WO2022272090A1 - Composition d'hydrogel et méthodes d'utilisation - Google Patents
Composition d'hydrogel et méthodes d'utilisation Download PDFInfo
- Publication number
- WO2022272090A1 WO2022272090A1 PCT/US2022/034942 US2022034942W WO2022272090A1 WO 2022272090 A1 WO2022272090 A1 WO 2022272090A1 US 2022034942 W US2022034942 W US 2022034942W WO 2022272090 A1 WO2022272090 A1 WO 2022272090A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- corneal
- inlay
- inclusive
- collagen
- cornea
- Prior art date
Links
- 239000000017 hydrogel Substances 0.000 title claims abstract description 160
- 239000000203 mixture Substances 0.000 title claims abstract description 135
- 238000000034 method Methods 0.000 title description 110
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 134
- 229920000642 polymer Polymers 0.000 claims abstract description 89
- 229920001059 synthetic polymer Polymers 0.000 claims abstract description 52
- 239000007943 implant Substances 0.000 claims abstract description 48
- 239000003999 initiator Substances 0.000 claims abstract description 14
- 102000008186 Collagen Human genes 0.000 claims description 117
- 108010035532 Collagen Proteins 0.000 claims description 117
- 229920001436 collagen Polymers 0.000 claims description 117
- -1 poly(ethylene glycol) Polymers 0.000 claims description 85
- 238000004132 cross linking Methods 0.000 claims description 32
- 229920001222 biopolymer Polymers 0.000 claims description 31
- 229920001223 polyethylene glycol Polymers 0.000 claims description 26
- 230000003287 optical effect Effects 0.000 claims description 24
- 238000006116 polymerization reaction Methods 0.000 claims description 16
- 230000000977 initiatory effect Effects 0.000 claims description 13
- 239000003431 cross linking reagent Substances 0.000 claims description 11
- 125000004386 diacrylate group Chemical group 0.000 claims description 11
- JUYQFRXNMVWASF-UHFFFAOYSA-M lithium;phenyl-(2,4,6-trimethylbenzoyl)phosphinate Chemical compound [Li+].CC1=CC(C)=CC(C)=C1C(=O)P([O-])(=O)C1=CC=CC=C1 JUYQFRXNMVWASF-UHFFFAOYSA-M 0.000 claims description 10
- ZSZRUEAFVQITHH-UHFFFAOYSA-N 2-(2-methylprop-2-enoyloxy)ethyl 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CC(=C)C(=O)OCCOP([O-])(=O)OCC[N+](C)(C)C ZSZRUEAFVQITHH-UHFFFAOYSA-N 0.000 claims description 6
- 230000003278 mimic effect Effects 0.000 claims description 5
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 claims description 3
- 201000010041 presbyopia Diseases 0.000 abstract description 36
- 208000006069 Corneal Opacity Diseases 0.000 abstract description 29
- 230000000007 visual effect Effects 0.000 abstract description 14
- 229920005615 natural polymer Polymers 0.000 abstract description 13
- 238000000465 moulding Methods 0.000 abstract description 11
- 210000004087 cornea Anatomy 0.000 description 271
- 210000004027 cell Anatomy 0.000 description 190
- 210000001508 eye Anatomy 0.000 description 187
- 230000029663 wound healing Effects 0.000 description 130
- 239000000463 material Substances 0.000 description 120
- 241001465754 Metazoa Species 0.000 description 100
- 208000027418 Wounds and injury Diseases 0.000 description 60
- 210000000695 crystalline len Anatomy 0.000 description 56
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 53
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 53
- 210000002744 extracellular matrix Anatomy 0.000 description 50
- 210000001519 tissue Anatomy 0.000 description 48
- 238000012360 testing method Methods 0.000 description 47
- 108091006146 Channels Proteins 0.000 description 45
- 210000000651 myofibroblast Anatomy 0.000 description 44
- 230000000694 effects Effects 0.000 description 42
- 230000004044 response Effects 0.000 description 42
- 210000002469 basement membrane Anatomy 0.000 description 40
- 238000003556 assay Methods 0.000 description 38
- 108090000623 proteins and genes Proteins 0.000 description 38
- 241000219739 Lens Species 0.000 description 37
- 230000003511 endothelial effect Effects 0.000 description 37
- 239000010410 layer Substances 0.000 description 37
