CORNEAL INLAY DESIGN AND METHODS OF CORRECTING VISION
20220273422 · 2022-09-01
Inventors
- Nicholas J. Manesis (Aliso Viejo, CA, US)
- Phihoa Tran-Hata (Aliso Viejo, CA, US)
- Alan Le (Aliso Viejo, CA, US)
- Khanh Nguyen (Aliso Viejo, CA, US)
Cpc classification
A61L2430/16
HUMAN NECESSITIES
A61L27/18
HUMAN NECESSITIES
A61L27/18
HUMAN NECESSITIES
A61L27/427
HUMAN NECESSITIES
International classification
A61F2/14
HUMAN NECESSITIES
Abstract
A corneal inlay device comprising a flat or flat-like base and a dome or droplet top. The corneal inlay can be used to treat, for example without limitation, presbyopia, while reducing or eliminating the risk of a patient developing corneal haze.
Claims
1) A method of treating presbyopia comprising placing in a cornea of a mammalian subject a corneal inlay device of high water content the corneal inlay device comprising a thickness, a diameter, a flat or flat-like base and a dome or droplet shaped top, the dome or droplet shaped top forming a contact angle with the base, wherein the corneal inlay device, when placed in 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.
2) The method of claim 1, wherein the placing of the corneal inlay device is by cutting a flap in the cornea and positioning the inlay beneath the flap.
3) The method of claim 1, wherein the placing of the corneal inlay device is by positioning the inlay device within a pocket formed in the cornea.
4) The method of claim 1, wherein the placing of the corneal inlay device is in the cornea at a depth of about 100 microns to about 200 microns, inclusive.
5) The method of claim 1, wherein the placing of the corneal inlay device is in the cornea at a depth of about 130 microns to about 160 microns, inclusive.
6) The method of claim 1, wherein the contact angle is between 1° and 180°.
7) The method of claim 1, wherein the thickness of the corneal inlay ranges from at least 25 microns, at least 26 microns, at least 27 microns, at least 28 microns, at least 29 microns, at least 30 microns, at least 31 microns, at least 32 microns, at least 33 microns, at least 34 microns, at least 35 microns, at least 36 microns, at least 37 microns, at least 38 microns, at least 39 microns, at least 40 microns, at least 41 microns, at least 42 microns, at least 43 microns, at least 44 microns, at least 45 microns, at least 46 microns, at least 47 microns, at least 48 microns, at least 49 microns, at least 50 microns, at least 51 microns, at least 52 microns, at least 53 microns, at least 54 microns, at least 55 microns, at least 56 microns, at least 57 microns, at least 58 microns, at least 59 microns, to 60 microns.
8) The method of claim 5, wherein the thickness of the corneal inlay ranges from at least 32 microns, at least 33 microns, at least 34 microns, at least 35 microns, at least 36 microns, at least 37 microns, at least 38 microns, at least 39 microns, at least 40 microns, at least 41 microns, at least 42 microns, at least 43 microns, at least 44 microns, at least 45 microns, at least 46 microns, at least 47 microns, at least 48 microns, at least 49 microns, to 50 microns.]
9) The method of claim 1, wherein diameter of the corneal inlay 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.
10) The method of claim 1, wherein the corneal inlay device comprises water, a hydrophilic polymer, and a protein.
11) The method of claim 10, wherein the protein is an isolated protein, a recombinant protein, a synthetic protein, or a peptidomimetic.
12) The method of claim 10, wherein the hydrophilic polymer comprises polyethylene glycol (“PEG”), poly(2-methacryloyloxyethyl phosphorylcholine) (MPC), or both.
13) The method of claim 1, wherein water content of the corneal inlay is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%.
14) The method of claim 1, wherein the corneal inlay device is optically transparent, biocompatible, permeable and refractive.
15.-28. (canceled)
Description
BRIEF DESCRIPTION OF THE DRAWINGS
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DETAILED DESCRIPTION OF THE INVENTION
Glossary
Anatomical Terms
[0098] 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. Within the head itself, 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. On the limbs or other appendages, a point closer to the main body is “proximal”; a point farther away is “distal”. Three basic reference planes are used in zoological anatomy. 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.
[0099] When referring to humans, the body and its parts are always described using the assumption that the body is standing upright. Portions of the body which are closer to the head end are “superior” (corresponding to cranial in animals), while those farther away are “inferior” (corresponding to caudal in animals). Objects near the front of the body are referred to as “anterior” (corresponding to ventral in animals); those near the rear of the body are referred to as “posterior” (corresponding to dorsal in animals). A transverse, axial, or horizontal plane is an X-Y plane, parallel to the ground, which separates the superior/head from the inferior/feet. 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.
[0100] 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.
[0101] The term “ipsilateral” as used herein means on the same side, the term “contralateral” as used herein means on the other side, and 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.
[0102] The term “biocompatible” as used herein, means causing no clinically relevant tissue irritation, injury, toxic reaction, or immunologic reaction to human tissue based on a clinical risk/benefit assessment.
[0103] The term “collagen” as used herein 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.
[0104] The term “contact angle” as used herein refers to the angle that a liquid creates with a solid surface or capillary walls of a porous material when both materials come into contact. It is determined by properties of the solid and the liquid, the interaction and repulsion forces between liquid and solid, and by the three phase interface properties (gas, liquid and solid). The balance between the cohesive forces of similar molecules such as between the liquid molecules (i.e. hydrogen bonds and Van der Waals forces) and the adhesive forces between dissimilar molecules such as between the liquid and solid molecules (i.e. mechanical and electrostatic forces) will determine the contact angle created in the solid and liquid interface. Contact angle is a common way to measure the wettability of a surface or material. https://chem.libretexts.org/Bookshelves/Physical_and_Theoretical_Chemistry_Textbook_Maps/Supplemental_Modules_(Physical_and_Theoretical_Chemistry)/Physical_Properties_of_Matter/States_of_Matter/Properties_of_Liquids/Contact_Angle s, visited 5/17/19)
[0105] The term “corneal apex” as used herein refers to the point of maximum curvature.
[0106] The term “corneal vertex” as used herein refers to the point located at the intersection of an individual's line of fixation and the corneal surface.
[0107] The term “curvature” as used herein refers to a degree of curving of a continuously bending line, without angles.
[0108] 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.
[0109] The term “elasticity” as used herein 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.
[0110] The term “focal length” of a lens as used herein refers to the distance at which a lens focuses parallel rays of light. Given its diopter, the focal length of a lens can be calculated from the equation: focal length in mm=1000/diopter.
[0111] The term “hydrogel” as used herein 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.
[0112] The term “hydrophilic” as used herein refers to a material or substance having an affinity for polar substances, such as water.
[0113] The term “index of refraction” as used herein 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.
[0114] The term “isolated” as used herein 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. The terms “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.
[0115] The term “matrix” as used herein 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.
[0116] The term “miosis” as used herein means excessive constriction (shrinking) of the pupil. In miosis, the diameter of the pupil is less than 2 millimeters (mm),
[0117] The term “permeable” as used herein means permitting the passage of substances, such as oxygen, glucose, water and ions, as through a membrane or other structure.
[0118] The term “protein” is used herein to refer to a large complex molecule or polypeptide composed of amino acids. The sequence of the amino acids in the protein is determined by the sequence of the bases in the nucleic acid sequence that encodes it.
[0119] The term “peptide” as used herein refers to a molecule of two or more amino acid chemically linked together. A peptide may refer to a polypeptide, protein or peptidomimetic.
[0120] The term “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.
