspended by ligaments), and the ciliary ring (which adjoins the choroid).
  • the choroid is the pigmented vascular layer of the eye between the retina and the sclera.
  • the vitreous body is a transparent, colorless, semisolid mass composed of collagen fibrils and hyaluronic acid that fills the posterior cavity of the eye between the lens and the retina.
  • the anterior chamber is an aqueous humor-filled space inside the eye between the iris and the cornea’s innermost surface.
  • the macula is an oval shaped pigmented area near the center of the retina.
  • the optic disc is the raised disk on the retina at the point of entry of the optic nerve, which lacks visual receptors, thus creating a blind spot.
  • FIG. 2 is an illustration showing the cornea, which is avascular and exhibits the following five layers, from the anterior (nearer to the front) to posterior (nearer to the rear) direction: the epithelium, Bowman's layer, stroma, Descemet's membrane, and the endothelium.
  • the epithelium is a layer of cells that can be thought of as covering the surface of the cornea.
  • the cornea is covered externally by a stratified nonkeratinizing epithelium (5-6 layers of cells, about 50 microns in thickness) with three types of cells: superficial cells, wing cells and basal cells (deepest cell layer). Desmosomes form tight junctions in between the superficial cells.
  • the basal cells are the only corneal epithelial cells capable of mitosis; the basement membrane of epithelial cells is 40-60 nm in thickness and is made up of type IV collagen and laminin secreted by basal cells.
  • the epithelial layer is highly sensitive due to numerous nerve endings and has excellent regenerative power.
  • epithelium of central and peripheral cornea there are differences between epithelium of central and peripheral cornea.
  • the epithelium In the central cornea, the epithelium has 5-7 layers, the basal cells are columnar; there are no melanocytes or Langerhans cells, and the epithelium is uniform to provide a smooth regular surface.
  • the epithelium In the peripheral cornea, the epithelium is 7-10 layered, the basal cells are cuboidal, there are melanocytes and Langerhans cells, and there are undulating extensions of the basal layer. (Sridhar, M.S., “Anatomy of cornea and ocular surface,” Indian J. Ophthalmol. (2016) 66(2): 190-194).
  • Bowman membrane is structureless and acellular.
  • the stroma is the thickest layer of the cornea and gives the cornea much of its strength. Most refractive surgeries involve manipulating stroma cells. Specifically, the substantia basement (stroma) forms 90% of the cornea's thickness and is made up of keratocytes and extracellular matrix. Fibrils of the stroma crisscross at 90° angles; these fibrils are of types I, III, V, and VII collagen.
  • Descemet's membrane and the endothelium are considered the posterior portion of the cornea.
  • Descemet membrane is structureless, homogeneous, and measures 3- 12 microns; it is composed of the anterior banded zone and the posterior nonbanded zone; the Descemet membrane is rich in type IV collagen fibers.
  • the cornea is covered internally by the comeal endothelium, a single layer, 5 microns thick, of simple cuboidal and hexagonal cells with multiple orthogonal arrays of collagen in between.
  • the endothelium is derived from the neural crest and functions to transport fluid from the anterior chamber to the stroma. Because the cornea is avascular, its nutrients are derived mainly from diffusion from the endothelium layer. (Duong, H-V. Q. “Eye Globe Anatomy,” https://emedicine.medscape.com/article/1923010-0verview, updated Nov. 9, 2017).
  • the shape of the cornea is aspheric, meaning that it departs slightly from the spherical form.
  • the central cornea is about 3D steeper than the periphery.
  • the cornea is divided into zones that surround fixation and blend into one another.
  • the central zone of 1-2 mm closely fits a spherical surface.
  • Adjacent to the central zone is the paracentral zone, a 3-4 mm doughnut with an outer diameter of 7-8 mm that represents an area of progressive flattening from the center.
  • the paracentral and central zones constitute the apical zone.
  • the central and paracentral zones are primarily responsible for the refractive power of the cornea.
  • Adjacent to the paracentral zone is the peripheral zone, with an outer diameter of approximately 11 mm.
  • the peripheral zone is also known as the transitional zone, as it is the area of greatest flattening and asphericity of the normal cornea.
  • the optical zone is the portion of the cornea that overlies the entrance pupil of the iris; it is physiologically limited to approximately 5.4 mm because of the Stiles-Crawford effect (the reduction of the brightness when a light beam's entry into the eye is shifted from the center to the edge of the pupil has from the outset been shown to be due to a change in luminous efficiency of radiation when it is incident obliquely on the retina. (See G. Westheimer, “Directional sensitivity of the retina: 75 years of Stiles-Crawford effect,” Proc. R. Soc. B. (2008) 275 (1653): 2777-86).
  • the corneal apex is the point of maximum curvature.
  • the comeal vertex is the point located at the intersection of a subject’s line of fixation and the corneal surface. .
  • the cornea must be clear, smooth and healthy for good vision. If it is scarred, swollen, or damaged, light is not focused properly into the eye.
  • wound healing refers to the process by which the body repairs trauma to any of its tissues, especially those caused by physical means and with interruption of continuity.
  • a wound-healing response often is described as having three distinct phases- injury, inflammation and repair.
  • Injury often results in the disruption of normal tissue architecture, initiating a healing response.
  • the body responds to injury with an inflammatory response, which is crucial to maintaining the health and integrity of an organism.
  • the closing phase of wound healing consists of an orchestrated cellular re organization guided by a fibrin (a fibrous protein that is polymerized to form a “mesh” that forms a clot over a wound site)-rich scaffold formation, wound contraction, closure and re- epithelialization.
  • corneal epithelial healing largely depends on limbal epithelial stem cells (LESCs) stem cells, which, in many species, including humans, exclusively reside in the corneoscleral junction, and remodeling of the basement membrane.
  • LSCs limbal epithelial stem cells
  • LESCs In response to injury, LESCs undergo few cycles of proliferation and give rise to many transit-amplifying cells (TACS), which appear to make up most of the basal epithelium in the limbus and peripheral cornea.
  • TACS transit-amplifying cells
  • the LESCs are thought to migrate into the central cornea, proliferate rapidly afterwards, and eventually terminally differentiate into central comeal epithelial cells.
  • keratocytes During stromal healing, keratocytes get transformed to motile and contractile myofibroblasts largely due to activation of the transforming growth factor b system.
  • the kinetics of epithelial wound healing includes two distinct phases: an initial latent phase, and a closure phase.
  • the initial latent phase includes cellular and subcellular reorganization to trigger migration of the epithelial cells at the wound edge.
  • the closure phase includes several continuous processes starting with cell migration, which is independent of cell mitosis.
  • TLRs Toll-like receptors
  • NF-KB nuclear factor KB
  • MAP kinases MAP kinases
  • AP activator protein
  • TLR signaling pathway is activated in response to its ligands, such as pathogen associated molecular patterns (“PAMPs”, for viruses and bacteria) and damage- associated molecular patterns (DAMPs) as a result of tissue injury.
  • PAMPs pathogen associated molecular patterns
  • DAMPs damage- associated molecular patterns
  • IL-1 and TNF-a are activated to reorganize cellular and subcellular structures initiating cell migration, the first step of the healing process.
  • initial factors include IL-1 and TNF-a (Id., citing Wilson SE, et al. Stromal-epithelial interactions in the cornea. Prog. Retin. Eye Res. (1999) 18: 293-309), EGF and PDGF (Id., citing Tuominen, IS et al, Human tear fluid PDGF-BB, TNF-a and TGF-bI vs comeal haze and regeneration of comeal epithelium and subbasal nerve plexus after PRK. Exp. Eye Res.
  • EGFR transactivation has been shown to enhance intracellular signaling in corneal epithelial wound healing in the presence of non-EGF ligands, such as IGF, insulin and HGF, by activating ERK and PBK/Akt pathways (Id., citing Lyu J, Transactivation of EGFR mediates insulin- stimulated ERK1/2 activation and enhanced cell migration in human comeal epithelial cells. Mol. Vis. (2006) 12: 1403-1410; Spix JK, et al., Hepatocyte growth factor induces epithelial cell motility through transactivation of the epidermal growth factor receptor. Exp. Cell Res. (2007) 313: 3319-3325).
  • HGF Hepatocyte growth factor
  • KGF keratinocyte growth factor
  • PEDF pigment epithelium-derived factor
  • MMPs matrix metalloproteinases
  • ECM extracellular matrix
  • cellular nucleotides e.g., ATP
  • EGFR epidermal growth factor receptor
  • EGFR and purinergic signaling are also involved in the phosphorylation of paxillin, a focal adhesion-associated phosphotyrosine-containing protein that contains a number of motifs that mediate protein- protein interactions (see Schaller, MD, “Paxillin: a focal adhesion associated adaptor protein,” Oncogene (2001) 20: 6459-72) needed for cell migration (Id., citing Kimura K, et al., Role of JNK-dependent serine phosphorylation of paxillin in migration of corneal epithelial cells during wound closure. Invest. Ophthalmol. Vis. Sci. (2008) 49: 125-132; Mayo C, et al., Regulation by P2X7: epithelial migration and stromal organization in the cornea. Invest. Ophthalmol. Vis. Sci. (2008) 49: 4384-4391).
  • IGF1 Insulin-like growth factor 1
  • laminin-332 which facilitates epithelial cell migration in vitro
  • FGF-2-induced wound healing in comeal endothelial cells requires Cdc42 activation and Rho inactivation through the phosphatidylinositol 3-kinase pathway. Invest. Ophthalmol. Vis. Sci. (2006) 47: 1376-1386).
  • IGF1 receptor can also be engaged in cross-talk with b ⁇ chain-containing integrins important for comeal epithelial cell migration (Id., citing Seomun Y, Joo CK. Lumican induces human comeal epithelial cell migration and integrin expression via ERK 1/2 signaling. Biochem. Biophys. Res. Commun. (2008) 372: 221-225) through their recruitment to lipid rafts (Id., citing Salani B, et al., IGF-I induced rapid recruitment of integrin b ⁇ to lipid rafts is caveolin- 1 dependent. Biochem. Biophys. Res. Commun. (2009) 380: 489-492). Overall, significant cross-talk in corneal wound healing has been revealed between several growth factors through transactivation of signaling pathways, and between growth factors and extracellular mediators of this process. This cross-talk underlines the complex nature of epithelial wound healing.
  • Corneal epithelium makes its own ECM in the form of a specialized epithelial basement membrane that is positioned between basal epithelial cells and the stroma and apposed to the underlying collagenous Bowman’s layer. It provides structural support and regulates, through various receptors, epithelial migration, proliferation, differentiation, adhesion and apoptosis (Id., citing Azar DT, et ah, Altered epithelial-basement membrane interactions in diabetic corneas. Arch. Ophthalmol. (1992) 110: 537-40; Kurpakus MA, et ah, The role of the basement membrane in differential expression of keratin proteins in epithelial cells. Dev. Biol.
  • Corneal epithelial basement membrane is composed of specialized networks of type IV collagens, laminins, nidogens and perlecan, as are most basement membranes (Id., citing Nakayasu K, et ah, Distribution of types I, II, III, IV and V collagen in normal and keratoconus corneas. Ophthalmic Res. (1986) 18: 1-10; Martin GR, Timpl R. Laminin and other basement membrane components. Annu. Rev. Cell Biol.
  • Immune system cells such as neutrophils, play a major role in corneal epithelial wound healing, which might be due to their ability to release growth factors that impact the epithelium (Li Z, et al., Lymphocyte function-associated antigen- 1 -dependent inhibition of corneal wound healing. Am. J. Pathol. (2006) 169: 1590-600; Li Z, et al., Platelet response to corneal abrasion is necessary for acute inflammation and efficient re- epithelialization. Invest. Ophthalmol. Vis. Sci. (2006) 47: 4794-4802).
  • corneal epithelium The major function of corneal epithelium is to protect the eye interior by serving as a physical and chemical barrier against infection by tight junctions and sustaining the integrity and visual clarity of cornea.
  • IL-la The cytokine, IL-la, which is stored in epithelial cells and released when the cell membrane is damaged by external insults.
  • Secreted IL-la can cause increased immune infiltration of the cornea leading to neovascularization, which may result in visual loss.
  • Id The major function of corneal epithelium is to protect the eye interior by serving as a physical and chemical barrier against infection by tight junctions and sustaining the integrity and visual clarity of cornea.
  • IL-1RN an IL-la antagonist
  • IL-1RN prevents leucocyte invasion of the cornea and suppresses neovascularization, which may help preserve vision
  • corneal epithelial wounding prompts an acute inflammatory response in the limbal blood vessels leading to accumulation of leukocytes and neutrophils (Id., citing Li SD, Huang L. Non- viral is superior to viral gene delivery. J. Control Release.
  • Platelets also accumulate in the limbus and migrate to the stroma in response to wounded epithelium, which is necessary for efficient re- epithelialization through cell adhesion molecules such as P-selectin (Id., citing Li Z, et al., Platelet response to corneal abrasion is necessary for acute inflammation and efficient re- epithelialization. Invest. Ophthalmol. Vis. Sci.
  • the epithelial BM likely functions as a comeal regulatory structure that limits the fibrotic response in the stroma by modulating the availability of epithelium-derived TGF-bI, PDGF, and perhaps other growth factors and extracellular matrix components, to stromal cells, including myofibroblast precursors. (Id). It may also regulate levels of stromal cell-produced epithelial modulators of motility, proliferation, and differentiation like keratinocyte growth factor (KGF) that transition through the BM in the opposite direction.
  • KGF keratinocyte growth factor
  • Wilson SE et al., Hepatocyte growth factor, keratinocyte growth factor, their receptors, fibroblast growth factor receptor-2, and the cells of the cornea. Invest Ophthalmol Vis Sci.
  • corneal epithelial BM may modulate epithelial-to- stroma and stroma-to-epithelial interactions by regulating cytokines and growth factor movement from one cell layer to the other.
  • Latvala et al. observed that the distribution of a6 and b4 integrins adjacent to the BM changes during epithelial wound healing after epithelial abrasion in the rabbit cornea. (Id., citing Latvala T, et al, Distribution of alpha 6 and beta 4 integrins following epithelial abrasion in the rabbit cornea. Acta Ophthalmol Scand. (1996) 74: 21-25). Stepp et al. have demonstrated that the re-epithelialization of small wounds is accompanied by increased a6b4 integrin.
  • Stromal remodeling occurs upon direct damage to the stroma and its cells (as exemplified by photorefractive keratectomy (PRK) and LASIK (used for myopia correction)) and upon death of stromal cells (keratocytes) caused by damage to or removal of corneal epithelium by various physical or chemical factors (Id., citing Nakayasu K. Stromal changes following removal of epithelium in rat cornea. Jpn. J. Ophthalmol. (1988) 32: 113-125; Szerenyi KD, et ah, Keratocyte loss and repopulation of anterior comeal stroma after de- epithelialization. Arch. Ophthalmol.
  • Wilson SE et ah
  • Epithelial injury induces keratocyte apoptosis: hypothesized role for the interleukin- 1 system in the modulation of corneal tissue organization and wound healing.
  • Exp. Eye Res. (1996) 62:325- 327; Wilson SE, et al, The comeal wound healing response: cytokine mediated interaction of the epithelium, stroma, and inflammatory cells. Prog. Retin. Eye Res. (2001) 20: 625-637; Wilson SE, et al., Apoptosis in the initiation, modulation and termination of the comeal wound healing response.
  • Such damage triggers a release of inflammatory cytokines from epithelial cells and/or tears (Id., citing Maycock NJ, Marshall J. Genomics of comeal wound healing: a review of the literature. Acta Ophthalmol. (2014) 92: el70-84), mainly IL-1 (a and b) that cause rapid apoptosis through Fas/Fas ligand system and later, necrosis of mainly anterior keratocytes. These cells die preferentially directly beneath the epithelial wounds, rather than also beyond their edges.
  • the following stromal remodeling with replenishment of these cells from the areas adjacent to the depleted one (Id., citing Zieske JD, et al., Activation of epidermal growth factor receptor during comeal epithelial migration. Invest. Ophthalmol. Vis. Sci. (2000) 41: 1346-1355) also constitutes a wound healing process and may result in fibrotic changes, especially if the epithelial basement membrane was initially damaged (Id., citing Stramer BM, et al., Molecular mechanisms controlling the fibrotic repair phenotype in cornea: implications for surgical outcomes. Invest. Ophthalmol. Vis. Sci. (2003) 44:4237-4246; Fini ME, Stramer BM.
  • Fibroblasts downregulate the expression of differentiated keratocyte proteins, such as comeal crystallins (transketolase and aldehyde dehydrogenase 1A1), and keratan sulfate proteoglycans, and start producing proteinases (mostly MMPs) needed to remodel the wound ECM (Id., citing Fini ME. Keratocyte and fibroblast phenotypes in the repairing cornea. Prog. Retin. Eye Res. (1999) 18: 529-551; Jester JV, et ah, Corneal stromal wound healing in refractive surgery: the role of myofibroblasts. Prog. Retin. Eye Res.
  • fibroblasts After they reach the wound bed, fibroblasts start expressing a-smooth muscle actin (a-SMA) and desmin, upregulate the expression of vimentin (Id., citing Chaurasia SS, et ah, “Dynamics of the expression of intermediate filaments vimentin and desmin during myofibroblast differentiation after comeal injury” Exp. Eye Res. (2009) 89: 590-59), and become highly motile and contractile myofibroblasts needed to remodel wound ECM and contract the wound.
  • a-SMA a-smooth muscle actin
  • desmin upregulate the expression of vimentin (Id., citing Chaurasia SS, et ah, “Dynamics of the expression of intermediate filaments vimentin and desmin during myofibroblast differentiation after comeal injury” Exp. Eye Res. (2009) 89: 590-59), and become highly motile and contractile myofibroblasts needed to remodel wound ECM
  • Myofibroblasts generate contractile forces to close the wound gap, and the expression of a-SMA directly correlates with corneal wound contraction (Id., citing Jester JV, et al., Expression of alpha-smooth muscle (a-SM) actin during comeal stromal wound healing. Invest. Ophthalmol. Vis. Sci. (1995) 36: 809- 819).
  • a-SM alpha-smooth muscle
  • PTK phototherapeutic keratectomy
  • the appearance of myofibroblasts is delayed, and they start accumulating as late as four weeks after irregular PTK (Id., citing Barbosa FL, et al., Corneal myofibroblast generation from bone marrow-derived cells. Exp. Eye Res. (2010) 91:92-96).
  • TGF-b transforming growth factor beta
  • Corneal injury in animal models entails an inflammatory response by immune system cells, including monocytes/macrophages, T cells, polymorphonuclear (PMN) leukocytes and natural killer (NK) cells (Id., citing Gan L, et ak, Effect of leukocytes on comeal cellular proliferation and wound healing. Invest. Ophthalmol. Vis. Sci. (1999) 40: 575-581; Wilson SE, et ah, The corneal wound healing response: cytokine mediated interaction of the epithelium, stroma, and inflammatory cells. Prog. Retin. Eye Res.
  • infiltrating cells are usually defined by staining for CDllb, although in some studies a better characterization of these cells is provided (Id., citing Wilson SE, et ah, The comeal wound healing response: cytokine mediated interaction of the epithelium, stroma, and inflammatory cells. Prog. Retin. Eye Res. (2001) 20: 625-637; Liu Q, et ah, NK Cells Modulate the Inflammatory Response to Comeal Epithelial Abrasion and Thereby Support Wound Healing. J. Pathol. (2012) 181: 452-462; Li S, et ah, Macrophage depletion impairs comeal wound healing after autologous transplantation in mice. PLoS One.
  • Immune cells may come to the injured cornea from the limbal area or are mobilized from circulation (Id., citing Wilson SE, et ah, The corneal wound healing response: cytokine mediated interaction of the epithelium, stroma, and inflammatory cells. Prog. Retin. Eye Res. (2001) 20: 625-637).
  • a major attracting signal for such cells may be monocyte chemotactic protein- 1 (MCP-1), a cytokine, which can be secreted by activated fibroblasts and triggered by IL-1 or TNF-a (Id., citing Wilson SE, et ah, The comeal wound healing response: cytokine mediated interaction of the epithelium, stroma, and inflammatory cells. Prog. Retin. Eye Res. (2001) 20: 625-637). Another factor required for neutrophil influx following injury was identified as a stromal proteoglycan lumican (Id., citing Hayashi Y, et ah, Lumican is required for neutrophil extravasation following comeal injury and wound healing. J. Cell Sci.