- 206010052428 Wound Diseases 0.000 description 36
- 235000018102 proteins Nutrition 0.000 description 34
- 102000004169 proteins and genes Human genes 0.000 description 34
- 210000002919 epithelial cell Anatomy 0.000 description 31
- 230000006378 damage Effects 0.000 description 30
- 210000000981 epithelium Anatomy 0.000 description 30
- 230000004438 eyesight Effects 0.000 description 30
- 241000283973 Oryctolagus cuniculus Species 0.000 description 29
- 108090000765 processed proteins & peptides Proteins 0.000 description 29
- 102000004127 Cytokines Human genes 0.000 description 28
- 108090000695 Cytokines Proteins 0.000 description 28
- 238000004519 manufacturing process Methods 0.000 description 28
- 239000000243 solution Substances 0.000 description 28
- 239000000126 substance Substances 0.000 description 27
- 210000000399 corneal endothelial cell Anatomy 0.000 description 26
- 239000000523 sample Substances 0.000 description 26
- 238000001356 surgical procedure Methods 0.000 description 26
- 238000012937 correction Methods 0.000 description 25
- 208000014674 injury Diseases 0.000 description 25
- 230000008569 process Effects 0.000 description 25
- 210000001525 retina Anatomy 0.000 description 25
- 230000005012 migration Effects 0.000 description 24
- 238000013508 migration Methods 0.000 description 24
- 210000001747 pupil Anatomy 0.000 description 23
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 22
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 22
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 21
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 21
- 230000005540 biological transmission Effects 0.000 description 21
- 239000003102 growth factor Substances 0.000 description 21
- 230000035876 healing Effects 0.000 description 21
- 208000001491 myopia Diseases 0.000 description 21
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 21
- 210000004045 bowman membrane Anatomy 0.000 description 20
- 238000000338 in vitro Methods 0.000 description 20
- 230000001404 mediated effect Effects 0.000 description 20
- BMTZEAOGFDXDAD-UHFFFAOYSA-M 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium;chloride Chemical compound [Cl-].COC1=NC(OC)=NC([N+]2(C)CCOCC2)=N1 BMTZEAOGFDXDAD-UHFFFAOYSA-M 0.000 description 19
- 230000004913 activation Effects 0.000 description 19
- 238000011161 development Methods 0.000 description 19
- 230000018109 developmental process Effects 0.000 description 19
- 230000003993 interaction Effects 0.000 description 19
- 230000002093 peripheral effect Effects 0.000 description 18
- 239000011148 porous material Substances 0.000 description 18
- 102000004196 processed proteins & peptides Human genes 0.000 description 18
- 238000010561 standard procedure Methods 0.000 description 18
- 230000012292 cell migration Effects 0.000 description 17
- 230000008859 change Effects 0.000 description 17
- 238000001727 in vivo Methods 0.000 description 17
- 230000013011 mating Effects 0.000 description 17
- 235000001014 amino acid Nutrition 0.000 description 16
- 229940024606 amino acid Drugs 0.000 description 16
- 230000001413 cellular effect Effects 0.000 description 16
- 230000006870 function Effects 0.000 description 16
- 229920001184 polypeptide Polymers 0.000 description 16
- 230000008961 swelling Effects 0.000 description 16
- 239000007987 MES buffer Substances 0.000 description 15
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 15
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 15
- 150000001413 amino acids Chemical class 0.000 description 15
- 210000000744 eyelid Anatomy 0.000 description 15
- 208000014117 bile duct papillary neoplasm Diseases 0.000 description 14
- 210000003560 epithelium corneal Anatomy 0.000 description 14
- 210000002950 fibroblast Anatomy 0.000 description 14
- 238000002347 injection Methods 0.000 description 14
- 239000007924 injection Substances 0.000 description 14
- 239000000178 monomer Substances 0.000 description 14
- 230000037361 pathway Effects 0.000 description 14
- 208000028006 Corneal injury Diseases 0.000 description 13