[0121] The terms “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 are 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-α-amino protected N-α-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-α-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-α-amino protected amino acids can be obtained from Sigma, Cambridge Research Biochemical, or other chemical companies familiar to those skilled in the art. In addition, the polypeptides can be synthesized with other N-α-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., β-methyl amino acids, C-α-methyl amino acids, and N-α-methyl amino acids, etc.) to convey special properties. Synthetic amino acids include ornithine for lysine, and norleucine for leucine or isoleucine. In addition, the polypeptides can have peptidomimetic bonds, such as ester bonds, to prepare peptides with novel properties. For example, a peptide may be generated that incorporates a reduced peptide bond, i.e., R.sup.1—CH.sub.2—NH—R.sup.2, where R.sub.1 and R.sub.2 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. The terms “polypeptide”, “peptide” and “protein” 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.
[0122] The term “polymer” as used herein 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.
[0123] The term “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.
[0124] The term “recombinant protein” as used herein 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. To make a human recombinant protein, for example, 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.
[0125] 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; in passing from a denser into a rarer medium it 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.
[0126] “Refractive power” of a lens as used herein refers to the reciprocal of its focal length in meters, or D=1/f, where D is the power in diopters and f is the focal length in meters.
[0127] The term “RGD motif” as used herein 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.
[0128] The term “shape” as used herein refers to the quality of a distinct object or body in having an external surface or outline of specific form or figure.
[0129] The terms “subject” or “individual” or “patient” are used interchangeably to refer to a member of an animal species of mammalian origin, including but not limited to, 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.
[0130] The term “surface tension” as used herein refers to a property of a liquid that allows it to resist an external force due to the cohesive nature of its molecules. An attractive force exerted by the molecules of a liquid below the surface upon those at the surface-air interface, resulting from the high molecular concentration of a liquid compared to the low molecular concentration of a gas, creates an inward pull, or internal pressure, which tends to restrain the liquid from flowing.
[0131] The term “thickness” as used herein refers to a measure between opposite surfaces, from top to bottom, or in a direction perpendicular to that of the length and breadth.
[0132] The term “viscosity”, as used herein 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. Dynamic viscosity is usually denoted in poise (P) or centipoise (cP), wherein 1 poise=1 g/cm.sup.2, and 1 cP=0.01 P. Kinematic viscosity is the ratio of absolute or dynamic viscosity to density. Kinematic viscosity is usually denoted in Stokes (St) or Centistokes (cSt), wherein 1 St=10-4 m.sup.2/s, and 1 cSt=0.01 St.
[0133] The term “wetting” as used herein refers to how a liquid deposited on a solid (or liquid) substrate spreads out or the ability of liquids to form boundary surfaces with solid states. It is determined by measuring the contact angle that the liquid forms in contact with the solid or liquid. The smaller the contact angle or the surface tension, the larger the wetting tendency.
[0134] The term “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.
[0135] 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. The term “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.
[0136] The present disclosure relates to a corneal inlay device, insertion means, and construction means, as discussed in detail below in connection with
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[0138] In exemplary embodiments, the diameter 14 of corneal inlay 10 can range from 1 millimeters (“mm”) to 3 mm, inclusive, i.e., 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. According to some embodiments, the diameter 14 is at least 1.0 mm. According to some embodiments, the diameter 14 is at least 1.1 mm. According to some embodiments, the diameter 14 is at least 1.2 mm. According to some embodiments, the diameter 14 is at least 1.3 mm. According to some embodiments, the diameter 14 is at least 1.4 mm. According to some embodiments, the diameter 14 is at least 1.5 mm. According to some embodiments, the diameter 14 is at least 1.6 mm. According to some embodiments, the diameter 14 is at least 1.7 mm. According to some embodiments, the diameter 14 is at least 1.8 mm. According to some embodiments, the diameter 14 is at least 1.9 mm. According to some embodiments, the diameter 14 is at least 2.0 mm. According to some embodiments, the diameter 14 is at least 2.1 mm. According to some embodiments, the diameter 14 is at least 2.2 mm. According to some embodiments, the diameter 14 is at least 2.3 mm. According to some embodiments, the diameter 14 is at least 2.4 mm. According to some embodiments, the diameter 14 is at least 2.5 mm. According to some embodiments, the diameter 14 is at least 2.6 mm. According to some embodiments, the diameter 14 is at least 2.7 mm. According to some embodiments, the diameter 14 is at least 2.8 mm. According to some embodiments, the diameter 14 is at least 2.9 mm. According to some embodiments, the diameter 14 is at least 3.0 mm.
[0139] In exemplary embodiments, the thickness 12 of corneal inlay 10 can range from 25-60 microns, inclusive, i.e., at least 25 microns, at least 26 microns, at least 27 microns, at least 28 microns, at least 29 microns, at least 30 microns, at least 31 microns, at least 32 microns, at least 33 microns, at least 34 microns, at least 35 microns, at least 36 microns, at least 37 microns, at least 38 microns, at least 39 microns, at least 40 microns, at least 41 microns, at least 42 microns, at least 43 microns, at least 44 microns, at least 45 microns, at least 46 microns, at least 47 microns, at least 48 microns, at least 49 microns, at least 50 microns, at least 51 microns, at least 52 microns, at least 53 microns, at least 54 microns, at least 55 microns, at least 56 microns, at least 57 microns, at least 58 microns, at least 59 microns, or 60 microns. According to some embodiments, the thickness 12 of corneal inlay 10 can range from 32 microns to 50 microns, inclusive, i.e., at least 32 microns, at least 33 microns, at least 34 microns, at least 35 microns, at least 36 microns, at least 37 microns, at least 38 microns, at least 39 microns, at least 40 microns, at least 41 microns, at least 42 microns, at least 43 microns, at least 44 microns, at least 45 microns, at least 46 microns, at least 47 microns, at least 48 microns, at least 49 microns, or 50 microns.]
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[0142] The corneal inlay 10 changes the refractive power of the cornea by altering the shape of the anterior corneal surface. In
[0143] In some embodiments in which a corneal inlay is positioned beneath a flap, the inlay 10 is implanted between about 100 microns (micrometers) and about 200 microns deep in the cornea. In some embodiments the inlay is positioned at a depth of between about 130 microns to about 160 microns. According to some embodiments, the inlay 10 is positioned at depth of 100 microns. According to some embodiments, the inlay 10 is positioned at depth of 101 microns. According to some embodiments, the inlay 10 is positioned at depth of 102 microns. According to some embodiments, the inlay 10 is positioned at depth of 103 microns. According to some embodiments, the inlay 10 is positioned at depth of 104 microns. According to some embodiments, the inlay 10 is positioned at depth of 105 microns. According to some embodiments, the inlay 10 is positioned at depth of 106 microns. According to some embodiments, the inlay 10 is positioned at depth of 107 microns. According to some embodiments, the inlay 10 is positioned at depth of 108 microns. According to some embodiments, the inlay 10 is positioned at depth of 109 microns. According to some embodiments, the inlay 10 is positioned at depth of 110 microns. According to some embodiments, the inlay 10 is positioned at depth of 111 microns. According to some embodiments, the inlay 10 is positioned at depth of 112 microns. According to some embodiments, the inlay 10 is positioned at depth of 113 microns. According to some embodiments, the inlay 10 is positioned at depth of 114 microns. According to some embodiments, the inlay 10 is positioned at depth of 115 microns. According to some embodiments, the inlay 10 is positioned at depth of 116 microns. According to some embodiments, the inlay 10 is positioned at depth of 117 microns. According to some embodiments, the inlay 10 is positioned at depth of 118 microns. According to some embodiments, the inlay 10 is positioned at depth of 119 microns. According to some embodiments, the inlay 10 is positioned at depth of 120 microns. According to some embodiments, the inlay 10 is positioned at depth of 121 microns. According to some embodiments, the inlay 10 is positioned at depth of 122 microns. According to some embodiments, the inlay 10 is positioned at depth of 123 microns. According to some embodiments, the inlay 10 is positioned at depth of 124 microns. According to some embodiments, the inlay 10 is positioned at depth of 125 microns. According to some embodiments, the inlay 10 is positioned at depth of 126 microns. According to some embodiments, the inlay 10 is positioned at depth of 127 microns. According to some embodiments, the inlay 10 is positioned at depth of 128 microns. According to some embodiments, the inlay 10 is positioned at depth of 129 microns. According to some embodiments, the inlay 10 is positioned at depth