  • MCP-1 monocyte chemotactic protein- 1
  • TNF-a TNF-a
  • Another factor required for neutrophil influx following injury was identified as a stromal proteoglycan lumican (Id., citing Hayashi
  • myofibroblasts Id., citing Barbosa FL, et al., Corneal myofibroblast generation from bone marrow-derived cells. Exp. Eye Res. (2010) 91: 92-96
  • Direct involvement of immune cells in the wound healing has been also suggested from recent studies. Blocking PMN entry into cornea by fucoidin (inhibitor of leucocyte adhesion to vascular endothelium) delayed wound healing after PRK in rabbits (Id., citing Gan L, et al., Effect of leukocytes on comeal cellular proliferation and wound healing. Invest. Ophthalmol. Vis. Sci. (1999) 40: 575-581).
  • stromal wound healing is accompanied by several events that may be responsible for ECM changes in this location: death of keratocytes, secretion of proinflammatory and profibrotic cytokines including IL-1, TNF-a, and MCP-1, transient appearance of cells that do not normally form the stroma (PMNs, macrophages, myofibroblasts), and production of ECM-degrading enzymes by activated cells.
  • death of keratocytes secretion of proinflammatory and profibrotic cytokines including IL-1, TNF-a, and MCP-1
  • transient appearance of cells that do not normally form the stroma PMNs, macrophages, myofibroblasts
  • production of ECM-degrading enzymes by activated cells production of ECM-degrading enzymes by activated cells.
  • ECM remodeling including its degradation, expression of ectopic components (provisional matrix formation by new cell types), and reassembly of the new ECM to form a more or less normal structure (Id., citing Zieske JD, et al., Kinetics of keratocyte proliferation in response to epithelial debridement. Exp. Eye Res. (2001) 72: 33- 39; Torricelli AA, Wilson SE. Cellular and extracellular matrix modulation of comeal stromal opacity. Exp. Eye Res. (2014) 129: 151-160). As a result, new ECM formed during wound healing often accumulates aberrant proteins, both in composition and structure.
  • These components which are normally scarce in or absent from adult corneal stroma, include type III, VIII, XIV, and XVIII collagen, limbal isoforms of type IV collagen, embryonic fibronectin isoforms, thrombospondin- 1 (TSP-1), tenascin-C, fibrillin-1, and hevin (an ECM- associated secreted glycoprotein belonging to the secreted protein acidic and rich in cysteine (SPARC) family of matricellular proteins (Id., citing Saika S, et al., Epithelial basement membrane in alkali-burned corneas in rats. Immunohistochemical study. Cornea.
  • Keratocyte activation to fibroblasts is mediated by FGF-2, TGF-b, and PDGF, and their proliferation, by EGF, HGF, KGF, PDGF, IL-1 and IGF-I (Id., Citing Stem ME, et al., Effect of platelet-derived growth factor on rabbit comeal wound healing. Wound Repair Regen. (1995) 3: 59-65; Baldwin HC, Marshall J. Growth factors in corneal wound healing following refractive surgery: A review. Acta. Ophthalmol. Scand. (2002) 80: 238-247; Jester JV, Ho-Chang J. Modulation of cultured corneal keratocyte phenotype by growth factors/cytokines control in vitro contractility and extracellular matrix contraction.
  • TGF-b is key to fibroblast to myofibroblast transformation, it actually inhibits keratocyte proliferation and migration (Id., citing Baldwin HC, Marshall J.
  • TGF-b isoforms 1 and 2 (Id., citing Torricelli AA, Wilson SE. Cellular and extracellular matrix modulation of corneal stromal opacity. Exp. Eye Res. (2014) 129: 151-160), as well as bone morphogenetic protein 1 (BMP-1), which is capable of inducing formation of cartilage in vivo (Id., citing Malecaze F, et ah, Upregulation of bone morphogenetic protein- 1 /mammalian tolloid and procollagen C- proteinase enhancer-1 in comeal scarring. Invest. Ophthalmol. Vis. Sci.
  • TGF-b may be responsible for myofibroblast emergence, wound contraction and fibrotic scar formation.
  • TGF-b also promotes deposition of excessive ECM in the wound bed that may result in scar formation directly, as well as by stimulating production of other factors including connective tissue growth factor (CTGF) and IGF-I (Id., citing Izumi K, et ah, Involvement of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in comeal fibroblasts during comeal wound healing.
  • CGF connective tissue growth factor
  • IGF-I IGF-I
  • topical rosiglitazone a ligand of peroxisome proliferator activated receptor g (PPAR-g) reduced a-SMA expression and scarring in cat corneas upon excimer laser ablation of anterior stroma without compromising wound healing.
  • PPAR-g peroxisome proliferator activated receptor g
  • Inhibitors of mechanistic target of rapamycin (mTOR) and p38 MAP kinase signaling were able to markedly reduce the expression of a-SMA and collagenase in corneal cells and injured corneas (Id., citing Jung JC, et al., Constitutive collagenase-1 synthesis through MAPK pathways is mediated, in part, by endogenous IL-la during fibrotic repair in corneal stroma. J. Cell Biochem. (2007) 102: 453-462; Huh MI, et al., Distribution of TGF-b isoforms and signaling intermediates in corneal fibrotic wound repair. J. Cell Biochem.
  • corneal endothelial cells especially human, have very low proliferation rates (Id., citing Mimura T, et al., Corneal endothelial regeneration and tissue engineering. Prog. Retin. Eye Res. (2013) 35: 1- 17). It is generally considered that corneal endothelium closes the wound gap mainly by migration and increased cell spreading. These two processes are pharmacologically separable and, depending on the wound nature, their relative contribution may vary (Id., citing Joyce NC, et al., In vitro pharmacologic separation of corneal endothelial migration and spreading responses. Invest. Ophthalmol. Vis. Sci.
  • FGF-2-induced wound healing in corneal endothelial cells requires Cdc42 activation and Rho inactivation through the phosphatidylinositol 3-kinase pathway.
  • Invest. Ophthalmol. Vis. Sci. (2006) 47:1 376-1386 although this view is challenged by the fact that healing corneal endothelial cells mostly divide amitotically, with formation of binuclear cells (Id., citing Landshman N, et al., Cell division in the healing of the corneal endothelium of cats. Arch. Ophthalmol. (1989) 107: 1804-1808).
  • Endothelial wound healing is associated with a transient acquisition of fibroblastic morphology and actin stress fibers by migrating cells, which is consistent with endothelial-mesenchymal transformation (EnMT) (Id., citing Lee HT, et al., FGF-2 induced by interleukin- 1 beta through the action of phosphatidylinositol 3-kinase mediates endothelial mesenchymal transformation in corneal endothelial cells. J. Biol. Chem. (2004) 279: 32325- 32332; Miyamoto T, et al., Endothelial mesenchymal transition: a therapeutic target in retrocomeal membrane. Cornea.
  • Inducers of EnMT and fibrotic changes in the endothelial layer include FGF-2, which may come from PMNs migrating to the cornea during epithelial and stromal wound healing (Id., citing Lee HT, et al., FGF-2 induced by interleukin- 1 beta through the action of phosphatidylinositol 3-kinase mediates endothelial mesenchymal transformation in comeal endothelial cells. J. Biol. Chem.
  • IL- 1b citing Lee JG, et al., Endothelial mesenchymal transformation mediated by IL-Ib- induced FGF-2 in corneal endothelial cells. Exp. Eye Res. (2012) 95: 35-39
  • TGF-b Id. citing Sumioka T, et al., Inhibitory effect of blocking TGF ⁇ /Smad signal on injury-induced fibrosis of corneal endothelium. Mol. Vis. (2008) 14: 2272-2281).
  • EnMT may lead to fibrotic complications of healing, such as the formation of retrocorneal fibrous membrane, (Id., citing Ichijima H, et al., In vivo confocal microscopic studies of endothelial wound healing in rabbit cornea. Cornea. (1993) 12: 369-378.), some ways of attenuating EMT have been proposed. These include inhibiting the expression of connexin 43 (Id., citing Nakano Y, et al., Connexin 43 knockdown accelerates wound healing but inhibits mesenchymal transition after corneal endothelial injury in vivo. Invest. Ophthalmol. Vis. Sci.
  • TGF-b type I receptor (Id., citing Okumura N, et al., Inhibition of TGF-b signaling enables human comeal endothelial cell expansion in vitro for use in regenerative medicine. PLoS One. (2013) 8: e58000). The latter technique also facilitates endothelial cell propagation in culture.
  • ECM proteins fibronectin and transpondin 1 were shown to facilitate cell migration (Id., citing Munjal ID, et al., Thrombospondin: biosynthesis, distribution, and changes associated with wound repair in corneal endothelium. Eur. J. Cell Biol. (1990) 52:252-263; Gundorova RA, et al., Stimulation of penetrating comeal wound healing by exogenous fibronectin. Eur. J. Ophthalmol.
  • FGF-2 stimulates migration through several pathways including p38, PBK/Akt, and protein kinase C/phospholipase A2 (Id., citing Rieck PW, et ah, Intracellular signaling pathway of FGF-2-modulated corneal endothelial cell migration during wound healing in vitro. Exp. Eye Res. (2001) 73: 639-650; L Lee HT, et ah, FGF-2 induced by interleukin-1 beta (IL-Ib) through the action of phosphatidylinositol 3-kinase mediates endothelial mesenchymal transformation in comeal endothelial cells. J. Biol. Chem.
  • IL-Ib interleukin-1 beta
  • IL-Ib stimulates migration through induction of FGF-2 (Id., citing Lee JG, et ah, Endothelial mesenchymal transformation mediated by IE-Ib-induced FGF-2 in comeal endothelial cells. Exp. Eye Res. (2012) 95: 35-39), as well as induction of Wnt5a that activate Cdc42 and inactivate RhoA (Id., citing eLe JG, Kay EP.
  • FGF-2-induced wound healing in corneal endothelial cells requires Cdc42 activation and Rho inactivation through the phosphatidylinositol 3-kinase pathway. Invest. Ophthalmol. Vis. Sci. (2006) 47:1376-1386; Lee JG, Heur M. Interleukin- 1b enhances cell migration through activator protein 1 (AP-1) and NF-KB pathway-dependent FGF2 expression in human comeal endothelial cells. Biol. Cell. (2013) 105:175-189 Lee JG, Heur M. Interleukin- 1b -induced Wnt5a enhances human comeal endothelial cell migration through regulation of Cdc42 and RhoA. Mol. Cell Biol. (2014) 34: 3535-3545). In the endothelial cells, interleukin- 1b stimulates cell migration directly and indirectly.
  • a diseased cornea may be replaced surgically with a clear, healthy cornea from a human donor (corneal transplantation) by a number of methods.
  • Phototherapeutic keratectomy is a type of laser eye surgery that is used to treat comeal dystrophies (meaning abnormal buildup of foreign material in the cornea), corneal scars, and some comeal infections.
  • comeal dystrophies meaning abnormal buildup of foreign material in the cornea
  • corneal scars meaning abnormal buildup of foreign material in the cornea
  • comeal infections meaning abnormal buildup of foreign material in the cornea
  • corneal scars meaning abnormal buildup of foreign material in the cornea
  • comeal dystrophies meaning abnormal buildup of foreign material in the cornea
  • comeal dystrophies meaning abnormal buildup of foreign material in the cornea
  • corneal scars corneal scars
  • comeal infections a laser to remove thin layers of diseased cornea tissue microscopically, allowing new tissue to grow on the smooth surface.
  • DALK deep anterior lamellar keratoplasty
  • partial thickness comeal transplant is performed; only the front and middle layers of the cornea are removed, with the endothelial layer kept in place.
  • Healing time after DALK is shorter than after a full corneal transplant. There is also less risk of having the new cornea rejected.
  • DALK is commonly used to treat keratoconus or bulging of the cornea.
  • PK penetrating keratoplasty
  • full thickness comeal transplant is performed to remove and replace the damaged cornea.
  • PK has a longer recovery period than other types of comeal transplants. Getting complete vision back after PK may take up to 1 year or longer. With a PK, there is a slightly higher risk than with other types of comeal transplants that the cornea will be rejected.
  • Endothelial keratoplasty is a surgery to replace this layer of the cornea with healthy donor tissue. It is known as a partial transplant since only the endothelium is replaced.
  • types of endothelial kertoplasty include DSEK (or DSAEK) — Descemet's Stripping (Automated) Endothelial Keratoplasty, and DMEK — Descemet's Membrane Endothelial Keratoplasty. Each procedure removes damaged cells from Descemet’s membrane by removing the damaged corneal layer through a small incision, and putting the new tissue in place. Much of the cornea is left untouched.
  • the eye lens is a flexible transparent biconvex structure embedded in the anterior segment of the eye and held in place by a ring of ciliary muscle.
  • the main function of the lens alongside the cornea is to refract incoming light to be focused on the retina.
  • the ciliary muscles help the lens change its shape, thereby changing its focal length. This process, which is generally referred to as accommodation, enables objects at various distances to be focused on the retina, producing sharp images.
  • Accommodation refers to the increase in thickness and convexity of the eye’s lens in response to ciliary muscle contraction in order to focus the image of an external object on the retina.
  • amplitude of accommodation refers to the difference in refractivity of the eye at rest and when fully accommodated.
  • the refractive power of the human eye is measured in diopters, which is a unit of measurement of the optical power of a lens and is equal to the reciprocal of the focal length measured in meters.
  • the total refractive power (optical power) of the relaxed eye is approximately 60 diopters.
  • the cornea accounts for approximately two-thirds of the refractive power (i.e., 40 diopters) and the lens accounts for the remaining one-third of the refractive power (i.e., 20 diopters).
  • Emmetropia refers to an eye that has no visual defects. It is the state of vision where a faraway object at a distance of infinity is in sharp focus with the eye lens in a neutral or relaxed state. An emmetropic eye does not require vision correction.
  • Abnormalities in the human eye can lead to vision impairment such as myopia (near-sightedness), hyperopia (farsightedness), astigmatism, and presbyopia.
  • Myopia occurs when the human eye is too long, relative to the focusing power of the cornea and the lens of the eye. This causes light rays to focus at a point in front of the retina, rather than directly on its surface.
  • Hyperopia or farsightedness
  • Astigmatism is a vision condition that causes blurred vision and occurs when the cornea is irregularly shaped. This prevents light rays from focusing properly on the retina.
  • Presbyopia is generally characterized by a decrease in the eye's ability to increase its power to focus on nearby objects due to, for example, a loss of elasticity in the crystalline lens that occurs over time.
  • young people under the age of 40 can easily focus both on distance and near objects.
  • Near objects can be seen clearly due to contraction of the ciliary muscle resulting in increase in lens curvature.
  • the focal length of the lens decreases, and the image of the object is focused on the retina.
  • the ciliary muscles progressively weaken and the lens starts to lose elasticity. Accommodation starts decreasing, making it difficult to see intermediate and near objects. This deficiency, which worsens as we age, is known as presbyopia.
  • presbyopia is to wear reading glasses.
  • Other solutions include multifocal or monovision contact lenses, monovision presbyopia-correcting Intraocular Lens (IOLs), LASIK, multifocal LASIK, conductive keratoplasty (a surgical procedure that uses low level radiofrequency energy to reshape the cornea) and refractive lens exchange.
  • IOLs monovision presbyopia-correcting Intraocular Lens
  • LASIK monovision presbyopia-correcting Intraocular Lens
  • multifocal LASIK multifocal LASIK
  • conductive keratoplasty a surgical procedure that uses low level radiofrequency energy to reshape the cornea
  • ophthalmic devices and/or procedures can be used to address presbyopia using three common approaches.
  • the diopter power of one eye is adjusted to focus distant objects and the power of the second eye is adjusted to focus near objects.
  • the appropriate eye is used to clearly view the object of interest.
  • multifocal or bifocal optics are used to simultaneously, in one eye, provide powers to focus both distant and near objects.
  • One common multifocal design includes a central zone of higher diopter power to focus near objects, surrounded by a peripheral zone of the desired lower power to focus distant objects.
  • the diopter power of one eye is adjusted to focus distance objects, and in the second eye a multifocal optical design is induced by the intracorneal inlay.
  • the subject therefore has the necessary diopter power from both eyes to view distant objects, while the near power zone of the multifocal eye provides the necessary power for viewing near objects.
  • the multifocal optical design is induced in both eyes. Both eyes therefore contribute to both distance and near vision.
  • LASIK Laser-assisted in situ keratomileusis
  • Corneal inlays are one of the options used to correct near vision in people with presbyopia.
  • a comeal inlay is an implant that is surgically inserted within the cornea beneath a portion of corneal tissue to increase the depth of focus or the refractive power of the central or paracentral cornea. Comeal inlays do not restore the ability to accommodate.
  • Corneal inlays can be positioned by, for example, cutting a flap in the cornea and positioning the inlay beneath the flap. The corneal flap is created by making an incision in the comeal tissue and separating the comeal tissue from the underlying stroma, with one segment remaining attached, which acts like a hinge.
  • the comeal inlay can also be positioned within a pocket (meaning a sac-like cavity) formed in the cornea.
  • Comeal inlays can alter the refractive power of the cornea by changing the shape of the anterior surface of the cornea, by creating an optical interface between the cornea and an implant by having an index of refraction different from that of the cornea (i.e., has intrinsic power), or both.
  • the cornea is the strongest refracting optical element in the eye, and altering the shape of the anterior surface of the cornea can therefore be a particularly useful method for correcting vision impairments caused by refractive errors.
  • the anterior comeal surface radius of curvature is assumed to be equal to the thickness of the lamellar comeal material (i.e., flap) between the anterior corneal surface and the anterior surface of a comeal inlay plus the radius of curvature of the anterior surface of the inlay.
  • a synthetic comeal onlay is an alternative approach to refractive correction that offers an adjustable and reversible procedure with minimal surgical intervention of the central optical zone. [See Evans, MDM et al., Progress in the Development of a Synthetic Corneal Onlay,” Investigative Ophthalmology & Visual Sci. (2002) 43 (10): 3196-3201].
  • a comeal onlay as currently conceptualized requires debridement or removal of the comeal epithelium and placement of a synthetic lenticule on the exposed stromal surface, leaving Bowman’s membrane intact.
  • the onlay material be transparent, nontoxic, biocompatible, biostable, and nutrient permeable and have surface characteristics that permit the migration and persistent adhesion of comeal epithelial tissue.
  • the present disclosure provides a corneal onlay device that comprises a biocompatible hydrogel molded with a water content ranging from 78% to 92% (w/w), inclusive , and describes in vitro assays supporting biocompatibility and its support for epithelial growth.
  • the described invention provides a corneal onlay device of water content ranging from about 78% to about 92% (w/w), inclusive to treat presbyopia that can be removed and replaced without invasive surgical intervention while decreasing or eliminating the risk of a patient developing comeal haze.
  • the comeal onlay implant is fabricated or formed from a hydrogel.
  • the hydrogels can be synthesized using a combination of biopolymers and synthetic monomers and/or polymers. The addition of a synthetic polymer not only improves the mechanical properties of the onlay, but also minimizes swelling, improves manufacturability/processability, and minimizes in-vivo degradation of corneal onlays.
  • the present disclosure also provides methods of making and characterization of the molded onlays for correcting presbyopia.
  • the present disclosure also describes an in- vitro method to confirm biocompatibility of the exemplary onlays and their ability to support epithelial growth.
  • the present disclosure also provides a method of treating presbyopia comprising placing on top of Bowman’s membrane of a mammalian subject a comeal onlay device comprising a water content ranging from about 78% to about 92% (w/w), inclusive. According to another aspect, the present disclosure provides a method of making the comeal onlay.
  • the present disclosure provides a method for providing visual correction for presbyopia without damaging the cornea/leaving cornea substantially intact, comprising exposing a surface of Bowman’s membrane by removing the comeal epithelium cell layer; gently cleaning the exposed surface of Bowman’s membrane; placing the corneal implant device and a material effective to adhere the corneal onlay onto the clean exposed surface of Bowman’s membrane; placing a protective contact lens over the onlay; allowing the epithelial layer to regrow on top of the onlay; and removing the contact lens without disturbing placement of the onlay once the epithelial layer is restored by the regrowth.
  • the method may provide correction of presbyopia without invasive surgical intervention.
  • the described invention provides a method of treating presbyopia comprising implanting on a comeal surface of a mammalian subject a corneal onlay device of water content ranging from 78% to 92% % (w/w), the corneal onlay device comprising a thickness, a diameter, a flat or flat-like base and a dome-shaped top, wherein the comeal onlay device, is effective to alter a shape of the anterior surface of a cornea, and to increase an eye's ability to increase its power to focus on nearby objects, with a reduced risk of development of corneal haze compared to a control.