- 108010067306 Fibronectins Proteins 0.000 description 13
- 102000016359 Fibronectins Human genes 0.000 description 13
- 238000000386 microscopy Methods 0.000 description 13
- 238000012014 optical coherence tomography Methods 0.000 description 13
- 230000002829 reductive effect Effects 0.000 description 13
- 230000001070 adhesive effect Effects 0.000 description 12
- 239000012530 fluid Substances 0.000 description 12
- 239000002609 medium Substances 0.000 description 12
- 230000035755 proliferation Effects 0.000 description 12
- 230000011664 signaling Effects 0.000 description 12
- 230000037314 wound repair Effects 0.000 description 12
- 210000000795 conjunctiva Anatomy 0.000 description 11
- 210000003239 corneal fibroblast Anatomy 0.000 description 11
- 238000002513 implantation Methods 0.000 description 11
- 238000001000 micrograph Methods 0.000 description 11
- 230000008439 repair process Effects 0.000 description 11
- 230000009466 transformation Effects 0.000 description 11
- 206010015548 Euthanasia Diseases 0.000 description 10
- 206010061218 Inflammation Diseases 0.000 description 10
- 102000000589 Interleukin-1 Human genes 0.000 description 10
- 108010002352 Interleukin-1 Proteins 0.000 description 10
- 239000000853 adhesive Substances 0.000 description 10
- 230000008901 benefit Effects 0.000 description 10
- 230000033228 biological regulation Effects 0.000 description 10
- 230000010261 cell growth Effects 0.000 description 10
- 210000002555 descemet membrane Anatomy 0.000 description 10
- 230000003176 fibrotic effect Effects 0.000 description 10
- 230000028709 inflammatory response Effects 0.000 description 10
- 210000000826 nictitating membrane Anatomy 0.000 description 10
- 230000000699 topical effect Effects 0.000 description 10
- 102000001301 EGF receptor Human genes 0.000 description 9
- 108060006698 EGF receptor Proteins 0.000 description 9
- 230000009471 action Effects 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 230000004663 cell proliferation Effects 0.000 description 9
- 230000001886 ciliary effect Effects 0.000 description 9
- 238000013461 design Methods 0.000 description 9
- 238000010586 diagram Methods 0.000 description 9
- 210000005081 epithelial layer Anatomy 0.000 description 9
- 238000005286 illumination Methods 0.000 description 9
- 238000011065 in-situ storage Methods 0.000 description 9
- 230000001965 increasing effect Effects 0.000 description 9
- 210000004969 inflammatory cell Anatomy 0.000 description 9
- 230000004054 inflammatory process Effects 0.000 description 9
- 108010044426 integrins Proteins 0.000 description 9
- 102000006495 integrins Human genes 0.000 description 9
- 210000003205 muscle Anatomy 0.000 description 9
- 229920002994 synthetic fiber Polymers 0.000 description 9
- LOGFVTREOLYCPF-KXNHARMFSA-N (2s,3r)-2-[[(2r)-1-[(2s)-2,6-diaminohexanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoic acid Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]1CCCN1C(=O)[C@@H](N)CCCCN LOGFVTREOLYCPF-KXNHARMFSA-N 0.000 description 8
- 102000007469 Actins Human genes 0.000 description 8
- 108010085238 Actins Proteins 0.000 description 8
- 206010002091 Anaesthesia Diseases 0.000 description 8
- 239000004971 Cross linker Substances 0.000 description 8
- 102000003972 Fibroblast growth factor 7 Human genes 0.000 description 8
- 108090000385 Fibroblast growth factor 7 Proteins 0.000 description 8
- 102000003745 Hepatocyte Growth Factor Human genes 0.000 description 8
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 description 8
- 102000003777 Interleukin-1 beta Human genes 0.000 description 8
- 108090000193 Interleukin-1 beta Proteins 0.000 description 8
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 8
- 102000038030 PI3Ks Human genes 0.000 description 8
- 108091007960 PI3Ks Proteins 0.000 description 8
- 230000004075 alteration Effects 0.000 description 8
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium peroxydisulfate Substances [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 8
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 8