of 130 microns. According to some embodiments, the inlay 10 is positioned at depth of 131 microns. According to some embodiments, the inlay 10 is positioned at depth of 132 microns. According to some embodiments, the inlay 10 is positioned at depth of 133 microns. According to some embodiments, the inlay 10 is positioned at depth of 134 microns. According to some embodiments, the inlay 10 is positioned at depth of 135 microns. According to some embodiments, the inlay 10 is positioned at depth of 136 microns. According to some embodiments, the inlay 10 is positioned at depth of 137 microns. According to some embodiments, the inlay 10 is positioned at depth of 138 microns. According to some embodiments, the inlay 10 is positioned at depth of 139 microns. According to some embodiments, the inlay 10 is positioned at depth of 140 microns. According to some embodiments, the inlay 10 is positioned at depth of 141 microns. According to some embodiments, the inlay 10 is positioned at depth of 142 microns. According to some embodiments, the inlay 10 is positioned at depth of 143 microns. According to some embodiments, the inlay 10 is positioned at depth of 144 microns. According to some embodiments, the inlay 10 is positioned at depth of 145 microns. According to some embodiments, the inlay 10 is positioned at depth of 146 microns. According to some embodiments, the inlay 10 is positioned at depth of 147 microns. According to some embodiments, the inlay 10 is positioned at depth of 148 microns. According to some embodiments, the inlay 10 is positioned at depth of 149 microns. According to some embodiments, the inlay 10 is positioned at depth of 150 microns. According to some embodiments, the inlay 10 is positioned at depth of 151 microns. According to some embodiments, the inlay 10 is positioned at depth of 152 microns. According to some embodiments, the inlay 10 is positioned at depth of 153 microns. According to some embodiments, the inlay 10 is positioned at depth of 154 microns. According to some embodiments, the inlay 10 is positioned at depth of 155 microns. According to some embodiments, the inlay 10 is positioned at depth of 156 microns. According to some embodiments, the inlay 10 is positioned at depth of 157 microns. According to some embodiments, the inlay 10 is positioned at depth of 158 microns. According to some embodiments, the inlay 10 is positioned at depth of 159 microns. According to some embodiments, the inlay 10 is positioned at depth of 160 microns. According to some embodiments, the inlay 10 is positioned at depth of 161 microns. According to some embodiments, the inlay 10 is positioned at depth of 162 microns. According to some embodiments, the inlay 10 is positioned at depth of 163 microns. According to some embodiments, the inlay 10 is positioned at depth of 164 microns. According to some embodiments, the inlay 10 is positioned at depth of 165 microns. According to some embodiments, the inlay 10 is positioned at depth of 166 microns. According to some embodiments, the inlay 10 is positioned at depth of 167 microns. According to some embodiments, the inlay 10 is positioned at depth of 168 microns. According to some embodiments, the inlay 10 is positioned at depth of 169 microns. According to some embodiments, the inlay 10 is positioned at depth of 170 microns. According to some embodiments, the inlay 10 is positioned at depth of 171 microns. According to some embodiments, the inlay 10 is positioned at depth of 172 microns. According to some embodiments, the inlay 10 is positioned at depth of 173 microns. According to some embodiments, the inlay 10 is positioned at depth of 174 microns. According to some embodiments, the inlay 10 is positioned at depth of 175 microns. According to some embodiments, the inlay 10 is positioned at depth of 176 microns. According to some embodiments, the inlay 10 is positioned at depth of 177 microns. According to some embodiments, the inlay 10 is positioned at depth of 178 microns. According to some embodiments, the inlay 10 is positioned at depth of 179 microns. According to some embodiments, the inlay 10 is positioned at depth of 180 microns. According to some embodiments, the inlay 10 is positioned at depth of 181 microns. According to some embodiments, the inlay 10 is positioned at depth of 182 microns. According to some embodiments, the inlay 10 is positioned at depth of 183 microns. According to some embodiments, the inlay 10 is positioned at depth of 184 microns. According to some embodiments, the inlay 10 is positioned at depth of 185 microns. According to some embodiments, the inlay 10 is positioned at depth of 186 microns. According to some embodiments, the inlay 10 is positioned at depth of 187 microns. According to some embodiments, the inlay 10 is positioned at depth of 188 microns. According to some embodiments, the inlay 10 is positioned at depth of 189 microns. According to some embodiments, the inlay 10 is positioned at depth of 190 microns. According to some embodiments, the inlay 10 is positioned at depth of 191 microns. According to some embodiments, the inlay 10 is positioned at depth of 192 microns. According to some embodiments, the inlay 10 is positioned at depth of 193 microns. According to some embodiments, the inlay 10 is positioned at depth of 194 microns. According to some embodiments, the inlay 10 is positioned at depth of 195 microns. According to some embodiments, the inlay 10 is positioned at depth of 196 microns. According to some embodiments, the inlay 10 is positioned at depth of 197 microns. According to some embodiments, the inlay 10 is positioned at depth of 198 microns. According to some embodiments, the inlay 10 is positioned at depth of 199 microns. According to some embodiments, the inlay 10 is positioned at depth of 200 microns. According to some embodiments, the depth in the cornea for a pocket may be greater than for a flap. According to some exemplary embodiments, because depth in the cornea for the pocket is greater than for the flap, a thicker inlay may be needed in order to impart a refractive correction.
[0144] The elastic (Young's) modulus of the corneal inlay 10 can, 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 corneal inlay 10 can exceed the tolerance. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.05 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.06 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.07 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.08 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.09 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.10 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.11 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.12 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.13 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.14 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.15 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.16 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.17 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.18 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.19 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.20 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.21 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.22 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.23 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.24 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.25 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.26 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.27 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.28 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.29 MPa. According to some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.30 MPa.
[0145] The elongation at break of the corneal inlay 10 can be 58.30% with a tolerance of ±4.49%. However, in some embodiments, the elongation at break of the corneal inlay 10 can exceed the tolerance. According to some embodiments, the elongation at break of the corneal inlay 10 can be at least 48%. According to some embodiments, the elongation at break of the corneal inlay 10 can be at least 49%. According to some embodiments, the elongation at break of the corneal inlay 10 can be at least 50%. According to some embodiments, the elongation at break of the corneal inlay 10 can be at least 21%. According to some embodiments, the elongation at break of the corneal inlay 10 can be at least 52%. According to some embodiments, the elongation at break of the corneal inlay 10 can be at least 53%. According to some embodiments, the elongation at break of the corneal inlay 10 can be at least 54%. According to some embodiments, the elongation at break of the corneal inlay 10 can be at least 55%. According to some embodiments, the elongation at break of the corneal inlay 10 can be at least 56%. According to some embodiments, the elongation at break of the corneal inlay 10 can be at least 57%. According to some embodiments, the elongation at break of the corneal inlay 10 can be at least 58%. According to some embodiments, the elongation at break of the corneal inlay 10 can be at least 59%. According to some embodiments, the elongation at break of the corneal inlay 10 can be at least 60%. According to some embodiments, the elongation at break of the corneal inlay 10 can be at least 61%. According to some embodiments, the elongation at break of the corneal inlay 10 can be at least 62%. According to some embodiments, the elongation at break of the corneal inlay 10 can be at least 63%. According to some embodiments, the elongation at break of the corneal inlay 10 can be at least 64%. According to some embodiments, the elongation at break of the corneal inlay 10 can be at least 65%. According to some embodiments, the elongation at break of the corneal inlay 10 can be at least 66%. According to some embodiments, the elongation at break of the corneal inlay 10 can be at least 67%. According to some embodiments, the elongation at break of the corneal inlay 10 can be at least 68%. According to some embodiments, the elongation at break of the corneal inlay 10 can be at least 69%. According to some embodiments, the elongation at break of the corneal inlay 10 can be at least 70%.