  • the implanting of the comeal onlay device is by removing a portion of an epithelial layer of the cornea and positioning the corneal onlay device on a cleaned surface of Bowman’s membrane of the cornea beneath the epithelial layer.
  • the portion of the epithelial layer is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.
  • the implanting of the comeal onlay device is by positioning the comeal onlay device on a cleaned surface of a Bowman’s membrane of the cornea.
  • the cleaned surface is a surface of the Bowman’s membrane of the cornea cleaned with a composition comprising mitomycin C (MMC) and isotonic sterile saline.
  • the cleaned surface is a surface of the Bowman’s membrane of the cornea cleaned with a composition comprising mitomycin C (MMC) and isotonic sterile saline.
  • the thickness of the comeal onlay device is at least 10 microns, at least 11 microns, at least 12 microns, at least 13 microns, at least 14 microns, at least 15 microns, at least 16 microns, at least 17 microns, at least 18 microns, at least 19 microns, at least 20 microns, at least 21 microns, at least 22 microns, at least 23 microns, at least 24 microns, at least 25 microns, at least 26 microns, at least 27 microns, at least 28 microns, at least 29 microns, or at least 30 microns.
  • the thickness of the corneal onlay ranges from at least 20 microns, at least 21 microns, at least 22 microns, at least 23 microns, at least 24 microns, at least 25 microns, at least 26 microns, at least 27 microns, at least 28 microns, at least 29 microns, to 30 microns.
  • a diameter of the comeal onlay device is at least 1 mm, 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 2.5 mm, 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.
  • the comeal onlay device is molded from a hydrogel.
  • the corneal onlay device comprises water, a natural polymer, and two synthetic polymers, the two synthetic polymers forming an interpenetrating polymer network, wherein the synthetic polymers and the natural polymer are at least partially interlaced on a molecular scale but not covalently bonded to each other and cannot be separated.
  • the natural polymer is a collagen.
  • the collagen is a porcine collagen.
  • a hydrogel for fabricating the corneal onlay device comprise at least 1%, at least 2%, at least 3%, at least 4%, or at least 5% by weight of the natural polymer.
  • one of the two synthetic polymers is poly(2-methacryloyloxyethyl phosphorylcholine) (MPC).
  • one of the two synthetic polymers is Poly(ethylene glycol) diacrylate (PEGDA).
  • the water content of the comeal onlay device ranges from about 70% to about 90%, inclusive.
  • the water content of the comeal onlay device ranges from about 78% to about 88%, inclusive.
  • the water content of the comeal onlay device ranges from about 78% to about 84%, inclusive.
  • the comeal onlay device is optically transparent, biocompatible, gas permeable and refractive.
  • the described invention provides a method for providing vision correction for presbyopia without damaging the cornea/leaving cornea substantially intact, the method comprising exposing a surface of Bowman’s membrane by removing a comeal epithelium cell layer, gently cleaning the exposed surface of the Bowman’s membrane, implanting a corneal implant device and optionally an adhesive material effective to adhere the comeal implant device onto the clean exposed surface of the Bowman’s membrane, wherein the corneal implant device is a corneal onlay, placing a protective contact lens over the comeal implant device in situ for at least 24 hr allowing the comeal epithelium cell layer to regrow over the corneal implant device, and removing the protective contact lens without disturbing placement of the corneal implant device, wherein the method may provide correction of presbyopia without invasive surgical intervention.
  • the described invention provides use of a corneal onlay device with low water content to treat presbyopia in a mammalian subject, the comeal device comprising a thickness, a diameter, a flat or flat-like base and a dome-shaped top, wherein the corneal onlay device when placed on a surface of the cornea is effective to alter a shape of the anterior surface of a cornea and to increase an eye's ability to increase its power to focus on nearby objects with a reduced risk of development of corneal haze, compared to a control.
  • the described invention provides a corneal onlay device for treating presbyopia, comprising a body defining a thickness, a diameter, a flat or flat-like base, and a dome-shaped top, wherein thickness is from 10 microns to 30 microns, inclusive, wherein the corneal onlay device is fabricated from a hydrogel composition comprising an interpenetrating polymer network of two polymers at least partially interlaced on a molecular scale but not covalently bonded to each other that cannot be separated, comprising a low water content of between 78%-92%, inclusive; and wherein in vitro, the hydrogel composition remains stable for at least two years.
  • FIG. 1 shows an illustrative view of the human eye; (from Allaboutvision.com/resources/anatomy.htm, Accessed March 2019).
  • FIG. 2 shows an illustrative view of the five layers of the cornea.
  • FIG. 3 shows an illustrative view of the effects of presbyopia on the human eye.
  • FIG. 4 shows an illustrative embodiment of the corneal onlay device of the present disclosure.
  • FIG. 5 is a diagram showing the comeal onlay of the present disclosure implanted under an epithelium layer of a cornea.
  • FIG. 6 shows an example of how a corneal onlay can provide near vision to a subject's eye while retaining some distance vision according to an embodiment of the present disclosure.
  • FIG. 7 is a graph showing a change in anterior comeal surface height and the corresponding induced added power.
  • FIG. 8 is a perspective view of an exemplary mold assembly for fabricating an exemplary hydrogel onlay in accordance with the present disclosure.
  • FIG. 9 is a side view of the exemplary mold assembly of FIG. 8.
  • FIG. 10 is a cross-sectional view of the exemplary mold assembly of FIG. 8.
  • FIG. 11 is a detailed view of the exemplary mold assembly of FIG. 10 showing a cavity formed between a first and second mold section.
  • FIG. 12 is a detailed view of the exemplary mold assembly of FIG. 11.
  • FIG. 13 is a perspective view of a first mold section of the exemplary mold assembly of FIG. 8.
  • FIG. 14 is a top view of a first mold section of FIG. 11.
  • FIG. 15 is a side view of a first mold section of FIG. 11.
  • FIG. 16 is a cross-sectional view of a first mold section of FIG. 15.
  • FIG. 17 is a detailed view of a first mold section of FIG. 16 showing a cavity formed in a top surface of the first mold section.
  • FIG. 18 is a perspective view of a second mold section of an exemplary mold assembly of FIG. 8.
  • FIG. 19 is a top view of a second mold section of FIG. 18.
  • FIG. 20 is a side view of a second mold section of FIG. 18.
  • FIG. 21 is a cross-sectional view of a second mold section of
  • FIG. 20 is a diagrammatic representation of FIG. 20.
  • FIG. 22 is a detailed view of a second mold section of FIG. 21;.
  • FIG. 23 is a top view- of an exemplary hydrogel onlay in accordance with the present disclosure.
  • FIG. 24 is a side view of the exemplary hydrogel onlay of FIG. 23.
  • FIG. 25 is a cross-sectional view of the exemplary hydrogel onlay of FIG. 23.
  • FIG. 26 is a detailed cross-sectional view of the exemplary hydrogel onlay of
  • FIG. 25 is a diagrammatic representation of FIG. 25.
  • FIG. 27 is a side view of an exemplary hydrogel meniscus onlay in accordance with the present disclosure.
  • FIG. 28 is a cross-sectional view of the exemplary hydrogel onlay of
  • FIG. 29 is a detailed cross-sectional view of the exemplary hydrogel onlay of FIG. 28.
  • FIG. 30 is an image of cell coverage on a corneal inlay made from biocompatible material after seven days.
  • FIG. 31 is an image of cell coverage on a corneal inlay made from non biocompatible material after seven days.
  • FIGS. 32A, 32B, 32C, 32D, and 32E illustrate guideline haze grading schemes for corneal haze scoring.
  • FIG. 33 is a bar graph showing thickness for different samples tested in the cell attachment assay at day 4.
  • FIG. 34 is a bar graph showing thickness for different samples tested in the cell attachment assay at day 7.
  • FIG. 35 is a bar graph showing thickness over time for different samples tested in the cell attachment assay.
  • FIGS. 36A, 36B, 36C, 36D, 36E, 36F, and 36G are microscopy images for different samples tested in the cell attachment assay at day 4, with FIG. 36A showing a control, FIG. 36B showing Nippi 10%, FIG. 36C showing Nippi 12%, FIG. 36D showing Nippi 15%, FIG. 36E showing Nippon 10%, FIG. 36F showing Ferentis 1823B, and FIG. 36G showing Ferentis 1837A.
  • FIGS. 37A, 37B, 37C, 37D, 37E, 37F, and 37G are microscopy images for different samples tested in the cell attachment assay at day 7, with FIG. 37A showing a control, FIG. 37B showing Nippi 10%, FIG. 37C showing Nippi 12%, FIG. 37D showing Nippi 15%, FIG. 37E showing Nippon 10%, FIG. 37F showing Ferentis 1823B, and FIG. 37G showing Ferentis 1837A.
  • FIG. 38 is a diagram illustrating placement of materials then seeded with cells during a cell attachment assay.
  • FIG. 39 is a bar graph showing thickness over time for different samples tested in the cell attachment assay.
  • FIGS. 40A, 40B, 40C, 40D, 40E, 40F, 40G, 40H, and 401 are microscopy images for different samples tested in the cell attachment assay at day 4, with FIG. 40A showing a control, FIG. 40B showing Ferentis 1842A, FIG. 40C showing Nippi 12%D12%, FIG. 40D showing Nippi 10%D10%, FIG. 40E showing Nippi 12%D10%, FIG. 40F showing Nippon 10%, FIG. 40G showing SA-13-31B, FIG. 40H showing SA-13-92A edge, and FIG. 401 showing SA-13-92A on sample.
  • FIGS. 41A, 41B, 41C, 41D, 41E, 41F, 41G, 41H, and 411 are microscopy images for different samples tested in the cell attachment assay at day 7, with FIG. 41A showing a control, FIG. 41B showing Ferentis 1842A, FIG. 41C showing Nippi 12%D12%, FIG. 41D showing Nippi 10%D10%, FIG. 41E showing Nippi 12%D10%, FIG. 41F showing Nippon 10%, FIG. 41G showing SA-13-31B, FIG. 41H showing SA-13-92A edge, and FIG. 411 showing SA-13-92A on sample.
  • FIG. 42 is a schematic diagram illustrating an MTT (3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay.
  • FIGS. 43A, 43B, 43C, 43D, 43E, and 43F are microscopy images for control samples tested in the cell attachment assay, with each of FIGS. 43A-43F showing control samples and, in particular, FIGS. 43A-43D showing control sample images for 4/6 samples, 80-100% confluent, and FIGS. 43E-43F showing control sample images for 2/6 samples mostly confluent, and a few patches in center.
  • FIGS. 44A, 44B, 44C, 44D, 44E, 44F, 44G, 44H, 441, and 44J are microscopy images for 1745A samples tested in the cell attachment assay, with FIGS. 44A- 44C showing 1745A sample images for 3/10 confluent at edges and nearly confluent in center, FIGS. 44D-44E showing 1745A sample images for 2/10 60-70% confluent in center, confluent at edges, and FIGS. 44F-44J showing 1745A sample images for 5/10 samples 30- 40% confluent in center, patchy, some holes.
  • FIG. 45 is an image of an MTT plate illustrating the setup for samples tested in the cell attachment assay.
  • FIG. 46 is a bar graph showing cell numbers for MTT results in the cell attachment assay for a sample and control.
  • FIG. 47 is a diagram of seeding materials during a cell attachment assay.
  • FIGS. 48A-48B are light microscopy images of PC-MPC cells attached to a sample.
  • FIG. 49 is a confocal microscopy image of a cross-section of PC-MPC material following incubation with epithelial cells. There are few multi-layer spots on top of the material.
  • FIGS. 50A-50B are confocal microscopy images of a cross-section of controls showing some multilayered structures as a baseline for comparison.
  • FIGS. 51A-51B are confocal microscopy images of a cross-section of 3D PEG gelatin material with epithelial cells on a plate and on surface demonstrating the ability of cells to form cell layers. Both have multi-layered spots.
  • FIG. 52 is a perspective view of an exemplary mold assembly for fabricating an exemplary hydrogel inlay having a disc- shaped configuration in accordance with the present disclosure
  • FIG. 53 is a side view of the exemplary mold assembly of FIG. 52;
  • FIG. 54 is a cross-sectional view of the exemplary mold assembly of FIG. 52;
  • FIG. 55 is a perspective view of a first mold section of the exemplary mold assembly of FIG. 52;
  • FIG. 56 is a top view of a first mold section of FIG. 55;
  • FIG. 57 is a side view of a first mold section of FIG. 55;
  • FIG. 58 is a cross-sectional view of a first mold section of FIG. 55;
  • FIG. 59 is a detailed view of a first mold section of FIG. 58 showing a cavity formed in a top surface of the first mold section;
  • FIG. 60 is a perspective view of a second mold section of an exemplary mold assembly of FIG. 52;
  • FIG. 61 is a top view of a second mold section of FIG. 52;
  • FIG. 62 is a side view of a second mold section of FIG. 52;
  • FIG. 63 is a cross-sectional view of a second mold section of FIG. 60.
  • FIG. 64 is a detailed view of a second mold section of FIG. 63.
  • adaptive immune response refers to an immune response mediated by uniquely specific recognition or a non-self entity by lymphocytes whose activation leads to elimination of the entity and the production of specific memory lymphocytes. Because these memory lymphocytes forestall disease in subsequent attacks by the same pathogen, the host immune system is said to have “adapted” to copy with the entity.
  • adhere and its other grammatical forms as used herein means to stick fast to a surface or substance.
  • the head end When referring to animals that typically have one end with a head and mouth, with the opposite end often having the anus and tail, the head end is referred to as the cranial end, while the tail end is referred to as the caudal end.
  • rostral refers to the direction toward the end of the nose, and caudal is used to refer to the tail direction.
  • the surface or side of an animal’s body that is normally oriented upwards, away from the pull of gravity, is the dorsal side; the opposite side, typically the one closest to the ground when walking on all legs, swimming or flying, is the ventral side.
  • a “sagittal” plane divides the body into left and right portions.
  • the “midsagittal” plane is in the midline, i.e. it would pass through midline structures such as the spine, and all other sagittal planes are parallel to it.
  • a “coronal” plane divides the body into dorsal and ventral portions.
  • a “transverse” plane divides the body into cranial and caudal portions.
  • a coronal or frontal plane is an Y-Z plane, perpendicular to the ground, which separates the anterior from the posterior.
  • a sagittal plane is an X-Z plane, perpendicular to the ground and to the coronal plane, which separates left from right.
  • the midsagittal plane is the specific sagittal plane that is exactly in the middle of the body.
  • Structures near the midline are called medial and those near the sides of animals are called lateral. Therefore, medial structures are closer to the midsagittal plane, lateral structures are further from the midsagittal plane. Structures in the midline of the body are median. For example, the tip of a human subject’s nose is in the median line.
  • ipsilateral as used herein means on the same side
  • the term “contralateral” as used herein means on the other side
  • the term “bilateral” as used herein means on both sides. Structures that are close to the center of the body are proximal or central, while ones more distant are distal or peripheral. For example, the hands are at the distal end of the arms, while the shoulders are at the proximal ends.
  • biocompatible means causing no clinically relevant tissue irritation, injury, toxic reaction, or immunologic reaction to human tissue based on a clinical risk/benefit assessment.
  • collagen refers to a natural, chemically synthesized, or synthetic protein rich in glycine and proline that in vivo is a major component of the extracellular matrix and connective tissues.
  • crosslay refers to an implantable device that is embedded within the comeal stroma.
  • corneal onlay refers to an implantable device placed onto the comeal surface.
  • corner apex refers to the point of maximum curvature.
  • cross vertex refers to the point located at the intersection of an individual’s line of fixation and the comeal surface.
  • cytokine refers to small soluble protein substances secreted by cells which have a variety of effects on other cells. Cytokines mediate many important physiological functions including growth, development, wound healing, and the immune response. They act by binding to their cell-specific receptors located in the cell membrane, which allows a distinct signal transduction cascade to start in the cell, which eventually will lead to biochemical and phenotypic changes in target cells. Generally, cytokines act locally.
  • type I cytokines which encompass many of the interleukins, as well as several hematopoietic growth factors
  • type II cytokines including the interferons and interleukin- 10
  • TNF tumor necrosis factor
  • IL-1 immunoglobulin super-family members
  • chemokines a family of molecules that play a critical role in a wide variety of immune and inflammatory functions.
  • the same cytokine can have different effects on a cell depending on the state of the cell. Cytokines often regulate the expression of, and trigger cascades of, other cytokines.
  • the term “demolding” as used herein refers to a process of removing a mold from a model or a casting from a mold.
  • the process can be, for example, by mechanical means, by hand, by the use of compressed air, etc.
  • the term “diopter” as used herein refers to a unit of measurement of the refractive power of a lens equal to the reciprocal of the focal length in meters.
  • elasticity refers to a measure of the deformation of an object when a force is applied. Objects that are very elastic like rubber have high elasticity and stretch easily.
  • extracellular matrix refers to a complex network of polysaccharides and proteins secreted by cells that serves as a structural element in tissues and also influences their development and physiology. It is composed of an interlocking mesh of fibrous proteins and glycosaminoglycans (GAGs). Examples of fibrous proteins found in the extracellular matrix include collagen, elastin, fribronectin, and laminin.
  • GAGs found in the extracellular matrix include proteoglycans (e.g., heparin sulfate), chondroitin sulfate, keratin sulfate, and non-proteoglycan polysaccharide (e.g., hyaluronic acid).
  • proteoglycan refers to a group of glycoproteins that contain a core protein to which is attached one or more glycosaminoglycans.
  • the extracellular matrix serves many functions, including, but not limited to, providing support and anchorage for cells, segregating one tissue from another tissue, and regulating intracellular communication.
  • fibroblast refers to a common cell type in connective tissue that secretes an extracellular matrix rich in collagen and other extracellular matrix macromolecules and that migrates and proliferates readily in wounded tissue and in tissue culture.
  • fixation or “visual fixation” as used herein refers to an optic skill that allows one to sustain gaze at a stationary object.
  • growth refers to a process of becoming larger, longer or more numerous, or an increase in size, number, or volume of cells in a cell population.
  • growth factor refers to an extracellular polypeptide signal molecule that can stimulate a cell to grow or proliferate.
  • Nonlimiting examples include epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). Most growth factors also have other actions.
  • hydrogel refers to a substance resulting in a solid, semisolid, pseudoplastic, or plastic structure containing a necessary aqueous component to produce a gelatinous or jelly-like mass.
  • hydrophilic refers to a material or substance having an affinity for polar substances, such as water.
  • immune response and “immune mediated” are used interchangeably herein to refer to any functional expression of a subject’s immune system, against either foreign or self-antigens, whether the consequences of these reactions are beneficial or harmful to the subject.
  • immune system refers to a complex arrangement of cells and molecules that maintain immune homeostasis to preserve the integrity of the organism by elimination of all elements judged to be dangerous.
  • Responses in the immune system may generally be divided into two arms, referred to as “innate immunity” and “adaptive immunity.”
  • the two arms of immunity do not operate independently of each other, but rather work together to elicit effective immune responses.
  • implant refers to material inserted or grafted into a tissue.
  • index of refraction refers to a measure of the extent to which a substance/medium slows down light waves passing through it. Its value determines the extent to which light is refracted (bent) when entering or leaving the substance/medium. It is the ratio of the velocity of light in a vacuum to its speed in a substance or medium.
  • innate immunity or innate immune response
  • soluble factors including the complement system and the chemokine/cytokine system
  • specialized cell types including mast cells, macrophages, dendritic cells (DCs), and natural killer cells (NKs).
  • integrins refers to the principal receptors used by animal cells to bind to the extracellular matrix. They are heterodimers and function as transmembrane linkers between the extracellular matrix and the actin cytoskeleton. A cell can regulate the adhesive activity of its integrins from within.
  • interlaced and its other grammatical forms as used herein refers to a state of being united by intercrossing; of being passed over and under each other; of being weaved together; intertwined; or being connected intricately.
  • isolated refers to material, such as, but not limited to, a nucleic acid, peptide, polypeptide, or protein, which is: (1) substantially or essentially free from components that normally accompany or interact with it as found in its naturally occurring environment.
  • substantially free or “essentially free” are used herein to refer to considerably or significantly free of, or more than about 95% free of, more than about 96% free of, more than about 97% free of, more than about 98% free of, or more than about 99% free of.