- 230000037005 anaesthesia Effects 0.000 description 8
- 210000003484 anatomy Anatomy 0.000 description 8
- 230000015556 catabolic process Effects 0.000 description 8
- 230000000295 complement effect Effects 0.000 description 8
- 210000003683 corneal stroma Anatomy 0.000 description 8
- 230000007423 decrease Effects 0.000 description 8
- 230000001419 dependent effect Effects 0.000 description 8
- 230000004069 differentiation Effects 0.000 description 8
- 238000009826 distribution Methods 0.000 description 8
- 210000003038 endothelium Anatomy 0.000 description 8
- 210000000871 endothelium corneal Anatomy 0.000 description 8
- 230000002055 immunohistochemical effect Effects 0.000 description 8
- 238000007918 intramuscular administration Methods 0.000 description 8
- 210000002540 macrophage Anatomy 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 229920001282 polysaccharide Polymers 0.000 description 8
- 206010016654 Fibrosis Diseases 0.000 description 7
- 208000032843 Hemorrhage Diseases 0.000 description 7
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 7
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 7
- 108010046722 Thrombospondin 1 Proteins 0.000 description 7
- 102100036034 Thrombospondin-1 Human genes 0.000 description 7
- 230000006907 apoptotic process Effects 0.000 description 7
- 230000003115 biocidal effect Effects 0.000 description 7
- 239000000560 biocompatible material Substances 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 230000034994 death Effects 0.000 description 7
- 238000006731 degradation reaction Methods 0.000 description 7
- 210000002889 endothelial cell Anatomy 0.000 description 7
- 230000004761 fibrosis Effects 0.000 description 7
- 150000004676 glycans Chemical class 0.000 description 7
- 210000000987 immune system Anatomy 0.000 description 7
- 230000001976 improved effect Effects 0.000 description 7
- 239000011159 matrix material Substances 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- 210000004379 membrane Anatomy 0.000 description 7
- 239000012528 membrane Substances 0.000 description 7
- 210000001328 optic nerve Anatomy 0.000 description 7
- 210000000056 organ Anatomy 0.000 description 7
- 239000005017 polysaccharide Substances 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 208000014733 refractive error Diseases 0.000 description 7
- 238000007634 remodeling Methods 0.000 description 7
- 238000012552 review Methods 0.000 description 7
- 210000000130 stem cell Anatomy 0.000 description 7
- 210000002536 stromal cell Anatomy 0.000 description 7
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 7
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 6
- 101800001318 Capsid protein VP4 Proteins 0.000 description 6
- 102000011068 Cdc42 Human genes 0.000 description 6
- 108050001278 Cdc42 Proteins 0.000 description 6
- 101800003838 Epidermal growth factor Proteins 0.000 description 6
- 241000282412 Homo Species 0.000 description 6
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 6
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 6
- 108010085895 Laminin Proteins 0.000 description 6
- 102000007547 Laminin Human genes 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 102000035195 Peptidases Human genes 0.000 description 6
- 108091005804 Peptidases Proteins 0.000 description 6
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 6
- 239000002202 Polyethylene glycol Substances 0.000 description 6
- 102100033237 Pro-epidermal growth factor Human genes 0.000 description 6
- 102000001708 Protein Isoforms Human genes 0.000 description 6
- 108010029485 Protein Isoforms Proteins 0.000 description 6
- 102100027609 Rho-related GTP-binding protein RhoD Human genes 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229920002125 Sokalan® Polymers 0.000 description 6
- 102000007000 Tenascin Human genes 0.000 description 6
- 108010008125 Tenascin Proteins 0.000 description 6
- 102000002689 Toll-like receptor Human genes 0.000 description 6
- 108020000411 Toll-like receptor Proteins 0.000 description 6
- 102000046299 Transforming Growth Factor beta1 Human genes 0.000 description 6