[0146] The tensile strength (meaning the resistance of a material to breaking under tension) of the corneal inlay 10 can be 0.07 MPa with a tolerance of ±0.02 MPa. In some embodiments, the tensile strength of the corneal inlay can exceed the tolerance. According to some embodiments, the tensile strength of the corneal inlay 10 can be at least 0.01 MPa. According to some embodiments, the tensile strength of the corneal inlay 10 can be at least 0.02 MPa. According to some embodiments, the tensile strength of the corneal inlay 10 can be at least 0.03 MPa. According to some embodiments, the tensile strength of the corneal inlay 10 can be at least 0.04 MPa. According to some embodiments, the tensile strength of the corneal inlay 10 can be at least 0.05 MPa. According to some embodiments, the tensile strength of the corneal inlay 10 can be at least 0.06 MPa. According to some embodiments, the tensile strength of the corneal inlay 10 can be at least 0.07 MPa. According to some embodiments, the tensile strength of the corneal inlay 10 can be at least 0.08 MPa. According to some embodiments, the tensile strength of the corneal inlay 10 can be at least 0.09 MPa. According to some embodiments, the tensile strength of the corneal inlay 10 can be at least 0.10 MPa. According to some embodiments, the tensile strength of the corneal inlay 10 can be at least 0.11 MPa. According to some embodiments, the tensile strength of the corneal inlay 10 can be at least 0.12 MPa. According to some embodiments, the tensile strength of the corneal inlay 10 can be at least 0.13 MPa. According to some embodiments, the tensile strength of the corneal inlay 10 can be at least 0.14 MPa. According to some embodiments, the tensile strength of the corneal inlay 10 can be at least 0.15 MPa.
[0147] The backscatter (meaning deflection of radiation or particles through an angle of 180°) of the corneal inlay 10 can be 0.90% with a tolerance of ±0.17%. However, in some embodiments, the backscatter of the corneal inlay 10 can exceed the tolerance. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.65%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.66%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.67%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.68%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.69%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.70%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.71%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.72%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.73%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.74%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.75%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.76%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.77%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.78%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.79%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.80%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.81%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.82%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.83%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.84%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.85%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.86%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.87%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.88%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.89%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.90%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.91%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.92%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.93%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.94%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.95%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.96%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.97%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.98%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 0.99%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 1.00%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 1.01%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 1.02%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 1.03%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 1.04%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 1.05%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 1.06%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 1.07%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 1.08%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 1.09%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 1.10%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 1.11%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 1.12%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 1.13%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 1.14%. According to some embodiments, the backscatter of the corneal inlay 10 can be at least 1.15%.
[0148] The light transmission (meaning the moving of electromagnetic waves through) of the corneal inlay 10 can be 92.4% with a tolerance of ±0.95%. In some embodiments, the elastic modulus of the corneal inlay 10 can exceed the tolerance. According to some embodiments, the light transmission of the corneal inlay 10 can be at least 85.0%. According to some embodiments, the light transmission of the corneal inlay 10 can be at least 86.0%. According to some embodiments, the light transmission of the corneal inlay 10 can be at least 87.0%. According to some embodiments, the light transmission of the corneal inlay 10 can be at least 88.0%. According to some embodiments, the light transmission of the corneal inlay 10 can be at least 89.0%. According to some embodiments, the light transmission of the corneal inlay 10 can be at least 90.0%. According to some embodiments, the light transmission of the corneal inlay 10 can be at least 91.0%. According to some embodiments, the light transmission of the corneal inlay 10 can be at least 92.0%. According to some embodiments, the light transmission of the corneal inlay 10 can be at least 93.0%. According to some embodiments, the light transmission of the corneal inlay 10 can be at least 94.0%. According to some embodiments, the light transmission of the corneal inlay 10 can be at least 95.0%. According to some embodiments, the light transmission of the corneal inlay 10 can be at least 96.0%. According to some embodiments, the light transmission of the corneal inlay 10 can be at least 97.0%. According to some embodiments, the light transmission of the corneal inlay 10 can be at least 98.0%. According to some embodiments, the light transmission of the corneal inlay 10 can be at least 99.0%. According to some embodiments, the light transmission of the corneal inlay 10 can be 100.0%.
[0149] The morphology (meaning form) of the corneal inlay 10 can be a fibrillary network with nano-pores. According to some embodiments, the nano-pores of the corneal inlay 10 can have a diameter of at least 0.1 μm. According to some embodiments, the nano-pores of the corneal inlay 10 can have a diameter of at least 0.2 μm. According to some embodiments, the nano-pores of the corneal inlay 10 can have a diameter of at least 0.3 μm. According to some embodiments, the nano-pores of the corneal inlay 10 can have a diameter of at least 0.4 μm. According to some embodiments, the nano-pores of the corneal inlay 10 can have a diameter of at least 0.5 μm. According to some embodiments, the nano-pores of the corneal inlay 10 can have a diameter of at least 0.6 μm. According to some embodiments, the nano-pores of the corneal inlay 10 can have a diameter of at least 0.7 μm. According to some embodiments, the nano-pores of the corneal inlay 10 can have a diameter of at least 0.8 μm. According to some embodiments, the nano-pores of the corneal inlay 10 can have a diameter of at least 0.9 μm. According to some embodiments, the nano-pores of the corneal inlay 10 can have a diameter of at least 1.0 μm. According to some embodiments, the nano-pores can have a diameter of approximately 0.4 μm According to some embodiments, the storage temperature for the corneal inlay 10 can range from about 2°-6° 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.
[0150] Presbyopic Inlays
[0151] According to some embodiments, the diameter of the corneal inlay 10 is small in comparison with the diameter of the pupil for correcting presbyopia. In some embodiments, a corneal inlay 10 (e.g., 1 mm to 3 mm in diameter) is implanted centrally in the cornea to induce an “effect” zone on the anterior corneal surface that is smaller than the optical zone of the cornea for providing near vision. Here, the “effect” zone is the area of the anterior corneal surface affected by the corneal inlay 10. The implanted corneal inlay 10 increases 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.
[0152] 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. Typically, a person suffering from presbyopia requires reading glasses to provide near vision.
[0153]
[0154] To increase the diopter power within the “effect” zone 50, the corneal inlay 10 has a curvature higher than the curvature of the pre-implant anterior corneal surface in order to increase the curvature of the anterior corneal surface within the “effect” zone 50. The corneal inlay 10 can further increase the diopter power within the “effect” zone 52 by having an index of refraction that is higher than the index of refraction of the cornea (n.sub.cornea=1.376). Thus, 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. For early presbyopia (e.g., about 45 to 55 years of age), 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.
[0155] An advantage of corneal inlay 10 is that when concentrating on nearby objects 54, the pupil naturally becomes smaller (e.g., near point miosis) making the corneal inlay effect even more effective. Further increases in the corneal inlay effect can be achieved by increasing the illumination of a nearby object (e.g., turning up a reading light).
[0156] Because the inlay is smaller than the diameter of the pupil 44, light rays 56 from distant objects 58 bypass the inlay 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
[0157] 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 corneal refractive procedures. After the distance corrective procedure is completed, the corneal inlay 10 can be implanted in the cornea to provide near vision. Since LASIK requires the creation of a flap, the corneal inlay 10 may be inserted concurrently with the LASIK procedure. The corneal inlay 10 can also be inserted into the cornea after the LASIK procedure since the flap can be re-opened. Therefore, the corneal inlay 10 can be used in conjunction with other refractive procedures, such as LASIK for correcting myopia or hyperopia.