  • the isolated material optionally comprises material not found with the material in its natural environment; or (2) the material has been synthetically (non- naturally) altered by deliberate human intervention.
  • matrix refers to a three dimensional network of fibers that contains voids (or "pores") where the woven fibers intersect.
  • the structural parameters of the pores including the pore size, porosity, pore interconnectivity/ tortuosity and surface area, can affect how substances (e.g., fluid, solutes) move in and out of the matrix.
  • MPC methacryloyloxyethyl pho sphorylcholine
  • miosis as used herein means excessive constriction (shrinking) of the pupil. In miosis, the diameter of the pupil is less than 2 millimeters (mm),
  • myeloid as used herein means of or pertaining to bone marrow.
  • Granulocytes and monocytes collectively called myeloid cells, are differentiated descendants from common progenitors derived from hematopoietic stem cells in the bone marrow. Commitment to either lineage of myeloid cells is controlled by distinct transcription factors followed by terminal differentiation in response to specific colony-stimulating factors and release into the circulation.
  • myeloid cells Upon pathogen invasion, myeloid cells are rapidly recruited into local tissues via various chemokine receptors, where they are activated for phagocytosis as well as secretion of inflammatory cytokines, thereby playing major roles in innate immunity. [Kawamoto, H., Minato, N. Inti J. Biochem. Cell Biol. (2004) 36 (8): 1374-9].
  • myofibroblast refers to a differentiated cell type essential for wound healing that participates in tissue remodeling following an insult. Myofibroblasts are typically activated fibroblasts, although they can also be derived from other cell types, including epithelial cells, endothelial cells, and mononuclear cells.
  • PEGDA poly(ethylene glycol)diacrylate.
  • permeable means permitting the passage of substances, such as oxygen, glucose, water and ions, as through a membrane or other structure.
  • porosity refers to the ratio between the pore volume and the total volume of a material.
  • peptide refers to a molecule of two or more amino acids chemically linked together.
  • a peptide may refer to a polypeptide, protein or peptidomimetic.
  • peptidomimetic refers to a small protein-like chain designed to mimic or imitate a peptide.
  • a peptidomimetic may comprise non-peptidic structural elements capable of mimicking (meaning imitating) or antagonizing (meaning neutralizing or counteracting) the biological action(s) of a natural parent peptide.
  • polypeptide and protein are used herein in their broadest sense to refer to a sequence of subunit amino acids, amino acid analogs, or peptidomimetics. The subunits are linked by peptide bonds, except where noted.
  • the polypeptides described herein may be chemically synthesized or recombinantly expressed. Polypeptides of the described invention can be chemically synthesized. Synthetic polypeptides, prepared using the well-known techniques of solid phase, liquid phase, or peptide condensation techniques, or any combination thereof, can include natural and unnatural amino acids.
  • Amino acids used for peptide synthesis may be standard Boc (N-a-amino protected N-a-t-butyloxycarbonyl) amino acid resin with the standard deprotecting, neutralization, coupling and wash protocols of the original solid phase procedure of Merrifield (1963, J. Am. Chem. Soc 85:2149-2154), or the base-labile N-a-amino protected 9-fluorenylmethoxycarbonyl (Fmoc) amino acids first described by Carpino and Han (1972, J. Org. Chem. 37:3403-3409). Both Fmoc and Boc N- a-amino protected amino acids can be obtained from Sigma, Cambridge Research Biochemical, or other chemical companies familiar to those skilled in the art.
  • polypeptides can be synthesized with other N-a-protecting groups that are familiar to those skilled in this art.
  • Solid phase peptide synthesis may be accomplished by techniques familiar to those in the art and provided, 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. 35:161-214, or using automated synthesizers.
  • the polypeptides of the invention may comprise D-amino acids (which are resistant to L-amino acid-specific proteases in vivo), a combination of D- and L-amino acids, and various "designer" amino acids (e.g., b-methyl amino acids, C-a-methyl amino acids, and N-a-methyl amino acids, etc.) to convey special properties.
  • D-amino acids which are resistant to L-amino acid-specific proteases in vivo
  • various "designer" amino acids e.g., b-methyl amino acids, C-a-methyl amino acids, and N-a-methyl amino acids, etc.
  • synthetic amino acids include ornithine for lysine, and norleucine for leucine or isoleucine.
  • the polypeptides can have peptidomimetic bonds, such as ester bonds, to prepare peptides with novel properties.
  • a peptide may be generated that incorporates a reduced peptide bond, i.e., R'-CfL- NH-R 2 , where Ri and R2 are amino acid residues or sequences.
  • a reduced peptide bond may be introduced as a dipeptide subunit.
  • Such a polypeptide would be resistant to protease activity, and would possess an extended half-live in vivo. Accordingly, these terms also apply to amino acid polymers in which one or more amino acid residue is an artificial chemical analogue of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers. When incorporated into a protein, that protein is specifically reactive to antibodies elicited to the same protein but consisting entirely of naturally occurring amino acids.
  • polypeptide also are inclusive of modifications including, but not limited to, glycosylation, lipid attachment, sulfation, gamma- carboxylation of glutamic acid residues, hydroxylation and ADP-ribosylation. It will be appreciated, as is well known and as noted above, that polypeptides may not be entirely linear. For instance, polypeptides may be branched as a result of ubiquitination, and they may be circular, with or without branching, generally as a result of posttranslational events, including natural processing event and events brought about by human manipulation which do not occur naturally. Circular, branched and branched circular polypeptides may be synthesized by non-translation natural process and by entirely synthetic methods, as well.
  • polymer refers to any of various chemical compounds made of smaller, identical molecules (called monomers) linked together. Polymers generally have high molecular weights. The incorporation of two different monomers, A and B, into a polymer chain in a statistical fashion leads to copolymers. In the limit, single monomers may alternate regularly in the chain and these are known as alternating copolymers. The monomers can be combined in a more regular fashion, either by linking extended linear sequences of one to linear sequences of the other by end-to-end addition to give block copolymers, or by attaching chains of B at points on the backbone chain of A, forming a branched structure known as a graft copolymer. [00191] The term “proliferate” and its various grammatical forms as used herein means to increase rapidly in numbers; to multiply.
  • protein is used herein to refer to a large complex molecule or polypeptide composed of amino acids.
  • sequence of the amino acids in the protein is determined by the sequence of the bases in the nucleic acid sequence that encodes it.
  • recombinant DNA refers to a DNA molecule formed by laboratory methods whereby DNA segments from different sources are joined to produce a new genetic combination.
  • recombinant protein refers to a protein encoded by recombinant DNA that has been cloned in a system that supports expression of the gene and translation of messenger RNA within a living cell.
  • a gene of interest is isolated, cloned into an expression vector, and expressed in an expression system.
  • Exemplary expression systems include prokaryotic organisms, as bacteria, and eukaryotic organisms, such as yeast, insect cells, plants, and mammalian cells in culture.
  • the term “refraction” as used herein refers to the deflection of a ray of light when it passes from one medium into another of different optical density.
  • a denser medium provides more matter from which the light can scatter, so light will travel more slowly in a dense medium.
  • a slower speed means a higher index of refraction.
  • Light travels much faster in rarer medium (meaning a less dense medium, for example: air).
  • rarer medium meaning a less dense medium, for example: air
  • In passing from a denser into a rarer medium the light is deflected away from a line perpendicular to the surface of the refracting medium. In passing from a rarer to a denser medium, it is bent towards this perpendicular line.
  • the term “refraction” also refers to the act of determining the nature and degree of the refractive errors in the eye and correction of the same.
  • RGD motif refers to arginylglycylaspartic acid, the binding motif of fibronectin to cell adhesion molecules, which can serve as a cell adhesion site of extracellular matrix, cell surface proteins, and integrins.
  • shape refers to the quality of a distinct object or body in having an external surface or outline of specific form or figure.
  • 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, mouse, rat, cat, goat, sheep, horse, hamster, ferret, pig, dog, guinea pig, rabbit and a primate, such as, for example, a monkey, ape, or human.
  • mammalian origin including but not limited to, mouse, rat, cat, goat, sheep, horse, hamster, ferret, pig, dog, guinea pig, rabbit and a primate, such as, for example, a monkey, ape, or human.
  • thickness refers to a measure between opposite surfaces, from top to bottom, or in a direction perpendicular to that of the length and breadth.
  • tolerance limits refers to the end points of a tolerance interval.
  • transactivation refers to stimulating transcription of a gene in a host cell by binding to DNA. Genes can be transactivated naturally (e.g., by a virus or a cellular protein) or artificially.
  • viscosity refers to the property of a fluid that resists the force tending to cause the fluid to flow. Viscosity is a measure of the fluid's resistance to flow. The resistance is caused by intermolecular friction exerted when layers of fluids attempt to slide by one another. Viscosity can be of two types: dynamic (or absolute) viscosity and kinematic viscosity. Absolute viscosity or the coefficient of absolute viscosity is a measure of the internal resistance. Dynamic (or absolute) viscosity is the tangential force per unit area required to move one horizontal plane with respect to the other at unit velocity when maintained a unit distance apart by the fluid.
  • Kinematic viscosity is the ratio of absolute or dynamic viscosity to density.
  • wt % or "weight percent” or “percent by weight” or “wt/wt%” of a component, unless specifically stated to the contrary, refers to the ratio of the weight of the component to the total weight of the composition in which the component is included, expressed as a percentage.
  • the term “Young’s modulus” as used herein refers to a measure of elasticity, equal to the ratio of the stress acting on a substance to the strain produced.
  • the term “stress” as used herein refers to a measure of the force put on an object over an area.
  • strain as used herein refers to the change in length divided by the original length of the object. Change in length is proportional to the force put on it and depends on the substance from which the object is made. Change in length is proportional to the original length and inversely proportional to the cross-sectional area. Fracture is caused by a strain placed on an object such that it deforms (a change of shape) beyond its elastic limit and breaks.
  • the present disclosure relates to a corneal onlay device, insertion means, and construction means, as discussed in detail below in connection with FIGS. 4-8. .
  • FIG. 4 is a diagram showing an example of a corneal onlay 10 of the present disclosure.
  • the corneal onlay 10 includes a thickness 12 and a diameter 14.
  • the comeal onlay 10 can have a dome or meniscus shape, including a flat or flat-like base and a dome or more or less spherical, convex shaped top.
  • the onlay 10 can include a base curve and a front curve, or be dome-shaped.
  • the thickness 12 can range from about 15 microns to about 30 microns. Because the corneal onlay 10 is biocompatible with the eye, it is capable of correcting presbyopia while reducing or eliminating the risk of a patient developing comeal haze.
  • the corneal onlay 10 can define a diameter 14 dimensioned smaller than the diameter of the pupil
  • the comeal onlay 10 can be implanted centrally in the cornea under the epithelium and over the Bowman’s membrane to induce an “effect” zone on the anterior epithelium surface that is smaller than the optical zone of the cornea, wherein the “effect” zone is the area of the anterior corneal surface affected by the comeal onlay 10.
  • the implanted corneal onlay 10 increases the curvature of the anterior comeal surface within the “effect” zone, thereby increasing the diopter power of the cornea within the “effect” zone by +1.5 to +3 diopters, inclusive. Because the comeal onlay 10 is smaller than the diameter of the pupil, light rays from distant objects bypass the onlay and refract through the region of the cornea peripheral to the “effect” zone to create an image of distant objects on the retina.
  • the corneal onlay of the present disclosure may be implanted centrally on Bowman’s membrane after removal of at least a portion of the epithelium, oriented substantially centrally to the cornea to induce an “effect” zone on the anterior surface of the regrown epithelium.
  • a regrowth period of 24-48 hours may allow the epithelium to regrow over the onlay.
  • the implanted comeal onlay may increase the curvature of the anterior surface of the regrown epithelium within the “effect zone”. Because the comeal onlay is smaller than the diameter of the pupil, light rays from distant objects bypass the onlay and refract through the region of the cornea peripheral to the “effect” zone to create an image of distant objects on the retina.
  • FIG. 5 is a schematic diagram showing the corneal onlay 10 implanted on Bowman’s membrane 28.
  • the comeal onlay 10 may have a substantially dome shape with an anterior surface 22 and a posterior surface 24.
  • the surgical procedure may initially involve removal of at least a portion (a central portion) of the epithelium 21 dimensioned to allow for positioning of the comeal onlay 10 onto the Bowman’s membrane 28.
  • the onlay 10 can be oriented substantially centrally relative to the cornea 20.
  • a biocompatible adhesive may be used to assist in adhering the onlay 10 to the Bowman’s membrane 28.
  • the stroma 26 remains unharmed during this procedure.
  • a contact lens 27 may be positioned on the epithelium 21 to cover the onlay 10 and the opening in the epithelium 21. After the epithelium regrows into the surgical area 29 to cover the onlay 10, the contact lens 27 may be removed.
  • the surgical procedure may initially involve cutting of a flap in the epithelium 21 to expose the Bowman’s membrane 28.
  • a portion of the anterior side of the epithelium 21 may be removed to accommodate positioning of the onlay 10 onto the Bowman’s membrane 28.
  • a biocompatible adhesive may be used to assist in adhering the onlay 10 to the Bowman’s membrane 28.
  • the flap of the epithelium 21 may be positioned over the onlay 10.
  • a contact lens 27 may be positioned on the epithelium 21 to cover the onlay 10. After the epithelium heals, the contact lens 27 may be removed.
  • the comeal onlay 10 may change the refractive power of the cornea by altering the shape of the anterior comeal surface.
  • the pre operative anterior corneal surface is represented by dashed line 30 and the post-operative anterior comeal surface induced by the underlying corneal onlay 10 is represented by solid line 32.
  • the elastic (Young’s) modulus of the comeal onlay 10 may, by way of example, be 0.18 megapascals (“MPa”) with a tolerance of ⁇ 0.06 MPa. However, in some embodiments, the elastic modulus of the comeal onlay 10 may exceed the tolerance. In some embodiments, the elastic modulus of the comeal onlay 10 may be at least 0.05 MPa. In some embodiments, the elastic modulus of the comeal onlay 10 may be at least 0.06 MPa. In some embodiments, the elastic modulus of the comeal onlay 10 may be at least 0.07 MPa. In some embodiments, the elastic modulus of the comeal onlay 10 may be at least 0.08 MPa.
  • the elastic modulus of the comeal onlay 10 may be at least 0.09 MPa. In some embodiments, the elastic modulus of the comeal onlay 10 may be at least 0.10 MPa. In some embodiments, the elastic modulus of the comeal onlay 10 may be at least 0.11 MPa. In some embodiments, the elastic modulus of the comeal onlay 10 may be at least 0.12 MPa. In some embodiments, the elastic modulus of the comeal onlay 10 may be at least 0.13 MPa. In some embodiments, the elastic modulus of the comeal onlay 10 may be at least 0.14 MPa. In some embodiments, the elastic modulus of the comeal onlay 10 may be at least 0.15 MPa.
  • the elastic modulus of the comeal onlay 10 may be at least 0.16 MPa. In some embodiments, the elastic modulus of the comeal onlay 10 may be at least 0.17 MPa. In some embodiments, the elastic modulus of the comeal onlay 10 may be at least 0.18 MPa. In some embodiments, the elastic modulus of the comeal onlay 10 may be at least 0.19 MPa. In some embodiments, the elastic modulus of the comeal onlay 10 may be at least 0.20 MPa. In some embodiments, the elastic modulus of the comeal onlay 10 may be at least 0.21 MPa. In some embodiments, the elastic modulus of the comeal onlay 10 may be at least 0.22 MPa.
  • the elastic modulus of the comeal onlay 10 may be at least 0.23 MPa. In some embodiments, the elastic modulus of the comeal onlay 10 may be at least 0.24 MPa. In some embodiments, the elastic modulus of the comeal onlay 10 may be at least 0.25 MPa. In some embodiments, the elastic modulus of the comeal onlay 10 may be at least 0.26 MPa. In some embodiments, the elastic modulus of the comeal onlay 10 may be at least 0.27 MPa. In some embodiments, the elastic modulus of the comeal onlay 10 may be at least 0.28 MPa. In some embodiments, the elastic modulus of the comeal onlay 10 may be at least 0.29 MPa. In some embodiments, the elastic modulus of the corneal onlay 10 may be at least 0.30 MPa.
  • “Elongation at break”, also called “fracture strain” or “tensile elongation at break” is the percentage increase in length that a material will achieve before breaking. It is a measurement that shows how much a material can be stretched — as a percentage of its original dimensions — before it breaks. In other words, it’s a percentage that shows a material’s ductility. A material with high ductility means it’s more likely to deform (but not break). Low ductility indicates that it’s brittle and will fracture easily under a tensile load.
  • the elongation at break of the corneal onlay 10 may be 58.30% with a tolerance of ⁇ 4.49%. However, in some embodiments, the elongation at break of the corneal onlay 10 may exceed the tolerance. In some embodiments, the elongation at break of the comeal onlay 10 may be at least 48%. In some embodiments, the elongation at break of the comeal onlay 10 may be at least 49%. In some embodiments, the elongation at break of the comeal onlay 10 may be at least 50%. In some embodiments, the elongation at break of the comeal onlay 10 may be at least 21%.
  • the elongation at break of the comeal onlay 10 may be at least 52%. In some embodiments, the elongation at break of the comeal onlay 10 may be at least 53%. In some embodiments, the elongation at break of the comeal onlay 10 may be at least 54%. In some embodiments, the elongation at break of the comeal onlay 10 may be at least 55%. In some embodiments, the elongation at break of the comeal onlay 10 may be at least 56%. In some embodiments, the elongation at break of the comeal onlay 10 may be at least 57%. In some embodiments, the elongation at break of the comeal onlay 10 may be at least 58%.
  • the elongation at break of the comeal onlay 10 may be at least 59%. In some embodiments, the elongation at break of the comeal onlay 10 may be at least 60%. In some embodiments, the elongation at break of the comeal onlay 10 may be at least 61%. In some embodiments, the elongation at break of the comeal onlay 10 may be at least 62%. In some embodiments, the elongation at break of the comeal onlay 10 may be at least 63%. In some embodiments, the elongation at break of the comeal onlay 10 may be at least 64%. In some embodiments, the elongation at break of the comeal onlay 10 may be at least 65%.
  • the elongation at break of the comeal onlay 10 may be at least 66%. In some embodiments, the elongation at break of the comeal onlay 10 may be at least 67%. In some embodiments, the elongation at break of the comeal onlay 10 may be at least 68%. In some embodiments, the elongation at break of the comeal onlay 10 may be at least 69%. In some embodiments, the elongation at break of the corneal onlay 10 may be at least 70%.
  • the tensile strength (meaning the resistance of a material to breaking under tension) of the comeal onlay 10 may be 0.07 MPa with a tolerance of ⁇ 0.02 MPa. In some embodiments, the tensile strength of the corneal onlay may exceed the tolerance. In some embodiments, the tensile strength of the comeal onlay 10 may be at least 0.01 MPa. In some embodiments, the tensile strength of the corneal onlay 10 may be at least 0.02 MPa. In some embodiments, the tensile strength of the corneal onlay 10 may be at least 0.03 MPa. In some embodiments, the tensile strength of the corneal onlay 10 may be at least 0.04 MPa.
  • the tensile strength of the corneal onlay 10 may be at least 0.05 MPa. In some embodiments, the tensile strength of the corneal onlay 10 may be at least 0.06 MPa. In some embodiments, the tensile strength of the corneal onlay 10 may be at least 0.07 MPa. In some embodiments, the tensile strength of the corneal onlay 10 may be at least 0.08 MPa. In some embodiments, the tensile strength of the corneal onlay 10 may be at least 0.09 MPa. In some embodiments, the tensile strength of the corneal onlay 10 may be at least 0.10 MPa. In some embodiments, the tensile strength of the corneal onlay 10 may be at least 0.11 MPa.
  • the tensile strength of the corneal onlay 10 may be at least 0.12 MPa. In some embodiments, the tensile strength of the corneal onlay 10 may be at least 0.13 MPa. In some embodiments, the tensile strength of the corneal onlay 10 may be at least 0.14 MPa. In some embodiments, the tensile strength of the corneal onlay 10 may be at least 0.15 MPa.