- 101800002279 Transforming growth factor beta-1 Proteins 0.000 description 6
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 6
- 102100040247 Tumor necrosis factor Human genes 0.000 description 6
- 238000005299 abrasion Methods 0.000 description 6
- 238000010171 animal model Methods 0.000 description 6
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 6
- 229960001736 buprenorphine Drugs 0.000 description 6
- 238000012512 characterization method Methods 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000000942 confocal micrograph Methods 0.000 description 6
- 230000010595 endothelial cell migration Effects 0.000 description 6
- 229940116977 epidermal growth factor Drugs 0.000 description 6
- 238000011156 evaluation Methods 0.000 description 6
- 230000036541 health Effects 0.000 description 6
- 230000001771 impaired effect Effects 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- 230000004379 myopia Effects 0.000 description 6
- 210000000822 natural killer cell Anatomy 0.000 description 6
- 230000023603 positive regulation of transcription initiation, DNA-dependent Effects 0.000 description 6
- 230000008929 regeneration Effects 0.000 description 6
- 238000011069 regeneration method Methods 0.000 description 6
- 230000019491 signal transduction Effects 0.000 description 6
- 241000894007 species Species 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- 229920002101 Chitin Polymers 0.000 description 5
- 102000015225 Connective Tissue Growth Factor Human genes 0.000 description 5
- 108010039419 Connective Tissue Growth Factor Proteins 0.000 description 5
- 102000019149 MAP kinase activity proteins Human genes 0.000 description 5
- 108040008097 MAP kinase activity proteins Proteins 0.000 description 5
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 5
- 102000003945 NF-kappa B Human genes 0.000 description 5
- 108010057466 NF-kappa B Proteins 0.000 description 5
- 229930040373 Paraformaldehyde Natural products 0.000 description 5
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 5
- 206010038848 Retinal detachment Diseases 0.000 description 5
- 102100037599 SPARC Human genes 0.000 description 5
- 102000011117 Transforming Growth Factor beta2 Human genes 0.000 description 5
- 101800000304 Transforming growth factor beta-2 Proteins 0.000 description 5
- 230000004308 accommodation Effects 0.000 description 5
- 210000002159 anterior chamber Anatomy 0.000 description 5
- 210000001742 aqueous humor Anatomy 0.000 description 5
- 230000004888 barrier function Effects 0.000 description 5
- 210000000270 basal cell Anatomy 0.000 description 5
- 230000000903 blocking effect Effects 0.000 description 5
- 210000004204 blood vessel Anatomy 0.000 description 5
- 210000001185 bone marrow Anatomy 0.000 description 5
- 210000003161 choroid Anatomy 0.000 description 5
- 230000010393 epithelial cell migration Effects 0.000 description 5
- 229920002674 hyaluronan Polymers 0.000 description 5
- 229960003160 hyaluronic acid Drugs 0.000 description 5
- 230000004305 hyperopia Effects 0.000 description 5
- 201000006318 hyperopia Diseases 0.000 description 5
- 230000028993 immune response Effects 0.000 description 5
- 210000005036 nerve Anatomy 0.000 description 5
- 210000000440 neutrophil Anatomy 0.000 description 5
- 239000002773 nucleotide Substances 0.000 description 5
- 235000015097 nutrients Nutrition 0.000 description 5
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 5
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 5
- 229920002866 paraformaldehyde Polymers 0.000 description 5
- 239000000816 peptidomimetic Substances 0.000 description 5
- 229920000747 poly(lactic acid) Polymers 0.000 description 5
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 5
- 239000004926 polymethyl methacrylate Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 238000011084 recovery Methods 0.000 description 5
- 230000007480 spreading Effects 0.000 description 5
- 238000003892 spreading Methods 0.000 description 5
- 231100000331 toxic Toxicity 0.000 description 5