[0158]
[0159]
[0160] Material Chemistry of the Inlay
[0161] According to some embodiments, the inlay material comprises a biopolymer. According to some embodiments, the biopolymer is a synthetic self-assembling biopolymer. According to some embodiments, the biopolymer is a naturally-occurring biopolymer. Exemplary naturally-occurring biopolymers include, but are not limited to, protein polymers, collagen, polysaccharides, and photopolymerizable compounds. Exemplary protein polymers synthesized from self-assembling protein polymers include, for example, silk fibroin, elastin, collagen, and combinations thereof. According to some embodiments, the synthetic self-assembling biopolymer is a synthetic collagen. According to some embodiments, the collagen is a collagen mimetic peptide. As used herein, the term “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.
[0162] According to some embodiments, the inlay materials comprise a synthetic polymeric material. According to some embodiments the synthetic material is an optically transparent material. According to some embodiments the synthetic materials is a biocompatible material. According to some embodiments the synthetic material is a hydrophilic material. According to some embodiments the synthetic materials is a material permeable to low molecular weight nutrients so as to maintain corneal health. According to some embodiments the synthetic materials is a refractive material. According to some embodiments the synthetic material is optically transparent, biocompatible, hydrophilic, permeable and refractive.
[0163] 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 polyanhydride; 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; a poly(oxyethylene)/poly(oxypropylene) copolymer; a polyacetal, a polyketal; a polyphosphate; a (phosphorous-containing) polymer; a polyphosphoester; a polyhydroxyvalerate; a polyalkylene oxalate; a polyalkylene succinate; or a poly(maleic acid). 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).
[0164] Exemplary non-degradable biocompatible polymers include, without limitation, polysiloxane, polyvinyl alcohol, and polyimide,
[0165] Exemplary copolymers include, hydroxyethyl methacrylate and methyl methacrylate, and hydroxyethyl methacrylate copolymerized with polyvinyl pyrrolidone (PVP, to increase water retention) or ethylene glycol dimethacrylic acid (EGDM). Nexofilcon A (Bausch & Lomb) is a hydrophilic copolymer of 2-hydroxyethyl methacrylate and N-vinyl pyrrolidone.
[0166] Exemplary block polymers comprising blocks of hydrophilic biocompatible polymers or biopolymers or biodegradable polymers include polyethers, including polyethylene glycol, PEG; polyethylene oxide, PEO; polypropylene oxide, PPO, perfluoropolyethers (PFPEs) and block copolymers comprised of combinations thereof.
[0167] According to some embodiments, 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). For example, Cross-linked poly (acrylic acid) of high molecular weight is commercially available as Carbopol® (B.F./Goodrich Chemical Co., Cleveland, Ohio). 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). (4-(4,6-dimethoxy-1,3,5-triazin-2-yyl)-4methylmorpholinium choloride (DMTMM) or N-3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide (EDC/NHS) may be useful to synthesize hyaluronan derivatives. See, D'Este, M. et al, Carbohydrate Polymers (2014) 108: 239-246). 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, P J et al. Soft Matter (2012) 8: 10409-10418.
[0168] According to some embodiments, 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. According to some embodiments, the first polymer and the second polymer comprise one or more different end groups. For example, the first polymer can have a more polar end group than one or more end group(s) of the second polymer. According to some such embodiments, the first polymer will be more hydrophilic, relative to a second polymer (with the less polar end group) alone. According to some such embodiments, the first polymer comprises one or more carboxylic acid end groups, and the second polymer comprises one or more ester end groups.
[0169] According to some embodiments, the inlay material comprises a polymer matrix.
[0170] According to some embodiments, the inlay materials comprise an ultraviolet blocker.
[0171] The corneal inlay 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 inlay, the inlay may be made of a material with a higher index of refraction than the cornea, e.g., >1.376.
[0172] Materials that can be used to make the cornea inlay 10 include, but are not limited to, a self-assembling peptide hydrogel containing one or more non-protein amino acids (e.g., Thota, C K et al, Sci. Rep. 6: 31167; doi: 10.1038/srep31167 (2016), collagen mimetic peptide (“CMP”) conjugated with polyethylene glycol (“PEG”), lidofilcon A (a high water (>50% water nonionic hydrogel polymer), poly(2-hydroxyethyl methacrylate) (PolyHEMA), polysulfone, a silicone hydrogel polymer, water, and the like.
[0173] According to some embodiments, the composition of the corneal inlay 10 comprises water and CMP conjugated with PEG. According to some embodiments, the composition of the corneal inlay 10 comprises water, one or more hydrophilic polymers (e.g., PEG, MPC), and a mammalian collagen.
[0174] According to some embodiments, the water content can range from 80%-99%. According to some embodiments, the water content is at least 80%. According to some embodiments, the water content is at least 81%. According to some embodiments, the water content is at least 82%. According to some embodiments, the water content is at least 83%. According to some embodiments, the water content is at least 84%. According to some embodiments, the water content is at least 85%. According to some embodiments, the water content is at least 86%. According to some embodiments, the water content is at least 87%. According to some embodiments, the water content is at least 88%. According to some embodiments, the water content is at least 89%. According to some embodiments, the water content is at least 90%. According to some embodiments, the water content is at least 91%. According to some embodiments, the water content is at least 92%. According to some embodiments, the water content is at least 93%. According to some embodiments, the water content is at least 94%. According to some embodiments, the water content is at least 95%. According to some embodiments, the water content is at least 96%. According to some embodiments, the water content is at least 97%. According to some embodiments, the water content is at least 98%. According to some embodiments, the water content is at least 99%. According to some embodiments, the water content, by way of example, is at least 90%.
[0175]
Fabrication.
[0176] According to some embodiments, a reusable mold comprises a first mold half comprising a first mold surface in contact with a polymerizable and/or crosslinkable silicone containing the inlay forming composition and a second mold half comprising a second mold surface in contact with the inlay-forming composition. The first mold half and the second mold half may be configured to receive each other such that a cavity is formed between the first mold surface and the second mold surface. The cavity may define the shape of an inlay to be molded.
[0177] According to some embodiments, polymers can be injected into molds and corneal inlays then polymerized by a method appropriate for the particular polymer employed, e.g., chemically, by successive cross-linking of precursors using cross-linking agents, thermally, or by photopolymerization. After polymerization, the inlay can be removed from the mold (demolded), washed and stored in buffer with a preservative until use.
[0178] According to some embodiments, the corneal inlay is cast as a flat, thin, round disc. According to some embodiments, the fabricated inlay is cast as a hemispherical dome. According to some embodiments, the fabricated inlay is cast as a spherical lens.
[0179] Where a range of values is provided, it is understood that 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.
[0180] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, exemplary methods and materials have been described. All publications mentioned herein are incorporated herein by reference to disclose and described the methods and/or materials in connection with which the publications are cited.
[0181] It must be noted that as used herein and in the appended claims, the singular forms “a”, “and”, and “the” include plural references unless the context clearly dictates otherwise.
[0182] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application and each is incorporated by reference in its entirety. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
EXAMPLES
[0183] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.
Example 1. Evaluating Corneal Haze after Corneal Implants of Various Inlay Materials in New Zealand White Rabbits (Non-GLP)
[0184] Background. This study is designed to evaluate corneal haze after corneal implants of various inlay materials in rabbits. This information can only be obtained from living systems that were treated with the inlay materials. The rabbit is a standard species used in ocular studies based upon historical data and FDA requirements. New Zealand White (NZW) rabbits, which are recognized as a preferred and optimal model for assessing study endpoints, have proven to be useful in ophthalmic research. Their ocular anatomy and physiology are similar to humans, and their eyes have similar metabolic pathways.
[0185] A. Proposed Study Duration: 5-6 Months
[0186] B. Experimental Design [0187] 1. Test system [0188] Species: Oryctolagus cuiculus [0189] Strain: New Zealand White rabbits [0190] Sex: Male (all same sex) [0191] Weight: Approximately 3.5 to 4.5 kg at study start [0192] Number: 16 [0193] Method of identification: ear tag and cage label per SOPs [0194] Minimal acclimation: 5 days [0195] 2. Specialized animal husbandry and/or restraint [0196] (a) fasting: none [0197] (b) restraint: animals will be manually restrained per SOPs to facilitate examinations. [0198] (c) Housing: Animals will be singly housed prior to and during the study in order to decrease the likelihood of ocular injuries from cage mates.