  • the backscatter (meaning deflection of radiation or particles through an angle of 180°) of the comeal onlay 10 may be 0.90% with a tolerance of ⁇ 0.17%. However, in some embodiments, the backscatter of the comeal onlay 10 may exceed the tolerance. In some embodiments, the backscatter of the corneal onlay 10 may be at least 0.65%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.66%. In some embodiments, the backscatter of the corneal onlay 10 may be at least 0.67%. In some embodiments, the backscatter of the corneal onlay 10 may be at least 0.68%.
  • the backscatter of the comeal onlay 10 may be at least 0.69%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.70%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.71%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.72%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.73%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.74%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.75%.
  • the backscatter of the comeal onlay 10 may be at least 0.76%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.77%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.78%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.79%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.80%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.81%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.82%.
  • the backscatter of the comeal onlay 10 may be at least 0.83%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.84%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.85%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.86%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.87%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.88%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.89%.
  • the backscatter of the comeal onlay 10 may be at least 0.90%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.91%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.92%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.93%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.94%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.95%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.96%.
  • the backscatter of the comeal onlay 10 may be at least 0.97%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.98%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 0.99%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 1.00%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 1.01%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 1.02%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 1.03%.
  • the backscatter of the comeal onlay 10 may be at least 1.04%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 1.05%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 1.06%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 1.07%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 1.08%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 1.09%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 1.10%.
  • the backscatter of the comeal onlay 10 may be at least 1.11%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 1.12%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 1.13%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 1.14%. In some embodiments, the backscatter of the comeal onlay 10 may be at least 1.15%
  • the light transmission (meaning the moving of electromagnetic waves through) of the comeal onlay 10 may be 92.4% with a tolerance of ⁇ 0.95%. In some embodiments, the elastic modulus of the corneal onlay 10 may exceed the tolerance. In some embodiments, the light transmission of the corneal onlay 10 may be at least 85.0%. In some embodiments, the light transmission of the comeal onlay 10 may be at least 86.0%. In some embodiments, the light transmission of the comeal onlay 10 may be at least 87.0%. In some embodiments, the light transmission of the comeal onlay 10 may be at least 88.0%. In some embodiments, the light transmission of the comeal onlay 10 may be at least 89.0%.
  • the light transmission of the comeal onlay 10 may be at least 90.0%. In some embodiments, the light transmission of the comeal onlay 10 may be at least 91.0%. In some embodiments, the light transmission of the comeal onlay 10 may be at least 92.0%. In some embodiments, the light transmission of the comeal onlay 10 may be at least 93.0%. In some embodiments, the light transmission of the comeal onlay 10 may be at least 94.0%. In some embodiments, the light transmission of the comeal onlay 10 may be at least 95.0%. In some embodiments, the light transmission of the comeal onlay 10 may be at least 96.0%. In some embodiments, the light transmission of the comeal onlay 10 may be at least 97.0%.
  • the light transmission of the comeal onlay 10 may be at least 98.0%. In some embodiments, the light transmission of the comeal onlay 10 may be at least 99.0%. In some embodiments, the light transmission of the corneal onlay 10 may be
  • PEG is FDA approved in a number of applications and is broadly considered to be nontoxic, biocompatible and nonimmunogenic. [Id., citing Mehdizadeh, M. and Yang, J. Macromol. Biosci. (2013) 13: 271-88].
  • DuraSeal Xact Adhesion Barrier and Sealant System utilizes an NHS ester to achieve a hydrogel with adhesive cross-linking and bonding to tissues with reduced swelling [Id., citing Preul, MC et al. J. Neurosurg. Spin (2010) 12: 381-90; Fransen, P. Spine J. (2010) 10: 751-61; Kim, K. D et al. Global Spine J.
  • Cell-Tak is a nonimmunogenic extracellular matrix protein preparation isolated from the marine mussel, Mytilus edulis (Corning]
  • photochemical tissue bonding PTB
  • Riboflavin or Rose Bengal and UV light may be implemented to secure or glue the onlay in the desired position.
  • cyanoacrylate glue typically used for comeal lacerations/perforations and gluing small corneal patches on corneal perforations, comeal melts, and corneal wound leaks
  • the morphology (meaning form) of the corneal inlay 10 may be that of a fibrillary network with nano-pores.
  • the nano pores of the corneal inlay 10 may have a diameter of at least 0.1 pm.
  • the nano-pores of the comeal inlay 10 may have a diameter of at least 0.2 pm.
  • the nano-pores of the comeal inlay 10 may have a diameter of at least 0.3 pm.
  • the nano-pores of the comeal inlay 10 may have a diameter of at least 0.4 pm.
  • the nano-pores of the comeal inlay 10 may have a diameter of at least 0.5 pm.
  • the nano-pores of the corneal inlay 10 may have a diameter of at least 0.6 pm. In some embodiments, the nano-pores of the corneal inlay 10 may have a diameter of at least 0.7 pm. In some embodiments, the nano-pores of the corneal inlay 10 may have a diameter of at least 0.8 pm. In some embodiments, the nano-pores of the comeal inlay 10 may have a diameter of at least 0.9 pm. In some embodiments, the nano pores of the corneal inlay 10 may have a diameter of at least 1.0 pm. In some embodiments, the nano-pores may have a diameter of approximately 0.4 pm.
  • the storage temperature for the comeal inlay 10 may range from about 2° - 8° Celsius, i.e., about 2°C, 2.5°C, 3°C, 3.5°C, 4°C, 4.5°C, 5°C, 5.5°C, 6°C, 6.5°C, 7°C, 7.5°C, 8°C.
  • the diameter of the corneal onlay 10 for correcting presbyopia may be small in comparison with the diameter of the pupil.
  • a comeal onlay 10 e.g., ranging in size from about 1 mm to about 3 mm in diameter, inclusive, i.e., about 1 mm, about 1.1 mm, about 1.2 mm, about 1.3 mm, about 1.4 mm, about 1.5 mm, about 1.6 mm, about 1.7 mm, about 1.8 mm, about 1.9 mm, about 2.0 mm, about 2.1 mm, about 2.2 mm, about 2.3 mm, about 2.4 mm, about 2.5 mm, about 2.6 mm, about 2.7 mm, about 2.8 mm, about 2.9 mm, or about 3.0 mm in diameter, or the like) may be implanted substantially centrally on the Bowman’s membrane to induce an “effect” zone on the anterior corneal surface (e.g., epithelium surface) that is smaller than the anterior corneal surface (e.g., epithe
  • the “effect” zone is the area of the anterior corneal surface affected by the comeal onlay 10.
  • the implanted corneal onlay 10 increases the curvature of the anterior comeal surface within the “effect” zone, thereby increasing the diopter power of the cornea within the “effect” zone.
  • the corneal onlay once implanted on Bowman’s membrane, may increase the curvature of the anterior corneal surface within the “effect zone”, thereby increasing the diopter power of the cornea within the “effect zone”.
  • Distance vision is provided by the region of the cornea peripheral to the “effect” zone.
  • the onlay may be fabricated in different shapes and/or different thicknesses.
  • the onlay may include a base curve (e.g., anterior surface curve) and a front curve (e.g., a posterior surface curve).
  • the onlay may define a dome-shaped configuration.
  • the thickness of the onlay may range from about 15 microns to about 30 microns, inclusive, i.e., about 15 microns, about 16 microns, about 17 microns, about 18 microns, about 19 microns, about 20 microns, about 21 microns, about 22 microns, about 23 microns, about 24 microns, about 25 microns, about 26 microns, about 27 microns, about 28 microns, about 29 microns, or about 30 microns, with such thickness providing a correction of between about +1.5 to about +3.0 diopters, i.e., about +1.5, about +1.6, about +1.7, about +1.8, about +1.9, about +2.0, about +2.1, about +2.2, about +2.3, about +2.4, about +2.5, about +2.6
  • Presbyopia is characterized by a decrease in the ability of the eye to increase its power to focus on nearby objects due to a loss of elasticity in the crystalline lens with age.
  • a person suffering from presbyopia requires reading glasses to provide near vision.
  • FIG. 6 shows an example of how a comeal onlay 10 can provide near vision to a subject's eye while retaining some distance vision according to an embodiment of the invention.
  • the eye 40 comprises a cornea 42, a pupil 44, a crystalline lens 46 and a retina 48.
  • the comeal onlay 10 (not shown) is implanted substantially centrally on Bowman’s membrane of the cornea 42 to create a small diameter “effect” zone 50.
  • the corneal onlay 10 has a smaller diameter than the pupil 44 so that the resulting “effect” zone 50 has a smaller diameter than the optical zone of the cornea 42.
  • the “effect” zone 50 provides near vision by increasing the curvature of the anterior comeal surface, and therefore the diopter power within the “effect” zone 50.
  • the region 52 of the cornea peripheral to the “effect” zone provides distance vision.
  • the comeal onlay 10 has a curvature higher than the curvature of the anterior corneal surface in order to increase the curvature of the anterior corneal surface at the level of Bowman’s membrane within the “effect” zone 50.
  • the increase in the diopter power within the “effect” zone 50 can be due to the change in the anterior corneal surface induced by the corneal inlay 10 or a combination of the change in the anterior cornea surface and the index of refraction of the corneal inlay 10.
  • At least 1 diopter is typically required for near vision.
  • For complete presbyopia e.g., about 60 years of age or older, between 2 and 3 diopters of additional power are required.
  • An advantage of the corneal onlay 10 is that when concentrating on nearby objects 54, the pupil naturally becomes smaller (e.g., near point miosis) making the corneal onlay effect even more effective. Further increases in the corneal onlay effect can be achieved by increasing the illumination of a nearby object (e.g., turning up a reading light).
  • the onlay is smaller than the diameter of the pupil 44, light rays 56 from distant objects 58 bypass the onlay and refract using the region of the cornea peripheral to the “effect” zone to create an image of the distant objects on the retina 48, as shown in FIG. 6. This is particularly true with larger pupils. At night, when distance vision is most important, the pupil naturally becomes larger, thereby reducing the onlay effect and maximizing distance vision.
  • a subject's natural distance vision is in focus only if the subject is emmetropic (i.e., does not require glasses for distance vision). Many subjects are ammetropic, requiring either myopic or hyperopic refractive correction. Especially for myopes, distance vision correction can be provided by myopic Laser in Situ Keratomileusis (“LASIK”), Laser Epithelial Keratomileusis (“LASEK”), Photorefractive Keratectomy (“PRK”) or other similar comeal refractive procedures. After the distance corrective procedure is completed, the corneal onlay 10 can be implanted in the cornea to provide near vision.
  • LASIK Laser in Situ Keratomileusis
  • LASEK Laser Epithelial Keratomileusis
  • PRK Photorefractive Keratectomy
  • the corneal onlay 10 may be inserted concurrently with the LASIK procedure.
  • the comeal onlay 10 can also be inserted into the cornea after the LASIK procedure since the flap can be re-opened. Therefore, the comeal onlay 10 can be used in conjunction with other refractive procedures, such as LASIK for correcting myopia or hyperopia.
  • the corneal onlay 10 can be inserted into the cornea by removing the epithelium at the center of the cornea without use of a flap.
  • FIG. 7 is a plot of anterior corneal surface height (in microns) (y axis) vs. radius from center of comeal onlay (mm) (x-axis). The graph shows the change in anterior comeal surface height (in microns) and the corresponding induced added power (e.g., diopters).
  • the percentage by weight of the collagen within the hydrogel composition for forming the onlay can be about, e.g., l%-5%, inclusive 1-4% inclusive, 1-3% inclusive, 1-2%, inclusive 2-5% inclusive, 3-5%, inclusive 4-5% inclusive, 2- 4% inclusive, 3-4% inclusive, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9, 2%, 2.1%, 2.2%, 2.3%, 2.4% 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9% , 4%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5%, or the like.
  • the percentage by weight of the synthetic polymer within the hydrogel composition can be about, e.g., 1.5-7.2%, inclusive, 1.5-7% inclusive, 1.5-6% inclusive, 1.5-5% inclusive, 1.5-4% inclusive, 1.5-3% inclusive, 1.5-2% inclusive, 2-7.2% inclusive, 3-7.2% inclusive, 4-7.2% inclusive, 5-7.2% inclusive, 6-7.2% inclusive, 7-7.2% inclusive, 1.5-7%, inclusive 2-7% inclusive, 3-7% inclusive, 4-7% inclusive, 5-7% inclusive, 6-7% inclusive, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4% 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%,
  • the collagen can be a porcine atelocollagen, type 1, obtained from Nippi Collagen of North America Inc. However, it should be understood that any similar collagen can be used.
  • the onlay material comprises a biopolymer.
  • the natural biopolymer is a collagen.
  • the natural biopolymer is different from the collagen.
  • the percentage by weight of the natural polymer within the hydrogel composition can be substantially equal to the percentage by weight of the collagen.
  • the natural polymer is a collagen.
  • the biopolymer is a synthetic self-assembling biopolymer.
  • 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-assembling protein polymers include, for example, silk fibroin, elastin, collagen, and combinations thereof.
  • the synthetic self-assembling biopolymer is a synthetic collagen.
  • the synthetic self-assembling biopolymer is a recombinant human collagen.
  • the collagen is a collagen mimetic peptide.
  • mimetic refers to chemicals containing chemical moieties that mimic the function of a peptide. For example, if a peptide contains two charged chemical moieties having functional activity, a mimetic places two charged chemical moieties in a spatial orientation and constrained structure so that the charged chemical function is maintained in three-dimensional space.
  • the onlay materials comprise a synthetic polymeric material.
  • the synthetic material is an optically transparent material.
  • the synthetic materials is a biocompatible material.
  • the synthetic material is a hydrophilic material.
  • the synthetic materials is a material permeable to low molecular weight nutrients so as to maintain comeal health.
  • the synthetic materials is a refractive material.
  • the synthetic material is optically transparent, biocompatible, hydrophilic, permeable and refractive.
  • Exemplary biocompatible biodegradable polymers include, without limitation, a poly(lactide); a poly(glycolide); a poly(lactide-co-glycolide); a poly(lactic acid); a poly(glycolic acid); a poly(lactic acid-co-glycolic acid); a poly(caprolactone); a poly(orthoester); a poly anhydride; a poly(phosphazene); a polyhydroxyalkanoate; a poly(hydroxybutyrate); a polycarbonate; a tyrosine polycarbonate; a polyamide; a polyesteramide; a polyester; a poly(dioxanone); a poly(alkylene alkylate); a polyether (such as polyethylene glycol, PEG, and polyethylene oxide, PEO); polyvinyl pyrrolidone or PVP; a polyurethane; a polyetherester; a polyacetal; a polycyanoacrylate;
  • the water-soluble, biocompatible polymer poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) is a zwitterionic polymer that is able to form a more compact conformation in aqueous solution than poly(ethylene glycol) (PEG).
  • non-degradable biocompatible polymers include, without limitation, polysiloxane, polyvinyl alcohol, polyimide a polyacrylate; a polymer of ethylene- vinyl acetate, EVA; cellulose acetate; an acyl-substituted cellulose acetate; a non-degradable polyurethane; a polystyrene; a polyvinyl chloride; a polyvinyl fluoride; a poly(vinyl imidazole); a silicone-based polymer (for example, Silastic® and the like), a chlorosulphonate polyolefin; a polyethylene oxide; polysiloxane, polyvinyl alcohol, and polyimide, or a blend or copolymer thereof.
  • Exemplary copolymers may include, hydroxyethyl methacrylate and methyl methacrylate, and hydroxyethyl methacrylate copolymerized with polyvinyl pyrrolidone (PVP, to increase water retention) or ethylene glycol dimethacrylic acid (EGDM).
  • PVP polyvinyl pyrrolidone
  • EGDM ethylene glycol dimethacrylic acid
  • 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 may include polyethers, including polyethylene glycol, PEG; polyethylene oxide, PEO; polypropylene oxide, PPO, perfluoropolyethers (PFPEs) and block copolymers comprised of combinations thereof.
  • polyethers including polyethylene glycol, PEG; polyethylene oxide, PEO; polypropylene oxide, PPO, perfluoropolyethers (PFPEs) and block copolymers comprised of combinations thereof.
  • the hydrophilic polymer comprises a hydrogel polymer.
  • Hydrogels are water- swollen, cross-linked polymeric structures produced by the polymerization reaction of one or more monomers or by association of bonds, such as hydrogen bonds and strong van der Waals interactions between chains that exist in a state between rigid solids and liquid.
  • Aqueous gels are formed when high molecular weight polymers or high polymer concentration are incorporated in the formulations.
  • Hydrogels generally comprise a variety of polymers. Exemplary polymers include acrylic acid, acrylamide and 2-hydroxyethylmethacrylate (HEMA).
  • Cross-linked poly (acrylic acid) of high molecular weight 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 to mimic the phospholipid polar groups contained with cell membranes.
  • Polyoxamers commercially available as Pluronic® (BASF-Wyandotte, USA), are thermal setting polymers formed by a central hydrophobic part (polyoxypropylene) surrounded by a hydrophilic part (ethylene oxide).
  • Cellulosic derivatives most commonly used in ophthalmology include: methylcellulose; hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC) and sodium carboxymethylcellulose (CMC Na).
  • Photocrosslinked poly(ethylene glycol) diacrylate (PEGDA) hydrogels displaying collagen mimetic peptides (CMPs) that can be further conjugated to bioactive molecules via CMP-CMP triple helix association are described in Stahl, PJ et al. Soft Matter (2012) 8: 10409-10418.
  • a first polymer and a second polymer comprise one or more different non-repeating units, such as, for example, an end group, or a non-repeating unit in the backbone of the polymer.
  • the first polymer and the second polymer comprise one or more different end groups.
  • the first polymer can have a more polar end group than one or more end group(s) of the second polymer.
  • the first polymer will be more hydrophilic, relative to a second polymer (with the less polar end group) alone.
  • the first polymer comprises one or more carboxylic acid end groups
  • the second polymer comprises one or more ester end groups.
  • the onlay material comprises a polymer matrix.
  • the inlay materials may comprise an ultraviolet blocker that is added to the hydrogel composition before fabrication of the inlay material.
  • the inlay materials may comprise a dye (e.g., for easy handling of implant) added to the hydrogel composition before fabrication of the inlay material.
  • the dye can be a UV dye added to the hydrogel composition to allow for visibility of the device during illumination with UV light.
  • the corneal onlay 10 can have properties similar to those of the cornea in nature, and may be made of a hydrogel or other clear biocompatible material. To increase the optical power of the onlay, the onlay may be made of a material with a higher index of refraction than the cornea, e.g., >1.376.
  • the water content can range from 78%-92%, inclusive. In some embodiments, the water content can range from 78%-88% inclusive. In some embodiments, the water content is at least 78%. In some embodiments, the water content is at least 79%. In some embodiments, the water content is at least 80%. In some embodiments, the water content is at least 81%. In some embodiments, the water content is at least 82%. In some embodiments, the water content is at least 83%. In some embodiments, the water content is at least 84%. In some embodiments, the water content is at least 85%. In some embodiments, the water content is at least 86%. In some embodiments, the water content is at least 87%.
  • the water content is at least 88%. In some embodiments, the water content is at least 89%. In some embodiments, the water content is at least 90%. In some embodiments, the water content is at least 91%. In some embodiments, the water content is at least 92%. In some embodiments, the water content is less than 92%. In some embodiments, the water content is less than 90%. In some embodiments, the water content is less than 88%. In some embodiments, the water content ranges from at least 78%-91 % ., inclusive In some embodiments, the water content ranges from at least 78%-90% inclusive. In some embodiments, the water content ranges from at least 78%-89% inclusive. In some embodiments, the water content ranges from at least 78%-88% inclusive.
  • the water content ranges from at least 78%-87% inclusive. In some embodiments, the water content ranges from at least 78%-86% inclusive. In some embodiments, the water content ranges from at least 78%-85% inclusive. In some embodiments, the water content ranges from at least 78%-85% inclusive. In some embodiments, the water content ranges from at least 78%-84% inclusive. In some embodiments, the water content ranges from at least 78%-83%. inclusive In some embodiments, the water content ranges from at least 78%-82% inclusive. In some embodiments, the water content ranges from at least 78%-81% inclusive. In some embodiments, the water content ranges from at least 78%-80% inclusive. In some embodiments, the water content ranges from at least 78%-79% inclusive.
  • the water content ranges from at least 79%-92% inclusive. In some embodiments, the water content ranges from at least 80%-92% inclusive. In some embodiments, the water content ranges from at least 81 %-92% inclusive. In some embodiments, the water content ranges from at least 82%-92% inclusive. In some embodiments, the water content ranges from at least 83%-92% inclusive. In some embodiments, the water content ranges from at least 84%-92% inclusive. In some embodiments, the water content ranges from at least 85%-92% inclusive. In some embodiments, the water content ranges from at least 86%-92% inclusive. In some embodiments, the water content ranges from at least 87%-92% inclusive. In some embodiments, the water content ranges from at least 88%-92% inclusive.