- 230000002588 toxic effect Effects 0.000 description 5
- 238000002054 transplantation Methods 0.000 description 5
- 230000032258 transport Effects 0.000 description 5
- 210000004127 vitreous body Anatomy 0.000 description 5
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 4
- CPKVUHPKYQGHMW-UHFFFAOYSA-N 1-ethenylpyrrolidin-2-one;molecular iodine Chemical compound II.C=CN1CCCC1=O CPKVUHPKYQGHMW-UHFFFAOYSA-N 0.000 description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 4
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 4
- 208000002177 Cataract Diseases 0.000 description 4
- 102000000018 Chemokine CCL2 Human genes 0.000 description 4
- 102000004266 Collagen Type IV Human genes 0.000 description 4
- 108010042086 Collagen Type IV Proteins 0.000 description 4
- 241000282326 Felis catus Species 0.000 description 4
- 108010073385 Fibrin Proteins 0.000 description 4
- 102000009123 Fibrin Human genes 0.000 description 4
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- 229920002683 Glycosaminoglycan Polymers 0.000 description 4
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 description 4
- 206010021143 Hypoxia Diseases 0.000 description 4
- 102000019145 JUN kinase activity proteins Human genes 0.000 description 4
- 201000002287 Keratoconus Diseases 0.000 description 4
- 102000043136 MAP kinase family Human genes 0.000 description 4
- 108091054455 MAP kinase family Proteins 0.000 description 4
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 229920000954 Polyglycolide Polymers 0.000 description 4
- 108010067787 Proteoglycans Proteins 0.000 description 4
- 102000016611 Proteoglycans Human genes 0.000 description 4
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 4
- 102100023132 Transcription factor Jun Human genes 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- VAZSKTXWXKYQJF-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)OOS([O-])=O VAZSKTXWXKYQJF-UHFFFAOYSA-N 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 239000003855 balanced salt solution Substances 0.000 description 4
- 229940064804 betadine Drugs 0.000 description 4
- 229920000249 biocompatible polymer Polymers 0.000 description 4
- 239000012620 biological material Substances 0.000 description 4
- 230000001851 biosynthetic effect Effects 0.000 description 4
- 230000001275 ca(2+)-mobilization Effects 0.000 description 4
- 238000005266 casting Methods 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 210000002808 connective tissue Anatomy 0.000 description 4
- 230000008602 contraction Effects 0.000 description 4
- 239000013068 control sample Substances 0.000 description 4
- 238000001804 debridement Methods 0.000 description 4
- 229950003499 fibrin Drugs 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 230000004313 glare Effects 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 239000003292 glue Substances 0.000 description 4
- 230000007954 hypoxia Effects 0.000 description 4
- 210000002865 immune cell Anatomy 0.000 description 4
- 230000002757 inflammatory effect Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 230000015788 innate immune response Effects 0.000 description 4
- 238000003780 insertion Methods 0.000 description 4
- 230000037431 insertion Effects 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 210000000265 leukocyte Anatomy 0.000 description 4
- 210000004698 lymphocyte Anatomy 0.000 description 4
- 230000005499 meniscus Effects 0.000 description 4
- 229960004857 mitomycin Drugs 0.000 description 4
- 230000003472 neutralizing effect Effects 0.000 description 4
- 238000011587 new zealand white rabbit Methods 0.000 description 4
- 230000008520 organization Effects 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 244000052769 pathogen Species 0.000 description 4
- 230000000149 penetrating effect Effects 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 230000002980 postoperative effect Effects 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 230000001681 protective effect Effects 0.000 description 4