[0199] C. Test Articles
TABLE-US-00001 Test ID Expiry or Article Abbreviation Description No. Manufacturer Storage retest date 1 PEG Polyethylene Glycol (PEG); 1386B Ferentis Room N/A 82% Water Content; temperature (Diameter: ~2.5 mm inlay, thickness: ~40 microns) 2 MPC 2-methacryloyloxyethyl 1385A Ferentis Refrigerated N/A phosphorylcholine polymer; at 2-8° C. 82% Water Content; (Diameters - 2.5 mm disc, thickness: ~40 microns) 3 PEG-(CMP- Collagen Mimetic 1444A Ferrentis Refrigerated N/A RGD)-MPC Peptide with RGD motif- at 2-8° C. 2-methacryloyloxyethyl phosphorylcholine; 80% Water Content; (Diameter: ~2.5 mm disc, thickness: ~36 microns) 4 PC-MPC Porcine Collagen/ 1442B Ferentis Refrigerated N/A 2-methacryloyloxethyl at 2-8° C. phosphorylcholine (PC-MPC) polymer; 80% Water Content; (Diameter: ~2.5 mm disc, thickness: ~40 microns) 5 FIB-PEG- Fibronectin-Polyethylene- 1441 Ferrentis Refrigerated N/A CMP-MPC glycol-Collagen Mimetic at 2-8° C. Peptide-2-methacryloyloxethyl phosphorylcholine; 80% Water Content; (Diameter: ~2.5 mm disc, thickness: ~32 microns) 6 Biotrue 22% Nesofilcon A; TBD Optics Refrigerated N/A 78% Water Content; Medical at 2-8° C. (Diameter: ~2.5 mm disc, thickness: ~45 micron)′ 7 PC-MPC PorcineCollagen/ 1366B Ferrentis Refrigerated N/A Control 2-methacryloyloxethyl at 2-8° C. Article 1 phosphorylcholine (PC-MPC) polymer; 90% Water Content; (Diameter: ~2.5 mm disc, thickness: ~40 microns) 8 Raindrop Raindrop - Near Vision Inlay; 003450 Revision Room 2021 Jan. 16 Control Inlay 78% Water Content; Optics Temperature Article 2 (Diameter: ~2.0 mm inlay, thickness: ~34 microns)
Details of Test Article Administration
[0200] Pre-Treatment Examinations
[0201] 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 the Associate Director. Ocular findings will be scored according to a modified McDonald-Shadduck Scoring System (Appendix A). The acceptance criteria for placement on study will be scores of “0” for all variables.
[0202] Anesthesia
[0203] Animals will be anesthetized via an IM injection of a cocktail containing ketamine (up to approximately 50 mg/kg), glycopyrrolate (0.01 mg/kg, IM) and xylazine (up to approximately 10 mg/kg). Atipamezole hydrochloride (up to 1 mg/kg) may be used as a reversal agent. One to two drops of topical proparacaine hydrochloride anesthetic (0.5%) will be applied to the animals' eyes prior to the injection procedure. Additional topical ocular anesthesia dosing may be utilized during the procedure if needed.
[0204] Surgical Procedure for Nictitating Membrane Removal
[0205] Due to the ability of the nictitating membrane, or third eyelid, to push out the test article, each rabbit will have the nictitating membrane removed from both eyes prior to film placement. 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 10 days prior to test article administration.
[0206] Animals will be anesthetized as described above. Both eyes of each rabbit will be cleaned with betadine and then rinsed with balanced salt solution (BSS). One to two drops of topical proparacaine hydrochloride anesthetic (0.5%) will be applied to the nictitating membrane of each of the animal's eyes prior to the surgical procedure.
[0207] The nictitating membrane will be grasped with a pair of forceps and gently clamped at its base with a pair of hemostats. After clamping for approximately 1 to 2 minutes, the clamp will be removed and the nictitating membrane excised along the clamp line with scissors according to SOP ASI-112. The area may be blotted and medicated with topical gentamicin (0.3%) and neodecadron (1 to 2 drops). The contralateral eye will have its nictitating membrane removed with the same procedure. Triple antibiotic ointment will be applied topically once immediately following nictitating membrane removal. Post-operative recovery for the rabbits will be as described in SOPs ASI-079, ASI-057, and ASI-102 (if catheter placement is necessary). One injection of buprenorphine (0.02 to 0.05 mg/kg, IM/SC) may be given once following removal of the nictitating membranes if deemed necessary by the Attending Veterinarian. Any analgesic treatments will be administered to all study animals equally.
[0208] The day after surgery, animals will be examined to ensure there were no post surgical complications. Animals will receive triple antibiotic ointment for up to 3 days post-operatively. Additional buprenorphine may be administered as deemed necessary by the Attending Veterinarian (this could be more than once). If post-surgical complications occur, the Study Director and/or veterinary staff will be consulted as to the appropriate course of action to maintain the animal's health and well-being. The eyes will be allowed to heal for at least 10 days prior to the administration of the test article as described below.
[0209] Surgical Procedure for Test Article Administration
[0210] Test articles will be implanted in the corneas of both eyes of all study animals on Day 0 according to the study design in Table 1. Implantation procedures will be performed by the designated surgeon. Laser, microkeratome and surgical supplies will be provided by the Sponsor.
[0211] Animals will be anesthetized as outlined above. The eyes will be cleaned with betadine and then rinsed with BSS.
[0212] A flap or pseudo-pocket will be cut into each cornea using a laser or a microkeratome. The surgery type will be noted in the study data.
[0213] The appropriate inlay for each eye will be inserted into the flap or pseudo-pocket. Inlays will be stained with 25% fluorescein (provided by the Sponsor) to facilitate visualization during the implantation procedure.
[0214] After the surgical procedures, animals will be recovered from anesthesia per ASC SOPs.
[0215] Analgesics (e.g. buprenorphine [0.01 to 0.05 mg/kg, IM/SC]), antibiotics (e.g., triple antibiotic ointment or 0.3% tobramycin drops), and prednisolone as an anti inflammatory treatment will be administered on Days 1-3 after the surgical procedures as deemed necessary by the Study Director and/or the Attending Veterinarian. Analgesic, anti-inflammatory, and/or antibiotic regimens may be extended or otherwise modified as necessary based on the discretion of the Study Director and/or the Attending Veterinarian. Any such treatments will be recorded in the raw data.