  • the water content ranges from at least 89%-92% inclusive. In some embodiments, the water content ranges from at least 90%-92% inclusive. In some embodiments, the water content ranges from at least 91%-92% inclusive. In some embodiments, the water content ranges from at least 80%-88% inclusive. In some embodiments, the water content ranges from at least 82%-84% inclusive.
  • the low water content of the hydrogel composition used to fabricate the exemplary onlay can allow for ease of handling of the onlay. For example, too high of water content (e.g., above 92% w/w) can create more flexibility in the onlay, resulting in potentially greater difficulty for handling and damage to the onlay.
  • the water content ranging between 78% and 92% w/w, inclusive, can provide a pliable yet sufficiently strong/stiff material that can be easily handled during manufacturing and surgery.
  • the water content range of the hydrogel composition also substantially matches the 78%-80% water content of the cornea, allowing for improved biocompatibility.
  • onlays with water content above the 78%-92% range, inclusive, i.e., at least 78%, at least 79%, 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%, or 92% can have reduced biocompatibility with the cornea due to the lack of a match between the water content of the inlay (or onlay) and the cornea.
  • the substantial match in water content with the cornea results in the same or substantially same refractive index of the inlay and cornea.
  • the semi-synthetic composition of the onlay e.g., synthetic and collagen
  • the onlay comprises an interpenetrating polymer network (IPN).
  • IPPN interpenetrating polymer network
  • An IPN is a polymer comprising two or more networks that are at least partially interlaced on a molecule scale but not covalently bonded to each other and cannot be separated unless chemical bonds are broken (Inti Union of Pure& Applied Chemistry Compendium of Chemical Terminology (IUPAC Gold Book, v. 2.3.3 (2014-02-24), page 750). Mixtures of two or more polymers cannot be termed IPNs and are instead multicomponent polymer material.
  • IPNs have mechanical strength and stability. Also IPNs provide an opportunity to have two or more polymers with distinguishing properties. By modifying the interaction of the IPNs, a synergy can be achieved, which results in enhanced performance that surpasses that of either of the original polymers. Purkait, MK, et al. Interface Science and Technology (2016) vol. 25, chapter 3, section 3.2.3: 67-113).
  • the hydrogel polymer comprises an interpenetrating network (IPN) which includes two or more polymeric units in the network in which the polymers are interlaced with each other (Maity, S. et al. Green approaches in medicinal chemistry for sustainable drug design. Advances in Green Chemistry (2020) 617-49, citing Dragan, E.S. “Design and applications of interpenetrating polymer network hydrogels. A review. Chem. Eng. J. (2014) 243: 572-90).
  • IPN interpenetrating network
  • IPN hydrogel For the preparation of an IPN hydrogel, the polymers should meet the following criteria. First, there should be one polymer which can be synthesized and/or cross- linked with the other. Second, the polymers should have similar reaction rates. Lastly, there should not be any phase separation between/among the polymers (Id., citing (Bajpai, AK et al. Responsive polymers in controlled drug delivery. Prog. Polym. Sci. (2008) 33: 1088-18). Advantages of IPN hydrogels include their viscoelastic properties and easy swelling behavior without dissolving in any solvent (Id.). IPNs can be prepared by chemistry and (ii) by structure [Id., citing Myung, D. et al. Polym. Adv. Technol. (2008) 647-57; Naseri, N. et al. Biomacromolecules (2016) 17: 3714-23.
  • IPN hydrogels can be divided into simultaneous IPNs or sequential IPNs.
  • simultaneous IPNs both the networks are prepared simultaneously from the precursors by independent, noninterfering routs that will not interfere with one another.
  • sequential IPNs a network is made of a single network hydrogel by swelling into a solution comprising the mixture of monomer, initiator and activator, with or without a cross-linker. (Id.).
  • IPN hydrogels can be categorized into the following types:
  • the morphology of the latex IPN depends on the polymerization techniques of the IPN components;
  • thermoplastic IPNs which can be moldable, extruded and recycled. At least one component generally is a block copolymer. (Id.).
  • Molding can be used to fabricate the hydrogel onlay discussed herein.
  • FIGS. 8-22 show perspective, cross-sectional and detailed views of components of an exemplary mold assembly 100 for fabricating or forming the hydrogel onlays discussed herein.
  • the mold assembly 100 generally includes a first mold section 102 (e.g., a male mold section) and a second mold section 104 (e.g., a female mold section).
  • the mold assembly 100 can be fabricated for single-use purposes.
  • the material of fabrication of the mold assembly 100 can be transparent to UV light, allowing for cross-linking of the hydrogel composition within the mold assembly 100.
  • the mold sections 102, 104 are configured to fit complementary to each other to form a cavity 106 therebetween.
  • the cavity 106 is in the form of the onlay to be fabricated.
  • each of the mold sections 102, 104 includes one or more radial complementary channels that can assist with escape of air during molding.
  • the first mold section 102 can include a hemispherical cavity 108 formed in the mating surface, while the second mold section 104 can include a substantially flat cavity 110 formed in the mating surface.
  • the cavities 108, 110 align to define the overall shape or form of the hydrogel onlay (e.g., a dome-shaped onlay).
  • the cavity 110 can define an upwardly curved or hemispherical form such that when mated against each other, the cavities 108, 110 align to define an onlay having curved front (posterior) and base (posterior) surfaces). Both cavities 108, 110 define a substantially circular shape.
  • the diameter of the hemispherical cavity 108 can be about, e.g., 1.8-2.2 mm, inclusive, 1.8-2.1 mm inclusive, 1.8-2.0 mm inclusive, 1.8- 1.9 mm inclusive, 1.9-2.2 mm inclusive, 2.0-2.2 mm inclusive, 2.1-2.2 mm inclusive, 1.8 mm, 1.9 mm, 2.0 mm, 2.1 mm, 2.2 mm, or the like.
  • the radius of the hemispherical cavity 108 can be about, e.g., 16.213 mm.
  • the diameter of the flat cavity 110 can be about, e.g., 1.8-2.2 mm, inclusive, 1.8-2.1 mm inclusive, 1.8-2.0 mm inclusive, 1.8-1.9 mm inclusive, 1.9-2.2 mm inclusive, 2.0-2.2 mm inclusive, 2.1-2.2 mm inclusive, 1.8 mm, 1.9 mm, 2.0 mm, 2.1 mm, 2.2 mm, or the like.
  • the edge thickness of the cavity i.e., cavities 108, 110 mated together
  • the center thickness of the entire cavity can be about, e.g., 15-30 microns, 15-25 microns, inclusive, 15-20 microns, inclusive, 20-30 microns, inclusive, 25-30 microns, inclusive, 15 microns, 20 microns, 25 microns, 30 microns, or the like.
  • FIGS. 13-17 are perspective, top, side, cross-sectional and detailed views of the first mold section 102.
  • the mold section 102 includes a body 112 defining a substantially cylindrical configuration.
  • the body 112 includes a bottom surface 114 and an opposing top surface defining the substantially planar mating surface 116.
  • the mold section 102 includes a radial flange 118 extending near the outer perimeter of the body 112 from the top surface, and positioned slightly inwardly offset from the outer perimeter or edge of the body 112.
  • the mold section 102 includes a first radial channel 120 inwardly formed in the top surface adjacent to the radial flange 118.
  • the mold section 102 includes a second radial channel 122 inwardly formed in the top surface.
  • the second radial channel 122 defines a smaller diameter than the first radial channel 120, and is therefore disposed closer to the central longitudinal axis of the mold section 102.
  • the inner walls of the channels 120, 122 taper inwardly.
  • the inwardly extending hemispherical cavity 108 is formed in the top surface of the body 112 and is substantially aligned with a central longitudinal axis of the mold section 102.
  • a perimeter section 124 surrounds the cavity 108 and forms part of the mating surface 116.
  • FIGS. 18-22 are perspective, top, side, cross-sectional and detailed views of the second mold section 104.
  • the mold section 104 includes a body 126 defining a substantially cylindrical configuration complementary to the body 112 of the mold section 102.
  • the body 126 includes a bottom surface 128 and an opposing top surface defining the substantially planar mating surface 130.
  • the mold section 104 includes a radial edge 132 extending at or near the perimeter of the body 126 from the top surface.
  • the mold section 104 includes a first radial channel 134 inwardly formed in the top surface adjacent to the radial edge 132.
  • the mold section 104 includes a second radial channel 136 inwardly formed in the top surface.
  • the second radial channel 136 defines a smaller diameter than the first radial channel 134, and is therefore disposed closer to the central longitudinal axis of the mold section 104.
  • the diameters and edges of the radial channels 134, 136 are dimensioned substantially complementary to the diameters and edges of the respective radial channels 120, 122 of the mold section 102. As illustrated in FIG. 21, the inner walls of the channels 134, 136 taper inwardly.
  • the flat cavity 110 is formed in the top surface of the body 126 and is substantially aligned with a central longitudinal axis of the mold section 104. As noted above, rather than the flat cavity 110, the cavity 110 could define an upwardly curved surface such that a curved base of the onlay could be formed. A perimeter section 138 surrounds the cavity 110 and forms part of the mating surface 130.
  • the mold section 104 includes a transverse channel, cutout or slit extending through the radial flange 132 and the raised section of the body 126 between the channels 134, 136.
  • the transverse channel includes channels 140, 142 that extend through the radial flange 132 on opposing sides of the body 126, and channels 144, 146 that extend through the raised section of the body 126 between the channels 134, 136.
  • the bottom of the channels 140-146 is substantially aligned with the bottom surface of the channels 134, 136.
  • the channels 140-146 provide a fluidic connection between the channels 134, 136 (and also channels 120, 122 of the mold section 102 when both mold sections 102, 104 are mated to each other).
  • the uncrosslinked hydrogel composition can be placed within the cavity 110 of the mold section 104, and the mold section 102 can be aligned with and positioned over the mold section 104 such that the mating surfaces 116, 130 are positioned against each other.
  • the radial flange 118 of the mold section 102 is configured and dimensioned to fit within the radial edge 132 of the mold section 104, and against the outer wall of the channel 134 of the mold section 104, to ensure alignment and mating of the mold sections 102, 104 relative to each other.
  • the cavities 108, 110 are enclosed by the mating surfaces to ensure proper distribution of the hydrogel during formation of the onlay.
  • the channels 120, 122, 134, 136 are aligned to allow for escape of air and/or gas from the mold assembly 100. However, clamps should not obstruct UV light from reaching the hydrogel in the mold cavity.
  • the inlay is alloyed to further crosslink at ambient conditions before the only is demolded, further processed and characterized.
  • FIGS. 23-28 are front, side and cross-sectional views of an exemplary hydrogel inlay 200 fabricated using the mold assembly 100.
  • the exemplary hydrogel onlay can define a substantially similar configuration as the inlay 200.
  • the inlay 200 can define a substantially circular shape of a diameter of about, e.g., 1.8-2.2 mm inclusive, 1.8-2.1 mm inclusive, 1.8-2.0 mm inclusive, 1.8- 1.9 mm inclusive, 1.9-2.2 mm inclusive, 2.0-2.2 mm inclusive, 2.1-2.2 mm inclusive, 1.8 mm, 1.9 mm, 2.0 mm, 2.1 mm, 2.2 mm, or the like.
  • the inlay 200 can define an edge thickness of about, e.g., 0.015-0.025 mm inclusive, 0.015-0.02 mm inclusive, 0.02-0.025 mm inclusive, 0.015 mm, 0.02 mm, 0.025 mm, or the like.
  • the inlay 200 can define a center thickness of about, e.g., 0.04-0.06 mm inclusive, 0.05-0.06 mm inclusive, 0.04-0.05 mm inclusive, 0.04 mm, 0.05 mm, 0.06 mm, or the like.
  • the inlay 200 includes a substantially flat perimeter edge 202, a convex top surface 204, and a substantially flat bottom surface 206. As illustrated in FIG. 25, the body of the inlay 200 is solidly formed from the hydrogel (e.g., no openings or hollow cavities), with the inlay 200 tapering from the thickest area at the central longitudinal axis to the thinnest area at the perimeter edge 202.
  • the onlay can define a center thickness of about, e.g., 0.015 mm to 0.03 mm, 0.02 mm to 0.03 mm, 0.025 mm to 0.03 mm, 0.015 mm to 0.025 mm, 0.015 mm to 0.02 mm, 0.02 mm to 0.025 mm, 0.015 mm, 0.02 mm, 0.025 mm, 0.03 mm, or the like.
  • the cavities 108, 110 of the mold assembly 100 can be adjusted to form a hydrogel meniscus onlay 210 shown in FIGS. 27-29.
  • the onlay 210 can include a substantially circular shape having a diameter of about 1.9 ⁇ 0.3 mm (e.g., 1.6- 2.2 mm inclusive, 1.6-2.1 mm inclusive, 1.6-2.0 mm inclusive, 1.6- 1.9 mm inclusive, 1.6- 1.8 mm inclusive, 1.6- 1.7 mm inclusive, 1.7-2.2 mm inclusive, 1.8-2.2 mm inclusive, 1.9-2.2 mm inclusive, 2.0-2.2 mm inclusive, 2.1-2.2 mm inclusive, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2.0 mm, 2.1 mm, 2.22 mm, or the like), an edge thickness of about 0.005-0.012 mm inclusive (e.g., 0.005-0.011 mm inclusive, 0.005-0.010 mm inclusive, 0.005-0.009 mm inclusive,
  • the onlay 210 includes a substantially flat perimeter edge 212, a convex top surface 214, and a concave bottom surface 216. As illustrated in FIG. 28, the body of the onlay 210 is solidly formed from the hydrogel, with the onlay 210 tapering from the thickest area at the central longitudinal axis to the thinnest area at the perimeter edge 212.
  • the onlay can define a substantially disc-shaped configuration.
  • the disc-shaped inlay can define a diameter of about, e.g., 1.8-2.2 mm inclusive, 1.8-2.1 mm inclusive, 1.8-2.0 mm inclusive, 1.8-1.9 mm inclusive, 1.9-2.2 mm inclusive, 2.0-2.2 mm inclusive, 2.1-2.2 inclusive, 1.8 mm, 1.9 mm, 2.0 mm, 2.1 mm, 2.2 mm, or the like.
  • the disc-shaped inlay can define a thickness of about, e.g., 10-30 pm inclusive, 10-25 pm inclusive, 10-20 pm inclusive, 10-15 pm inclusive, 15-30 pm inclusive, 20-30 pm inclusive, 25-30 pm inclusive, or the like.
  • an approximately 10 mm diameter cavity mold can be used to fabricate the 10 mm disc.
  • 15-20 mm inclusive diameter molds can be used to fabricate the disc.
  • a 2 mm biopsy punch can be used to punch out the 2 mm x 30 pm disc-shaped onlay from the 10 mm disc.
  • a laser beam can be used to create the disc and/or disc-shaped inlays.
  • a disc 4 mm in diameter can be implanted into the cornea, and a femtosecond laser can be used to cut out an approximately 2 mm disc shaped inlay.
  • FIGS. 52-64 show perspective, cross-sectional and detailed views of components of an exemplary mold assembly 300 for fabricating or forming the hydrogel inlays having a disc-shaped configuration discussed herein.
  • the mold assembly 300 can be substantially similar in structure and/or function to the mold assembly 100, except for the distinctions noted herein.
  • the mold assembly 300 generally includes a first mold section 302 (e.g., a male mold section) and a second mold section 304 (e.g., a female mold section).
  • the mold assembly 300 can be fabricated for single-use purposes.
  • the material of fabrication of the mold assembly 300 can be transparent to UV light, allowing for cross-linking of the hydrogel composition within the mold assembly 300.
  • the mold sections 302, 304 are configured to fit complementary to each other to form a cavity 306 therebetween.
  • the cavity 306 is in the form of the disc-shaped inlay to be fabricated.
  • each of the mold sections 302, 304 includes one or more radial complementary channels that can assist with escape of air during molding.
  • the first mold section 302 includes a flat cavity 308 formed in the mating surface
  • the second mold section 304 includes a flat cavity 310 formed in the mating surface.
  • both cavities 308, 310 align to define the overall shape or form of the hydrogel disc that can be used to punch out a disc-shaped inlay.
  • Both cavities 308, 310 define a substantially circular shape.
  • the diameter of the cavity 308 can be about, e.g., 14-24 mm inclusive, 14-23 mm inclusive, 14-22 mm inclusive, 14-21 mm inclusive, 14-20 mm inclusive, 14-19 mm inclusive, 14-18 mm inclusive, 14-17 mm inclusive, 14-16 mm inclusive, 14-15 mm inclusive, 15-24 mm inclusive, 16-24 mm inclusive, 17-24 mm inclusive, 18-24 mm inclusive, 19-24 mm inclusive, 20-24 mm inclusive, 21-24 mm inclusive, 22-24 mm inclusive, 23-24 mm inclusive, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm inclusive, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21
  • the depth of the cavity 308 can be about, e.g., 0.4-0.6 mm inclusive, 0.4-0.55 mm inclusive, 0.4-0.5 mm inclusive, 0.4-0.45 mm inclusive, 0.45-0.6 mm inclusive, 0.5-0.6 mm inclusive, 0.55-0.6 mm inclusive, 0.4 mm, 0.45 mm, 0.5 mm, 0.55 mm, 0.6 mm, or the like.
  • the diameter of the cavity 310 can be about, e.g., 8-12 mm inclusive, 8-11.5 mm inclusive, 8- 11 mm inclusive, 8-10.5 mm inclusive, 8-10 mm inclusive, 8-9.5 mm inclusive, 8-9 mm inclusive, 8-8.5 mm inclusive, 8.5-12 mm inclusive, 9-12 mm inclusive, 9.5-12 mm inclusive, 10-12 mm inclusive, 10.5-12 mm inclusive, 11-12 mm inclusive, 11.5-12 mm inclusive, 8 mm, 8.5 mm, 9 mm, 9.5 mm, 10 mm, 10.5 mm, 11 mm, 11.5 mm, 12 mm, or the like.
  • the depth of the cavity 310 can be about, e.g., 0.3-0.5 mm inclusive, 0.3- 0.45 mm inclusive, 0.3-0.4 mm inclusive, 0.3-0.35 mm inclusive, 0.35-0.5 mm inclusive, 0.4- 0.5 mm inclusive, 0.45-0.5 mm inclusive, 0.3 mm, 0.35 mm, 0.4 mm, 0.45 mm, 0.5 mm, or the like.
  • FIGS. 55-59 are perspective, top, side, cross-sectional and detailed views of the first mold section 302.
  • the mold section 302 includes a body 312 defining a substantially cylindrical configuration.
  • the body 312 includes a bottom surface 314 and an opposing top surface defining the substantially planar mating surface 316.
  • the mold section 302 includes a radial flange 318 extending near the outer perimeter of the body 312 from the top surface, and positioned slightly inwardly offset from the outer perimeter or edge of the body 312.
  • FIGS. 60-64 are perspective, top, side, cross-sectional and detailed views of the second mold section 304.
  • the mold section 304 includes a body 326 defining a substantially cylindrical configuration complementary to the body 312 of the mold section 302.
  • the body 326 includes a bottom surface 328 and an opposing top surface defining the substantially planar mating surface 330.
  • the mold section 304 includes a radial edge 332 extending at or near the perimeter of the body 226 from the top surface.
  • the mold section 204 includes a first radial channel 234 inwardly formed in the top surface adjacent to the radial edge 332.
  • the mold section 304 includes a second radial channel 336 inwardly formed in the top surface.
  • the second radial channel 336 defines a smaller diameter than the first radial channel 334, and is therefore disposed closer to the central longitudinal axis of the mold section 304.
  • the diameters and edges of the radial channels 334, 336 are dimensioned substantially complementary to the diameters and edges of the mold section 302. As illustrated in FIG. 63, the inner walls of the channels 334, 336 taper inwardly.
  • the flat cavity 310 is formed in the top surface of the body 326 and is substantially aligned with a central longitudinal axis of the mold section 304.
  • a perimeter section 338 surrounds the cavity 310 and forms part of the mating surface 330.
  • the mold section 304 includes a transverse channel, cutout or slit extending through the radial flange 332 and the raised section of the body 326 between the channels 334, 336.
  • the transverse channel includes channels 340, 342 that extend through the radial flange 332 on opposing sides of the body 326, and channels 344, 346 that extend through the raised section of the body 326 between the channels 334, 336.
  • the bottom of the channels 340-346 is substantially aligned with the bottom surface of the channels 134, 136.
  • the channels 140- 146 provide a fluidic connection between the channels 334, 336.
  • the uncrosslinked hydrogel composition can be placed within the cavity 310 of the mold section 304, and the mold section 302 can be aligned with and positioned over the mold section 304 such that the mating surfaces 316, 330 are positioned against each other.
  • the radial flange 318 of the mold section 302 is configured and dimensioned to fit within the radial edge 332 of the mold section 304, and against the outer wall of the channel 334 of the mold section 304, to ensure alignment and mating of the mold sections 302, 304 relative to each other.
  • the cavities 308, 310 are enclosed by the mating surfaces to ensure proper distribution of the hydrogel during formation of the disc for the inlay.
  • the channels 134, 136 allow for escape of air and/or gas from the mold assembly 300.
  • a clamp can be used to secure the mold sections 302, 304 to each other prior to crosslinking, as long as the clamp does not obstruct UV light from reaching the hydrogel in the mold cavity.
  • the refractive index may be between about, e.g., 1.33-1.36, inclusive, 1.33- 1.35, inclusive, 1.33-1.34, inclusive, 1.34-1.36, inclusive, 1.35-1.36, inclusive, 1.34-1.35, inclusive, 1.33, 1.34, 1.35, 1.36, or the like, when measured at about 23 ⁇ 1°C.
  • the onlay may have a percent transmittance of between about, e.g., 94-98%, inclusive, 94-97%, inclusive, 94-96%, inclusive, 94-95%, inclusive, 95-98%, inclusive, 96-98%, inclusive, 97- 98%, inclusive, 95-97%, inclusive, 95-96%, inclusive, 94%, 95%, 96%, 97%, 98%, or the like, at about 300 nm.
  • the hydrogel may be injected into the mold and comeal onlays may then be polymerized by a method appropriate for the particular polymer(s) employed, e.g., chemically, by successive cross-linking of precursors using UV light, cross-linking agents, thermally, or by photopolymerization. After polymerization, the onlay can be removed from the mold (demolded), washed and stored in buffer with a preservative until use.
  • the cross-linking agent is Poly(ethylene glycol) diacrylate (PEGDA).
  • the cross-linking agent is any multi arm PEG acrylate or methacrylate (e.g., 3 or 4 or 8 arm PEG acrylate or methacrylate).
  • the hydrogel composition can be formed by initially hydrating the natural polymer, e.g., a collagen, in an acidic medium.
  • the dry collagen is mixed with a buffer at a pH of about 3.0, and sits at about 5 ⁇ 3°C for about 10 days (at a minimum 8 days).
  • the cross-linker(s), monomer(s) and/or polymer(s), and UV initiator are added to the hydrated collagen.
  • the cross-linker for the collagen ranges from about, e.g., 0.25-0.75% inclusive, 0.25-0.65% inclusive, 0.25-0.55% inclusive, 0.25-0.45% inclusive, 0.25-0.35% inclusive, 0.35-0.75% inclusive, 0.45-0.75% inclusive, 0.55-0.75% inclusive, 0.65-0.75% inclusive, 0.25%, 0.35%, 0.45%, 0.55%, 0.65%, 0.75%, or the like, by weight of the hydrogel composition.
  • the monomer ranges from about, e.g., 1.2-4.8% inclusive, 1.2-4.0% inclusive, 1.2-3.5% inclusive, 1.2-3.0% inclusive, 1.2-2.5% inclusive, 1.2-2.0% inclusive, 1.2-1.5% inclusive, 1.5-4.8% inclusive,
  • the cross-linker for the synthetic polymer (after monomer polymerization)ranges from about, 0.2-0.6% inclusive, 0.2-0.5% inclusive, 0.2-0.4% inclusive, 0.2-0.3% inclusive, 0.3-0.6% inclusive, 0.4-0.6% inclusive, 0.5-0.6% inclusive, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, or the like.
  • the hydrogel mixture is degassed and then added to the mold prior to cross-linking.
  • UV light is used to crosslink the hydrogel composition for about 15-30 minutes.
  • the inlay is then allowed to cross-link in ambient conditions for about 12-20 hours, resulting in complete polymerization of the composition.
  • the UV wavelength intensity ranges from about, e.g., 360-405 nm inclusive, 360-400 nm inclusive, 360-390 nm inclusive, 360- 380 nm inclusive, 360-370 nm inclusive, 370-405 nm inclusive, 380-405 nm inclusive, 390- 405 nm inclusive, 400-405 nm inclusive, 360 nm, 370 nm, 380 nm, 390 nm, 400 nm, 405 nm, or the like.
  • the crosslinked hydrogel can remain in a chamber overnight. Once removed, the inlay is hydrated in lx phosphate buffer then washed several times in phosphate buffer to extract unpolymerized material and residual crosslinker and/or UV initiator.
  • a single cavity mold e.g., male and female molds
  • 2-cavity molding e.g., multi cavity with two or more male and/or two or more female molds
  • cannula molding can be used to fabricate the onlay.
  • One side of a lenticule may be molded against a surface, the other side can be molded in free air.
  • the curved side is formed due to surface tension only, and is not in contact with a plastic surface as in 2-cavity molding. The result is a dome-shaped lenticule.
  • surface energy molding may be used to fabricate the onlay. Based on the surface energy of a solid surface or substrate, the pre-mix can be dropped onto the surface and forms a shape.
  • the shape is a dome geometry meaning flat on one side and curved on the other.
  • the surface energy of the substrate and the volume of pre-mix determine the final geometry of the molded article.
  • the corneal onlay may be cast as a flat, thin, round disc.
  • the fabricated onlay may be cast as a hemispherical dome.
  • the fabricated onlay may be cast as a spherical lens.
  • the fabricated onlay may be cast as a thin sheet. The mold can be adjusted as needed depending on the configuration of the desired onlay.
  • the corneal onlay improves near vision and decreases dependence on near- vision correction modalities on presbyopic patients.
  • the onlay may resemble a small contact lens implanted onto the cornea.
  • one onlay e.g., lens
  • the mode of action is based on addition of the lens to replacement epithelium, which gives rise to a micron size bump anterior to the cornea. This causes a small refractive change giving rise to about +1-5 to +3 diopters of correction, hence, enabling the patient to view items at near distance. Visual acuity at far distance is still maintained.
  • the onlay can have a center thickness of about 15-30 microns, inclusive; for example, about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29, or 30 microns.
  • the onlay is considered to be an optically clear hydrogel with a water content of about 70-92% , inclusive produced from porcine collagen.
  • an 80% water content, collagen-based hydrogel can be used as a corneal onlay implant. Fabrication of the onlay can involve accurate control and consideration of several parameters, e.g., overall geometry, center thickness, edge thickness, surface quality, smoothness/roughness, front radius of curvature, back radius of curvature.
  • the exemplary onlay provides several advantages that alone or in combination provide improved results post-implantation.
  • Lower water content is a stiffer material, which means it may be easier to manufacture and handle.
  • Our experience is that at a water content ranging from about 78%-92%, inclusive, or from about 78%-80%, inclusive, the index of refraction is similar to the index of refraction of both water and the cornea, therefore the onlay does not cause any refraction change.
  • the vision correction of the cornea is primarily due to the shape of the onlay
  • the onlay can be adhered to the Bowman’s membrane with, e.g., a biological coating (e.g., fibronectin, collagen, RGDS (Kobayashi, H. and Ikacia, Y., Current Eye Res. (2009) 10 (10): 899-908); or a biocompatible adhesive [see Rostron, CK et al. Arch. Ophthalmol. (1988) 106: 1103-6; Nam, S. and Mooney, D. Chem. Rev.
  • a biological coating e.g., fibronectin, collagen, RGDS (Kobayashi, H. and Ikacia, Y., Current Eye Res. (2009) 10 (10): 899-908
  • a biocompatible adhesive see Rostron, CK et al. Arch. Ophthalmol. (1988) 106: 1103-6; Nam, S. and Mooney, D. Chem. Rev.
  • PEG is FDA approved in a number of applications and is broadly considered to be nontoxic, biocompatible and nonimmunogenic. [Id., citing Mehdizadeh, M. and Yang, J. Macromol. Biosci. (2013) 13: 271-88].
  • DuraSeal Xact Adhesion Barrier and Sealant System utilizes an NHS ester to achieve a hydrogel with adhesive cross-linking and bonding to tissues with reduced swelling [Id., citing Preul, MC et al. J. Neurosurg. Spin (2010) 12: 381-90; Fransen, P.
  • Cell-Tak is a nonimmunogenic extracellular matrix protein preparation isolated from the marine mussel, Mytilus edulis (Corning].
  • photochemical tissue bonding PTB
  • Riboflavin or Rose Bengal and UV light may be implemented to secure or glue the onlay in the desired position.
  • cyanoacrylate glue typically used for comeal lacerations/perforations and gluing small corneal patches on corneal perforations, comeal melts, and corneal wound leaks
  • At least a portion of the epithelial layer may be removed from the cornea and the remaining surface cleaned before implantation of the onlay onto the Bowman’s membrane.
  • a portion of the epithelial layer e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100%] may be removed to reduce the thickness from the anterior side of the epithelial layer, thereby accommodating the onlay.
  • a central section of the epithelial layer may be removed entirely to accommodate implantation of the onlay, with the epithelial layer growing over the onlay in about 24-48 hours.
  • the onlay creates a bump in the cornea that improves presbyopia.
  • the hydrogel composition dries against the surface of the Bowman’s membrane, the onlay sticks to the Bowman’s membrane without the use of a biocompatible adhesive.
  • a contact lens can be positioned over the onlay to assist with the healing process.
  • the described onlay provides no inflammation post implantation, no necrosis, and no haze, even after implanting materials in rabbits for more than 2 years. It therefore is a truly biocompatible device.
  • each intervening value to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, 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.
  • the upper and lower limits of these smaller ranges which may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.
  • a collagen- synthetic polymer hydrogel inlay was formed from a collagen-2-Methacryloyloxyethyl phosphorylcholine (MPC)-Poly(ethylene glycol) diacrylate (PEGDA) composition.
  • the hydrogel composition included an IPN made of a natural polymer (e.g., collagen), and two synthetic polymers (i.e., MPC and PEGDA).
  • the water content of the composition ranged from about 94% to about 98% (referred to herein as a “high water content composition”). In some instances the hydrogel composition had a water content of between about 90% to about 96%.
  • the IPN for the high water content composition had a collagen/PEGDA weight ratio of about 4:1, and a PEGDA/MPC weight ratio varying from about 1:3 to about 1:1, inclusive, (i.e.., 1:3, 1:2, or 1:1).
  • the length of PEGDA was small enough to serve as both a crosslinking agent and a macro-monomer i.e., between about 200 to about 700 Da.
  • a crosslinking agent was used to crosslink collagen, while an ultraviolet (UV) initiator was used for simultaneously initiating the polymerization and crosslinking of MPC with PEGDA as a crosslinker.
  • the hydrogel composition was cross-linked with a UV initiator which can extend the mold fabrication time up to about 5 minutes.
  • cross-linking must occur in less than 30 seconds, minimizing the time allotted to ensuring the hydrogel is properly positioned in the mold.
  • Exemplary inlay 2 A second inlay was formed from a collagen-MPC- PEGDA composition.
  • the hydrogel composition included an IPN made of a natural polymer (e.g., collagen), and two synthetic polymers (i.e., MPC and PEGDA).
  • the composition had a water content ranging from about 78% to about 92% (referred to herein as a “low water content composition”).
  • the IPN for the low water content composition had a collagen/PEGDA weight ratio varying from about 1:3 to about 1:10, and a PEGDA/MPC weight ratio varying from about, e.g., 1:0.5-0.5:1, 1:0.6-0.5:1, 1:0.7-0.5:1, 1:0.8-0.5:1, 1:0.9- 0.5:1, 1:1-0.5:1, E0.5-0.6-:, 1:0.5-0.7:1, 1:0.5-0.8:1, 1:0.5-0.9:1, 1:0.5-1:1, or the like.
  • the length of PEGDA was greater than about 700 Da.
  • a crosslinking agent was used to crosslink collagen, while an initiator (e.g., UV) was used for simultaneously initiating polymerization and crosslinking of MPC and PEDGA.
  • One crosslinking chemistry can be, e.g., DMT-MM-APS/TMEDA.
  • DMT- MM was used to slowly crosslink collagen, while the redox pair, Ammonium Persulfate (APS)/TMEDA was used to polymerize and crosslink MPC, with PEGDA as the crosslinker. The entire process was performed at room temperature.
  • APS Ammonium Persulfate
  • Another crosslinking chemistry can be, e.g., DMT-MM-LAP.
  • DMT-MM was used to slowly crosslink collagen
  • a UV initiator Lithium phenyl-2, 4,6- trimethylbenzoylphosphinate (LAP) was used to polymerize and crosslink MPC, with PEGDA as the crosslinker.
  • the UV initiator can be 2,2-Dimethoxy-2- phenylacetophenone (DMPA) or Irgacure.
  • UV polymerization/crosslinking was performed in a UV chamber. After the completion of UV polymerization/crosslinking, the sample was removed from the UV chamber and the crosslinking of collagen was continued for about 12 more hours.
  • Example 3 Method of Making DMT-MM-APS/TMEDA Hydrogel Inlays comprising Water Content Ranging From About 94% to About 98%
  • crosslinking/initiating reagents were then prepared; 4% w/w solution of APS in MES buffer pH 2.90, 4% w/w solution of TMEDA solution in MES buffer pH 2.90, and a 12% solution of DMT-MM in MES buffer pH 2.90.
  • the tube labeled 1 was removed from 5 °C and 12.19 mg TMEDA solution was added and mixture was homogenized by vortexing. 52 mg of DMT-MM solution and 15.63 mg of APS solution were added to the tube and vortexed to properly mix.
  • the mixture was then centrifuged at 15 °C to remove air bubbles before casting in PMMA cavity molds and allowed to polymerize/crosslink for approximately 12 hours at room temperature, in a humidity chamber. After crosslinking the inlay was demolded and washed several times in lx phosphate buffer saline (PBS) buffer to remove residual reagents.
  • PBS lx phosphate buffer saline
  • Example 4 Method of Making DMT-MM-LAP Hydrogel Tnlays comprising a Water Content Ranging From About 94% to About 98% for Comparison Testing
  • a refractometer is used to determine the refractive index.
  • the refractometer is first calibrated with HPLC water and a calibration oil before measurements.
  • To measure the refractive index of the inlay excess water on the inlay (10 mm diameter by 100 mhi thickness) is blotted with the aid of KimWipes before it is placed on the measuring prism. Once the prism is closed, an adjustment knob is used to adjust and align a shadow-line to intersects a crosshairs. Once this is completed, the refractive index of the material as well as the temperature are read and recorded.
  • Percent transmission of a fully hydrated inlay sample is measured using a spectrophotometer, calibrated with HPLC water.
  • the sample (10 mm diameter by 100 pm thickness) is placed inside the cuvette, along with HPLC water and adjusted so that it is touching the bottom of the cuvette and pressed up against the front side.
  • the cuvette is then inserted into the cell holder compartment for a UV scan.
  • the percent transmission at 300 nm is recorded as the % transmittance of the materials.
  • MTT is used to measure cellular metabolic activity as an indicator of cell viability, proliferation and cytotoxicity. The darker the solution, the greater the number of viable metabolically active cells.
  • Protocol 12 mm discs are added to cover most of the well area of 24 well plates.
  • the following numbers of rabbit comeal fibroblasts were seeded in duplicate per well: 200K, 100K, 50K, 25K, 12.5K, 6.25K.
  • Cells were cultured in standard culture medium. 10 wells correspond to test samples; 6 wells correspond to controls (no discs).
  • An MTT calibration plate is seeded on day 3 with the same cell numbers. The calibration plate is evaluated by microscopy before the assay and confluency estimated. On day 4, water soluble yellow MTT (4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) is added to the cultures.
  • MTT is reduced to purple insoluble formazan by mitochondrial dehydrogenase in the mitochondria of viable cells.
  • the formazan is solubilized with detergent and measured spectrophotometrically.
  • Viable cells with active metabolism convert MTT into a purple colored formazan product with an absorbance maximum near 570 nm.
  • Rationale An in vitro cytophilicity assay using rabbit corneal fibroblasts measures migration of rabbit keratocytes onto a test material and their attachment. The test therefore addresses whether the material of the exemplary inlays is toxic to cells and whether cells can attach and grow on the material. If cell coverage on the material is judged acceptable (e.g., confluent, no dead cells, others), then the material is a candidate for a more detailed animal implant study. All materials passing this test have shown excellent biocompatibility in subsequent in vivo animal studies in rabbit eyes.
  • Protocol Passaged NZW rabbit comeal fibroblasts were seeded in media containing test article. Cell growth was monitored for up to seven days to see if cells attach and grow on the test article, if cell morphology is altered in the presence of the test article, and to measure the thickness of test article. Fully biocompatible test articles showed 100% cell confluence between four and seven days. When implanted in animals, these materials remained clear and transparent even after two years. Test articles that were not biocompatible showed less than 30% cell confluence after seven days. In some cases, no cell growth was observed. When implanted in animals, these materials became hazy between three to six months.
  • FIG. 30 shows an image of cell coverage on a biocompatible material
  • FIG. 31 shows an image of cell coverage on a non-biocompatible material.
  • the whitish or light-colored line in the images is the edge of material on the wall plate which serves as the control.
  • day seven cells were confluent on both material and control as seen in FIG. 30. While cells were confluent on the control in FIG. 31, no cells were found on the material.
  • Sample materials OM-PC-MPC 1% to 3% collagen.
  • Materials Ferentis secondary and non-secondary; and OM PC-MPC.
  • the OM-PC-MPC materials included a 1% collagen sample and a 2.5% collagen sample, each having water content of about 79-82% inclusive.
  • Table 1 is a list of samples tested in the cell attachment assay, including a Group ID, a description, and the number of samples/size.
  • the samples included (1) Nippon 07.14.20, 07.24.20 DMTMM 10%; (2) Nippi 07.24.20, 08.11.20 DMTMM 10%; (3) Nippi 07.24.20, 08.17.20 DMTMM 12%; (4) Nippi 07.24.20, 08.19.20 DMTMM 15%; and (5) Ferentis 1823B, Ferentis 1837A.
  • Table 1 is a list of samples tested in the cell attachment assay, including a Group ID, a description, and the number of samples/size. The samples included (1) Nippon 07.14.20, 07.24.20 DMTMM 10%; (2) Nippi 07.24.20, 08.11.20 DMTMM 10%; (3) Nippi 07.24.20, 08.17.20 DMTMM 12%; (4) Nippi 07.24.20, 08.19.20 DMT
  • FIGS. 33 and 34 show the measured thickness of the samples based on cell growth at days 4 and 7, respectively, and FIG. 35 shows the measured thickness over time for each of the samples.
  • Tables 2 and 3 show confluency and additional details regarding cell growth for each of the samples based on microscopy imaging at days 4 and 7, respectively.
  • FIGS. 36A-36G and 37A-37G are microscopy images for days 4 and 7, with FIGS. 36A and 37A showing an image of the control, FIGS. 36B and 37B showing images for Nippi 10%, FIGS. 36C and 37C showing images for Nippi 12%, FIGS. 36D and 37D showing images for Nippi 15%, FIGS. 36E and 37E showing images or Nippon 10%, FIGS.
  • FIGS. 36F and 37F showing images for Ferentis 1823B
  • FIGS. 36G and 37G showing images for Ferentis 1837A
  • the first and second row images of FIGS. 36B-36G and 37B-37G are general microscopy images of the samples
  • the third row of images of FIGS. 36B, 36E, 36G and 37B-37E show bubbles formed. [00326] Table 2. Microscopy results for different samples tested in cell attachment assay at day 4.
  • the cell attachment assay provided the following results. With respect to thickness:
  • Nippi 10% and Nippon 10% materials are the thickest (85-98 pm).
  • Nippi 15% are 76-78 pm.
  • Nippi 12% and Ferentis 1823B are 55-60 pm.
  • Ferentis 1837A materials are around 40 pm.
  • Thickness remains steady over culture time.
  • Table 4 provides a summary of the samples for a cell attachment assay.