Safety Precautions
[0216] 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 dose
TABLE-US-00002 TABLE 1 Study Design Surgery Slit-lamp Corneal Euthanasia and Animal # Eye Materials Technique * Examinations OCT Tissue Collection 1 OS RAINDROP Flap Baseline.sup.¥ and Baseline Day 180(±4).sup.#α: OD PC-MPC 80% H.sub.2O Days 7, and Days Whole Globes 2 OS RAINDROP Pseudo 30(±2), 14(±1) and OD PC-MPC 80% H.sub.2O Pocket 60(±2), 90(±4). 3 OS PC-MPC 90% H.sub.2O Flap 0(±4), Optional: OD PC-MPC 80% H.sub.2O 120(±4), additional 4 OS PC-MPC 90% H.sub.2O Pseudo 150(±4), and OCT OD PC-MPC 80% H.sub.2O Pocket 180(±4) images as 5 OS PEG 80% H.sub.2O Flap requested OD PEG 80% H.sub.2O by the 6 OS PEG 80% H.sub.2O Pseudo sponsor. OD PEG 80% H2O Pocket OCT will 7 OS BIOTRUE Flap be OD PC-MPC 90% H.sub.2O performed 8 OS BIOTRUE Pseudo prior to OD PC-MPC 90% H.sub.2O Pocket termination 9 OS MPC 82% H.sub.2O Flap OD 10 OS MPC 82% H2O Pseudo OD Pocket 11 OS PEG-CMP-RGD- Flap OD MPC 80% H.sub.2O 12 OS PEG-CMP-RGD- Pseudo OD MPC 80% H.sub.2O Pocket 13 OS FIB-PEG-CMP-MPC Flap OD 80% H.sub.2O 14 OS FIB-PEG-CMP-MPC Pseudo OD 80% H.sub.2O Pocket 15 OS LASER—SHAM Flap OD LASER—SHAM Pseudo Pocket 16 OS LASER—SHAM Flap OD LASER—SHAM Pseudo Pocket OD: right eye; OS: left eye * Surgery Type (laser flap, laser pseudo pocket, or a microkeratome flap) may change at the Sponsor’s discretion. .sup.¥Indirect ophthalmoscopy only for baseline. .sup.#Optional extensions with monthly examinations past Day 180(±4) for some or all animals may be added at the Sponsor’s discretion. .sup.αAnimals may be euthanized earlier and tissues collected in case of corneal damage developing.
[0217] In-Life Observations and Measurements Summary of Key Study Parameters is Presented in Appendix A.
[0218] Body Weights
[0219] Animals will be weighed prior to test article administration and termination.
[0220] General Health Observations
[0221] Animals will be observed within their cages once daily throughout the study period. Each animal will be observed for changes in general appearance and behavior. Any abnormal observations will be reported to the Study Director.
[0222] General health observations will be performed and recorded daily starting on Day 0 and continuing throughout the duration of the study. Health observations will include assessment of ocular abnormalities such as discharge, swelling, or hyperemia.
[0223] Slit-Lamp Examinations
[0224] Slit-lamp examinations will be performed at baseline prior to test article administration, and on Days 7, 30(±2), 60(±2), and 90(±4), 120(±4), 150(±4), and 180(±4) after test article administration.
[0225] Additional monthly examinations past Day 180(±4) may be added as an optional extension at the discretion of the Sponsor.
[0226] Slit-lamp examinations will be performed by the Study Director or the Associate Director and will assess only the ocular observation variables of the modified McDonald-Shadduck Scoring System (Appendix A) related to corneal haze/opacity. Severity (“Cornea”) and area (“Surface Area of Cornea Involvement”) of corneal haze/opacity will be assessed.
[0227] In addition, examinations will include scoring of corneal haze following the study-specific scoring system presented in Appendix B.
[0228] OCT Imaging
[0229] Optical coherence tomography (OCT) images will be taken at baseline and on Days 14(±1) and 90(±4) or prior to termination. More OCT time points may be added at the Sponsor's discretion.
[0230] OCT will be used to analyze the cornea cross-section, device placement, and geometry. Images will be taken to capture any ocular anomalies noted at the time of imaging. OCT examinations will be performed by the Study Director. All raw images taken will be provided to the Sponsor.
[0231] Animals may be anesthetized for OCT imaging as described above.
Calculations and Statistical Analysis
[0232] Data will be presented in tabular format and no calculations or statistical analysis will be performed on the data collected during the in-life portion of the study.
Terminal Procedures
[0233] Early Death/Unscheduled Sacrifice
[0234] If an animal dies on study, the time of death will be estimated as closely as possible and recorded. The animal may be necropsied; if so, the necropsy will be performed as soon as possible. If the necropsy cannot be performed immediately, the animal will be refrigerated (not frozen) to minimize tissue autolysis. Animals that are prematurely terminated may be necropsied after discussion with the Sponsor, and major organ findings noted.
[0235] If an animal is moribund as defined by SOP ASI-023 Care and Use of Animals, it will be euthanized as described below, which is in accordance to 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.
[0236] If possible, blood or other specimens may 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.
[0237] Specific ocular endpoints necessitating treatment and/or euthanasia would be:
[0238] Ocular infection
[0239] Ocular hemorrhage, hyperemia
[0240] Visual impairment that is manifesting in behavior abnormalities, pain, and/or distress to the animal
[0241] Loss of globe integrity
[0242] Corneal damage
[0243] In the event that an animal dies or is euthanized during the study, terminal procedures will be conducted as per SOPs.
[0244] Euthanasia
[0245] After completion of the final examination on Day 90 (±4), animals will be euthanized by an intravenous injection of a commercial barbiturate based euthanasia solution (approximately 150 mg/kg, to effect). If there is an indication of corneal damage, animals may be euthanized earlier and tissues will be collected. At the Sponsor's discretion, Day 90 (±4) euthanasia may be extended with weekly examinations. The euthanasia procedure will be performed in compliance with the 2013 American Veterinary Medical Association (AVMA) Guidelines on Euthanasia.
[0246] Tissue Collection: Tissues will be collected according to the method described below.
[0247] Method 1
[0248] Immediately following euthanasia, the anterior chamber of the eye will be perfused with 2% paraformaldehyde (PFA) in phosphate-buffered saline (PBS), pH 7.4, 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. After perfusion, 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.
[0249] 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.
[0250] Samples collected via this method will be shipped on cold packs via overnight shipment within 2 days of collection (to ensure receipt of samples within 3 days of collection) to the Sponsor's designated laboratory.
[0251] Method 2
[0252] Immediately following euthanasia, the eye will be harvested. The whole globe will be placed in the Davidson's solution immediately after trimming excessive tissues. A gauze pad should be used to keep the eye submerged if necessary for consistent fixation. Keep the globe in the Davidson's solution for 48 hours. The eye then is taken out of the solution and placed in 70% ethanol.
[0253] Samples collected via this method will be shipped in 70% ethanol solution to the Sponsor's designated laboratory.
[0254] A total of 32 corneas will be collected.
APPENDIX A. MODIFIED MEDONALD-SHADDUEK SCORING SYSTEM
[0255] (T. McDonald and J. A. Shadduck, “Eye irritation,” in Advances in Modern Toxicology: Dermatoxicology, F. Marzulli and H. I. Maibach, Eds., pp. 579-582, Hemisphere Publishing Corporation, Washington, D.C., USA, 1977)
[0256] Examination:
[0257] Use the slit lamp to observe the following: [0258] Pupillary Response [0259] Conjunctival Discharge [0260] Conjunctival Congestion [0261] Conjunctival Swelling [0262] Cornea [0263] Surface Area of Cornea Involvement [0264] Pannus [0265] Aqueous Flare [0266] Aqueous Cell [0267] Iris Involvement [0268] Lens
[0269] Use the Indirect Ophthalmoscope for the following: [0270] Vitreous Flare [0271] Vitreous Cell [0272] Vitreal Hemorrhage [0273] Retinal Detachment [0274] Retinal Hemorrhage [0275] Choroidal/Retinal Inflammation
[0276] Prepare animal for observation by using one of three solutions to dilate the pupil. Usually two drops of ophthalmic preparations of atropine, tropicamide, or phenylephrine is sufficient. The choice of dilator will generally be outlined in the study protocol. Wait until pupil of animal appears to be dilated. It may take up to 60 minutes to achieve pupil dilation.
[0277] Pupillary Response: Check for any blockage or a sluggish response in the pupillary region. Scoring will be taken as follows: [0278] 0=Normal pupil response. [0279] 1=Sluggish or incomplete pupil response. [0280] 2=No pupil response. [0281] 3=No pupil response due to pharmacological blockage.
[0282] Conjunctival Discharge: Discharge is defined as a whitish gray precipitate from the eye. Scoring will be taken as follows: [0283] 0=Normal. No discharge. [0284] 1=Discharge above normal and present on the inner portion of the eye but not on the lids or hairs of the eyelids. [0285] 2=Discharge is abundant, easily observed and has collected on the lids and hairs of the eyelids. [0286] 3=Discharge has been flowing over the eyelids so as to wet the hairs substantially on the skin around the eye.