  • the samples included (1) Nippi 08.25.20 12%, DMTMM 10% -APS 09.16.20; (2) Nippi 08.25.20 12%, DMTMM 12% -APS 09.16.20; (3) Nippi 09.03.20 10%, DMTMM 10%- Lithium 09.17.20; (4) Nippon 07.30.20 10%, DMTMM 10%-Lithium 09.15.20; (5) Ferentis 1842A; (6) SA-13-31B, Non collagen; and (7) SA-13-92A, Collagen 1%.
  • FIG. 39 is a bar graph showing thickness over time for different samples tested in the cell attachment assay at days 4 and 7 is provided.
  • FIGS. 40A-40I and FIG. 41A-41I show microscopy images for different samples tested in the cell attachment assay at days 4 and 7, respectively.
  • FIG. 40A and FIG. 41A show images for the control
  • FIG. 40B and FIG. 41B show images for Ferentis 1842A
  • FIG. 40C and FIG. 41C show images for Nippi 12% D12%
  • FIG. 41D and FIG. 42D show images for Nippi 10%D10%
  • FIG. 40E and FIG. 41E show images for Nippi 12%D10%;
  • FIG. 40F and FIG.41F show images for Nippon 10%
  • FIG. 40G and FIG. 41G show images for SA-13-31B
  • FIG. 40H and FIG. 41H show images for SA-13- 92A edge
  • FIG. 401 and FIG. 411 show images for SA-13-92A on sample.
  • Nippi 10%D10% and Nippi 12% 12% are thinnest (65-80 pm).
  • Nippi 12%D10% about are 160 pm in thickness.
  • Ferentis 1842A and SA-13-31B materials are around 170-200 pm in thickness.
  • SA-13-92A materials are around 500 pm in thickness.
  • Thickness remains steady over culture time.
  • Collagen coated control samples had a few patches of cells attached.
  • FIGS. 43A-43F show microscopy images for control samples tested in the cell attachment assay.
  • FIGS. 44A-44J show microscopy images for 1745A samples tested in the cell attachment assay. At day 3 microscopy imaging, it was hard to image edges due to 24 well plate. Imaged the center of each well to get an idea of cell growth on the materials compared to controls. Controls included: (1) 4/6 samples 70-100% confluent, and (2) 2/6 samples mostly confluent, a few patches in center. 1746A samples included: (1) 4/10 confluent at edges and nearly confluent in center, (2) 1/10 about 60% confluent in center, confluent at edges, and (3) 5/10 samples 30-40% confluent in center, patchy, some holes.
  • FIGS. 43A-43D show control sample images for 4/6 samples, 80-100% confluent.
  • FIGS. 43E-43F show control sample images for 2/6 samples mostly confluent, a few patches in center.
  • FIGS. 44A-44C show 1745A sample images for 3/10 confluent at edges and nearly confluent in center.
  • FIGS. 44D-44E show 1745A sample images for 2/1060-70% confluent in center, confluent at edges.
  • FIGS. 44F-44J show 1745A sample images for 5/10 samples 30-40% confluent in center, patchy, some holes.
  • FIG. 45 is an image of an MTT plate illustrating the setup for samples tested in the cell attachment assay.
  • FIG. 46 is a bar graph showing cell numbers for MTT results in the cell attachment assay for a sample and control.
  • FIG. 47 a diagram of seeding materials during a cell attachment assay is provided. Cells were seeded in 100 pL at edge of plate. The material was a 6-10 mm disc.
  • Possible control material denuded cornea.
  • PC-MPC collagen-methacryloyloxyethyl pho sphorylCholine
  • FIG. 49 a confocal microscopy image of a cross-section of PC-MPC material following incubation with epithelial cells.
  • the nuclei of the cells fluoresce in green and hence can be viewed under a confocal fluorescence microscope. There are few multi-layer spots on top of the material.
  • FIGS. 50A-50B confocal microscopy images of a cross- section of controls showing some multilayered structures as a baseline for comparison are provided.
  • the control was the bare tissue culture plate. Epithelial cells were able to grow over the plate surface.
  • Denuded cornea e.g., cornea with the epithelial layer scrapped off
  • FIGS. 51A-51B confocal microscopy images of a cross- section of 3D PEG gelatin material with epithelial cells on a plate and on surface demonstrating the ability of cells to form cell layers. Both have multi-layered spots;
  • Purpose/Obiective(s) The purpose of this animal study is to evaluate haze (e.g., assess material biocompatibility) after implantation of the Sponsor’s comeal implants comprising the described hydrogel composition in the eyes of New Zealand White rabbits (non-GLP) compared to control test articles shown in Table 7.
  • Sex Male or female (all same sex)
  • Housing - Animals will be singly housed prior to and during the study in order to decrease the likelihood of ocular injuries from cage mates.
  • Test Articles are shown in Table 7. [00372] Table 7. Test articles* data.
  • Test articles will be supplied by the Sponsor sterile for implantation and ready to administer. Test material accountability will be maintained according to ASC SOPs. After test article administration has completed, any leftover test articles will be directly transferred to the Sponsor by hand or shipped to the Sponsor on cold packs. 11. Pre- Treatment Procedures and Details of Test Article Administration a) Pre-Treatment Examinations
  • each animal Prior to placement on study, each animal will undergo an ophthalmic examination (slit-lamp biomicroscopy and indirect ophthalmoscopy) to be performed by the Study Director or Director of Ophthalmology. Ocular findings will be scored according to a modified McDonald-Shadduck Scoring System per SOP ASC-OC-OOl. The acceptance criteria for placement on study will be scores of “0” for all variables. b) Anesthesia
  • Animals will be anesthetized with an intramuscular (IM) injection of ketamine hydrochloride (up to approximately 50 mg/kg) and xylazine (up to approximately 10 mg/kg) or dexmedetomidine (approximately 0.25 mg/kg). Glycopyrrolate (approximately 0.01 mg/kg, IM) may be administered concurrently.
  • IM intramuscular
  • Atipamezole hydrochloride up to 1 mg/kg, IM
  • IM may be used as a reversal agent.
  • topical proparacaine hydrochloride anesthetic 0.5%) will be applied to the animals’ eyes. Additional topical ocular anesthesia dosing may be utilized during the procedures if needed.
  • Each rabbit will have the nictitating membrane removed from both eyes prior to test article administration. Since humans do not have nictitating membranes, removal of these membranes provides a model that more closely mimics human eyes.
  • Nictitating membranes will be removed at least 14 days prior to test article administration. Animals will be anesthetized as described herein. A 5% Betadine solution will be used to clean the eye and surrounding area. Betadine will be applied for ⁇ 5 minutes, after which the eye will be rinsed with balanced salt solution (BSS) and the surrounding area wiped with gauze.
  • BSS balanced salt solution
  • the nictitating membrane will be grasped with a pair of forceps and gently clamped at its base with a pair of hemostats.
  • the nictitating membrane will be excised along the clamp line with scissors.
  • the excised area will be sealed to stop any further bleeding.
  • BSS will be applied to the cauterized area.
  • the area may be blotted and medicated with topical gentamicin (0.3%) and/or antibiotic ophthalmic ointment.
  • the contralateral eye will have its nictitating membrane removed by the same procedure.
  • Test articles will be implanted in the corneas of both eyes of all study animals on Day 1 according to the study design in Table 2 (below). All surgical procedures will be performed by the Sponsor’s designated surgeon. ASC will provide technician support, anesthesia monitoring, and basic surgical equipment (including a surgical table, surgical microscope, and slit-lamp) and supplies (including sutures, gowns, etc.). Specialized surgical tools and supplies, including the laser and/or microkeratome, will be provided by the Sponsor.
  • Betadine will be used to clean the eye and surrounding area. Betadine will be applied for ⁇ 5 minutes, after which the eye will be rinsed with BSS and the surrounding area wiped with gauze.
  • a flap or pocket will be cut into each cornea using a laser or a microkeratome.
  • the surgery type utilized for each eye will be noted in the study data.
  • test articles will be inserted into the flap or pocket.
  • Test articles will be stained with 10 or 25% fluorescein solution (provided by the Sponsor) to facilitate visualization during the implantation procedure.
  • Antibiotic ophthalmic ointment e.g. triple antibiotic ointment
  • antibiotic eye drops e.g. 0.3% tobramycin
  • anti-inflammatory topical steroids e.g. 0.1% prednisolone acetate
  • Analgesic, anti-inflammatory, and/or antibiotic regimens may be extended or otherwise modified as necessary at the discretion of the veterinary staff in consultation with the Study Director and the Sponsor. All post-surgical treatments will be recorded in the raw data. 12. Safety Precautions
  • Standard laboratory safety procedures will be employed for handling the test articles. Specifically, gloves and lab coat along with appropriate vivarium attire will be worn while preparing and administering the test articles. Eye protection will be worn as appropriate during operation of the surgical laser.
  • OD right eye
  • OS left eye
  • OU both eyes
  • OCT optical coherence tomography
  • Baseline examinations will include indirect ophthalmoscopy and assess full set of ocular observation variables; remaining examinations will assess variables related to corneal haze/opacity only.
  • Surgical technique and type will be chosen on the day of surgery at the discretion of the Sponsor and recorded in the raw data for each eye. *Additional time points may be added at the discretion of the Sponsor with the approval of the Study Director and Attending Veterinarian.
  • Cageside observations will be performed once daily starting on Day 1 and continuing throughout the study. A survival check will be performed for each animal, and the animal will be evaluated for moribundity or other obvious illness or injury. Any findings of death, moribundity, or obvious illness or injury will be reported on the same day to the Study Director, the Sponsor, and the Attending Veterinarian.
  • Ocular findings will be scored according to a modified McDonald- Shadduck Scoring System per SOP ASC-OC-001.
  • Baseline examinations will include both slit-lamp biomicroscopy and indirect ophthalmoscopy and will assess all ocular observation variables. All other examinations will include slit-lamp biomicroscopy only and will assess only the ocular observation variables related to comeal haze/opacity, namely “Cornea” (severity of comeal haze/opacity) and “Surface Area of Cornea Involvement” (area of comeal haze/opacity).
  • examinations will include scoring of corneal haze following a study-specific scoring system.
  • OCT optical coherence tomography
  • an animal is moribund as defined by SOPs ASC-AC-007 and ASC-QP- 015, it will be euthanized as described below, which is in accordance with ASC’s policies on humane care of animals. If an animal possesses any of the following signs it will be considered as indicative of moribund condition: impaired ambulation which prevents the animal from reaching food or water, excessive weight loss and emaciation (>20%), lack of physical or mental alertness, difficult labored 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 Attending Veterinarian and Study Director. Any alternate endpoints (e.g. death, allowing ill animals to remain untreated and alive [i.e. moribund endpoints], etc.) must be justified in study documentation.
  • endpoints e.g. death, allowing ill animals to remain untreated and alive [i.e. moribund endpoint
  • blood or other specimens will be collected and analyzed as appropriate (e.g., for clinical pathology parameters) to help reveal the cause of malaise/morbidity. All unscheduled- sacrifice animals may be necropsied; if so, necropsy will be performed immediately, or, if this cannot be performed, the animal will be refrigerated to minimize autolysis and necropsied no later than 12 hours after death. All tissues listed in this protocol will be preserved.
  • Animals will be euthanized on Day 90 ( ⁇ 7).
  • the study may be extended for some or all study animals at the Sponsor’s discretion with the agreement of the Study Director and Attending Veterinarian, or animals may be euthanized earlier in case of comeal damage developing; in this case, the day(s) and time(s) when animals are euthanized will be recorded in the study data.
  • Animals will be euthanized by an intravenous injection of a commercial barbiturate based euthanasia solution (approximately 150 mg/kg, to effect).
  • the euthanasia procedure will be performed in compliance with the American Veterinary Medical Association (AVMA) Guidelines for Euthanasia of Animals: 2020 Edition.
  • AVMA American Veterinary Medical Association
  • the anterior chamber of the eye will be perfused with 2% PFA in PBS for 4 minutes to fix the cornea.
  • Perfusion will be performed using handheld syringes using a push-pull technique (two needles, one for pushing in PFA, one for pulling out aqueous humor). A slow push/pull will be used to maintain the internal pressure of the eye and avoid damage to the cornea.
  • the eye will be harvested. The cornea plus 1-2 mm limbal tissue will be excised using scalpel puncture and curved corneal scissors. The remaining eye will be discarded.
  • the excised cornea will be placed into a chilled container with 2% PFA.
  • the container will be sealed to prevent leakage or evaporation and immediately placed on wet ice until being stored refrigerated at 2-8°C.
  • the eye will be harvested. Excess tissues will be trimmed off, and the whole globe will be immediately placed in Davidson’s solution and stored at room temperature. To ensure consistent fixation, a gauze pad will be used to keep the eye submerged if necessary. After 48 hours in Davidson’s solution for 48 hours, the eye will be transferred into 70% ethanol.
  • the animals to be used in this study will be obtained from an approved vendor.
  • the name, address, and telephone number of the animal source will be included in the permanent animal records, and the source will be specified in the study file.
  • Animals selected for use in this study will be as uniform in age and weight as possible. Records of the dates of birth for the animals used in this study will be retained in the ASC archives, and the weight range at the time of group assignment will be specified in the study file.
  • the animals will be housed in individual cages and within the same room(s) as per ASC SOPs. Primary enclosures will be as specified in the USDA Animal Welfare Act (9 CFR, Parts 1, 2, and 3) and as described in the Guide for Care and Use of Laboratory Animals (ILAR publication, 2011, National Academy Press). The room(s) in which the animals will be kept will be documented in the study records.
  • No other species will be housed in the same room(s).
  • the rooms will be well ventilated (greater than 10 air changes per hour) with at least 60% fresh air.
  • a 12-hour light/12-hour dark photoperiod will be maintained, except when rooms must be illuminated during the dark cycle to accommodate necessary study procedures.
  • Room temperature and humidity will be recorded once daily as per ASC SOPs.
  • the study site is an AAALAC International-accredited site.
  • the care and use of animals will be conducted in accordance with the regulations of the USDA Animal Welfare Act (i.e., relevant sections of Section 9, Parts 1, 2, and 3, of the Code of Federal Regulations) and in compliance with ASC’s Animal Welfare Assurance (D16-00645 [A4282- 01]) filed with the Office of Laboratory Animal Welfare (OLAW) at the National Institutes of Health (NIH), as applicable.
  • Treatment of the animals will be in accordance with ASI SOPs and the conditions specified in the Guide for Care and Use of Laboratory Animals (ILAR publication, 2011, National Academy Press).
  • the study animals will be observed at least daily for signs of illness or distress, and any such observations will be promptly reported to the Attending Veterinarian and Study Director.
  • the Attending Veterinarian may make initial recommendations about treatment of the animal(s) and/or alteration of study procedures, which must be approved by the Study Director and the Sponsor.
  • Carcasses of deceased animals will be discarded following post mortem examination in accordance with applicable regulations on biological waste.
  • any unscheduled treatment of the animal(s) will be approved by the Study Director and the Sponsor. If the condition of the animal(s) is such that emergency measures must be taken, the Attending Veterinarian will attempt to consult with the Study Director and Sponsor prior to responding to the medical crisis, but the veterinary staff has authority to act immediately at their discretion to alleviate suffering. All unscheduled treatments will be recorded.
  • the draft report will include test article information and description, materials and methods, results, and conclusions.
  • the Sponsor will provide comments based on a review of the summary and data. Report finalization will be conducted on a mutually-agreeable timetable. Upon finalization, a copy of the final report will be provided to the Sponsor as a PDF file.
  • Haze grading is based on a scale used to grade post-PRK Haze, Arch. Ophthalmology (1992) (110): 1286-1291):
  • Trace Haze (Grade 1): Trace haze covering mid-peripheral and center of inlay. Visible with difficulty using diffuse illumination, visible by broad tangential illumination. May present with myopic shift, reduced hear point, visual symptoms (glare and halo).
  • FIGS. 32A-32E illustrate the guideline haze grading schemes for comeal haze scoring to be used during testing of the inlays. The best clinical judgment to grade the level of haze based on slit lamp presentation and associated clinical findings will be used.
  • FIGS. 32A and 32B show a clear, Grade 0 corneal haze score
  • FIG. 32C shows a trace
  • FIG. 32D shows a mild, Grade 2 comeal haze score
  • FIG. 32E shows a moderate, Grade 3 corneal haze score.
  • the clear, Grade 0 score reflects a sporadic, peripheral faint haze (clear center), not visible with diffuse slit lamp beam, minimally visible by oblique or slit beam. Vision is not affected.
  • the trace haze, Grade 1 score reflects a trace haze covering mid-peripheral and center of inlay. Visible with difficulty using diffuse illumination, visible by broad tangential illumination. May present with myoptic shift, reduced near point, visual symptoms (e.g., glare and halos).
  • the mild haze, Grade 2 score reflects a relatively dense, granular confluent haze, covering the entire inlay and outer periphery.
  • the haze is easily seen by diffuse and slit beam illumination.
  • the haze presents with myoptic shift, greatly reduced near point, and a marked increase in visual symptoms (e.g., glare and halos).
  • the moderate haze, Grade 3 score reflects a dense. Reticular, confluent haze presentation. Iris details are obscured with more severe symptoms of Grade 2 possible.
  • Pupillary Response Check for any blockage or a sluggish response in the pupillary region. Scoring will be taken as follows:
  • Discharge is defined as a whitish gray precipitate from the eye. Scoring will be taken as follows:
  • Conjunctival Congestion causes the blood vessels of the eye to become enlarged. Scoring will be taken as follows:
  • 0 Normal. May appear blanched to reddish pink without perilimbal injection (except at the 12:00 and 6:00 positions) with vessels of the palpebral and bulbar conjunctiva easily observed.
  • 1 A flushed, reddish color predominantly confined to the palpebral conjunctiva with some perilimbal injection but primarily confined to the lower and upper parts of the eye from the 4:00 to 7:00 and 11:00 to 1:00 positions.
  • Conjunctival Swelling meaning swelling of the conjunctiva. Scoring will be taken as follows:
  • Cornea Check the Cornea for any abnormalities. Scoring will be taken as follows:
  • 0 Normal Surface Area of Cornea Involvement: Check the eye for cloudiness in the stromal region. Scoring will be taken as follows:
  • Pannus Check for vascularization of Cornea. Scoring will be taken as follows:
  • Aqueous Flare Breakdown of the blood-aqueous barrier. Field size is a 1 mm x 1 mm slit beam. Scoring will be taken as follows (based on Jabs DA et ah, 2005):
  • Aqueous Cell Cellular observation in the aqueous humor. Field size is a 1 mm x 1 mm slit beam. Scoring will be taken as follows (based on Jabs DA et al., 2005):
  • Iris Involvement Check the iris for hyperemia of the blood vessels. Scoring will be taken as follows:
  • 0 Normal iris without any hyperemia of the blood vessels.
  • Lens Observe the lens for any cataracts. Scoring will be taken as follows:
  • Vitreous Flare Opacity or fogginess of the vitreous humor. Scoring will be taken as follows (based on Opremcak EM, 2012):
  • 0 None (nerve fiber layer [NFL] clearly visible)
  • l Faint (optic nerve and vessels clear, NFL hazy)
  • Vitreous Cell Cellular observation in the vitreous humor. Scoring will be taken as follows (based on Opremcak EM, 2012):
  • Vitreal Hemorrhage Observe the vitreous for any hemorrhage. Scoring will be taken as follows:
  • Retinal Detachment During a retinal detachment, bleeding from small retinal blood vessels may cloud the interior of the eye, which is normally filled with vitreous fluid. Scoring will be taken as follows:
  • Retinal Hemorrhage Abnormal bleeding of the blood vessels in the retina. Scoring will be taken as follows:
  • Choroidal/Retinal Inflammation Inflammation of the retina and/or choroid. Scoring will be taken as follows:

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Abstract

L'invention concerne un dispositif d'onlay cornéen comprenant une base plate ou de type plat et une partie supérieure en forme de dôme, et présentant une teneur en eau allant d'environ 78 % à environ 92 % (w/p) inclus. Le dispositif d'onlay cornéen peut être utilisé pour traiter, par exemple et sans caractère limitatif, la presbytie, le dispositif étant amovible et remplaçable sans intervention chirurgicale invasive, réduisant ou éliminant ainsi le risque qu'un patient développe une haze cornéenne.
PCT/US2022/034931 2021-06-24 2022-06-24 Dispositif médical d'onlay cornéen WO2022272082A1 (fr)

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Citations (6)

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