[0287] Conjunctival Congestion: Congestion causes the blood vessels of the eye to become enlarged. Scoring will be taken as follows: [0288] 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. [0289] 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. [0290] 2=Bright red color of the palpebral conjunctiva with accompanying perilimbal injection covering at least 75% of the circumference of the perilimbal region. [0291] 3=Dark, beefy red color with congestion of both the bulbar and palpebral conjunctiva along with pronounced perilimbal injection and the presence of petechia on the conjunctiva. The petechia generally predominates along the nictitating membrane and upper palpebral conjunctiva.
[0292] Conjunctival Swelling (meaning swelling of the conjunctiva). Scoring will be taken as follows: [0293] 0=Normal or no swelling of the conjunctival tissue [0294] 1=Swelling above normal without eversion of the eyelids (easily discerned by noting upper and lower eyelids are positioned as in the normal eye); swelling generally starts in the lower cul-de-sac near the inner canthus. [0295] 2=Swelling with misalignment of the normal approximation of the lower and upper eyelids; primarily confined to the upper eyelid so that in the initial stages, the misapproximation of the eyelids begins by partial eversion of the upper eyelid. In this stage the swelling is confined generally to the upper eyelid with some swelling in the lower cul-de-sac. [0296] 3=Swelling definite with partial eversion of the upper and lower eyelids essentially equivalent. This can be easily observed by looking at the animal head-on and noting the position of the eyelids; if the eye margins do not meet, eversion has occurred. [0297] 4=Eversion of the upper eyelid is pronounced with less pronounced eversion of the lower eyelid. It is difficult to retract the lids and observe the perilimbal region.
[0298] Cornea: Check the Cornea for any abnormalities. Scoring will be taken as follows: [0299] 0=Normal Cornea [0300] 1=Some loss of transparency. Only the epithelium and/or the anterior half of the stroma are involved. The underlying structures are clearly visible although some cloudiness may be readily apparent. [0301] 2=Involvement of the entire thickness of the stroma. With diffuse illumination, the underlying structures are just barely visible (can still observe flare, iris, pupil response, and lens). [0302] 3=Involvement of the entire thickness of the stroma. With diffuse illumination, the underlying structures cannot be seen.
[0303] 0=Normal Surface Area of Cornea Involvement: Check the eye for cloudiness in the stromal region. Scoring will be taken as follows: [0304] 1=1-25% area of stromal cloudiness. [0305] 2=26-50% area of stromal cloudiness. [0306] 3=51-75% area of stromal cloudiness. [0307] 4=76%-100% area of stromal cloudiness.
[0308] Pannus: Check for vascularization of Cornea. Scoring will be taken as follows: [0309] 0=No pannus (vascularization of the cornea) [0310] 1=Vascularization present but vessels have not invaded the entire cornea circumference. [0311] 2=Vessels have invaded 2 mm or more around entire corneal surface.
[0312] Aqueous Flare: Breakdown of the blood-aqueous barrier. Field size is a 1 mm×1 mm slit beam. Scoring will be taken as follows (based on Jabs D A et al., 2005): [0313] 0=None [0314] 1=Faint [0315] 2=Moderate (iris and lens details clear) [0316] 3=Marked (iris and lens details hazy) [0317] 4=Intense (fibrin or plastic aqueous)
[0318] Aqueous Cell: Cellular observation in the aqueous humor. Field size is a 1 mm×1 mm slit beam. Scoring will be taken as follows (based on Jabs D A et al., 2005): [0319] 0=None [0320] 0.5=Trace (1-5) [0321] 1=6-15 [0322] 2=16-25 [0323] 3=26-50 [0324] 4=>50
[0325] Iris Involvement: Check the iris for hyperemia of the blood vessels. Scoring will be taken as follows: [0326] 0=Normal iris without any hyperemia of the blood vessels. [0327] 1=Minimal injection of the secondary vessels but not tertiary vessels. Generally uniform but may be of greater intensity at the 12:00 to 1:00 or 6:00 position. If confined to this area, the tertiary vessels must be substantially hyperemic. [0328] 2=Minimal injection of tertiary vessels and minimal to moderate injection of the secondary vessels. [0329] 3=Moderate injection of the secondary and tertiary vessels with slight swelling of the iris stroma (the iris surface appears slightly rugose, usually most predominant near the 3:00 and 9:00 positions). [0330] 4=Marked injection of the secondary and tertiary vessels with marked swelling of the iris stroma. The iris appears rugose; may be accompanied by hemorrhage (hyphema) in the anterior chamber.
[0331] Lens: Observe the lens for any cataracts. Scoring will be taken as follows: [0332] 0=Lens clear. [0333] 1=Anterior (cortical/capsular). [0334] 2=Nuclear. [0335] 3=Posterior (cortical/optical). [0336] 4=Equatorial.
[0337] Vitreous Flare: Opacity or fogginess of the vitreous humor. Scoring will be taken as follows (based on Opremcak E M, 2012): [0338] 0=None (nerve fiber layer [NFL] clearly visible) [0339] 1=Faint (optic nerve and vessels clear, NFL hazy) [0340] 2=Moderate (optic nerve and vessels hazy) [0341] 3=Marked (optic nerve only visible) [0342] 4=Intense (no optic nerve visible)
[0343] Vitreous Cell: Cellular observation in the vitreous humor. Scoring will be taken as follows (based on Opremcak E M, 2012): [0344] 0=Trace (0-10) [0345] 1=11-20 [0346] 2=21-30 [0347] 3=31-100 [0348] 4=>100
[0349] Vitreal Hemorrhage: Observe the vitreous for any hemorrhage. Scoring will be taken as follows: [0350] 0=None [0351] 1=1-25% [0352] 2=26-50% [0353] 3=51-75% [0354] 4=76-100%
[0355] 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: [0356] 0=None [0357] 1=Rhegmatogenous (retinal detachment occurs when subretinal fluid accumulates in the potential space between the neurosensory retina and the underlying retinal pigment epithelium). [0358] 2=Exudative (occurs due to inflammation, injury, or vascular abnormalities that results in fluid accumulating underneath the retina without the presence of a hole, tear, or break). [0359] 3=Tractional (occurs when fibrous or fibrovascular tissue, caused by an injury, inflammation, or neovascularization that pulls the sensory retina from the retinal pigment epithelium).
[0360] Retinal Hemorrhage: Abnormal bleeding of the blood vessels in the retina. Scoring will be taken as follows: [0361] 0=None [0362] 1=1-25% [0363] 2=26-50% [0364] 3=51-75% [0365] 4=76-100%
[0366] Choroidal/Retinal Inflammation: Inflammation of the retina and/or choroid. Scoring will be taken as follows: [0367] 0=None [0368] 1=Mild [0369] 2=Moderate [0370] 3=Severe
REFERENCES
[0371] Jabs D A, Nussenblatt R B, Rosenbaum J T, Standardization of Uveitis Nomenclature (SUN) Working Group (2005). Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. American Journal of Ophthalmology 140(3): 509-516. [0372] Opremcak E M (2012). Uveitis: A Clinical Manual for Ocular Inflammation. New York: Springer Science+Business Media.
APPENDIX B: CORNEAL HAZE SCORING
[0373] Haze grading is based on a scale used to grade post-PRK Haze, Arch. Ophthalmology (1992) (110): 1286-1291):
[0374] Clear (Grade 0): sporadic, peripheral faint haze, (CLEAR CENTER), not visible with diffuse slit lamp beam, minimally visible by oblique or slit beam. Vision is not affected.
[0375] 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).
[0376] Mild (Grade 2)
[0377] Moderate (Grade 3)
[0378] While the present invention has been described with reference to the specific embodiments thereof it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adopt a particular situation, material, composition of matter, process, process step or steps, to the objective spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.