- 230000009822 protein phosphorylation Effects 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 230000004264 retinal detachment Effects 0.000 description 4
- 231100000241 scar Toxicity 0.000 description 4
- 230000036573 scar formation Effects 0.000 description 4
- 230000037390 scarring Effects 0.000 description 4
- 239000001797 sucrose acetate isobutyrate Substances 0.000 description 4
- 235000010983 sucrose acetate isobutyrate Nutrition 0.000 description 4
- UVGUPMLLGBCFEJ-SWTLDUCYSA-N sucrose acetate isobutyrate Chemical compound CC(C)C(=O)O[C@H]1[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O[C@@]1(COC(C)=O)O[C@@H]1[C@H](OC(=O)C(C)C)[C@@H](OC(=O)C(C)C)[C@H](OC(=O)C(C)C)[C@@H](COC(C)=O)O1 UVGUPMLLGBCFEJ-SWTLDUCYSA-N 0.000 description 4
- 238000011477 surgical intervention Methods 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 230000010388 wound contraction Effects 0.000 description 4
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 3
- 102100028728 Bone morphogenetic protein 1 Human genes 0.000 description 3
- 108090000654 Bone morphogenetic protein 1 Proteins 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- 101100356682 Caenorhabditis elegans rho-1 gene Proteins 0.000 description 3
- 102000047200 Collagen Type XVIII Human genes 0.000 description 3
- 108010001463 Collagen Type XVIII Proteins 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 102000016942 Elastin Human genes 0.000 description 3
- 108010014258 Elastin Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 102000003886 Glycoproteins Human genes 0.000 description 3
- 108090000288 Glycoproteins Proteins 0.000 description 3
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 description 3
- 101000588007 Homo sapiens SPARC-like protein 1 Proteins 0.000 description 3
- 206010020565 Hyperaemia Diseases 0.000 description 3
- 206010020675 Hypermetropia Diseases 0.000 description 3
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 3
- 102000014150 Interferons Human genes 0.000 description 3
- 108010050904 Interferons Proteins 0.000 description 3
- 108010076371 Lumican Proteins 0.000 description 3
- 102000011681 Lumican Human genes 0.000 description 3
- 238000000134 MTT assay Methods 0.000 description 3
- 206010027646 Miosis Diseases 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- 238000011887 Necropsy Methods 0.000 description 3
- 206010028851 Necrosis Diseases 0.000 description 3
- 206010029113 Neovascularisation Diseases 0.000 description 3
- 241001111421 Pannus Species 0.000 description 3
- 102000018546 Paxillin Human genes 0.000 description 3
- ACNHBCIZLNNLRS-UHFFFAOYSA-N Paxilline 1 Natural products N1C2=CC=CC=C2C2=C1C1(C)C3(C)CCC4OC(C(C)(O)C)C(=O)C=C4C3(O)CCC1C2 ACNHBCIZLNNLRS-UHFFFAOYSA-N 0.000 description 3
- 102100035846 Pigment epithelium-derived factor Human genes 0.000 description 3
- 108010003541 Platelet Activating Factor Proteins 0.000 description 3
- 229920002732 Polyanhydride Polymers 0.000 description 3
- 101150111584 RHOA gene Proteins 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 101710100111 SPARC Proteins 0.000 description 3
- 102100031581 SPARC-like protein 1 Human genes 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 108700031954 Tgfb1i1/Leupaxin/TGFB1I1 Proteins 0.000 description 3
- 108010018242 Transcription Factor AP-1 Proteins 0.000 description 3
- 102000056172 Transforming growth factor beta-3 Human genes 0.000 description 3
- 108090000097 Transforming growth factor beta-3 Proteins 0.000 description 3
- 102100031988 Tumor necrosis factor ligand superfamily member 6 Human genes 0.000 description 3
- 108050002568 Tumor necrosis factor ligand superfamily member 6 Proteins 0.000 description 3
- 206010046851 Uveitis Diseases 0.000 description 3
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 3
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 3
- 108700005077 Viral Genes Proteins 0.000 description 3
- 101150109862 WNT-5A gene Proteins 0.000 description 3
- 108700020483 Wnt-5a Proteins 0.000 description 3
- 102000043366 Wnt-5a Human genes 0.000 description 3
- 238000002679 ablation Methods 0.000 description 3
- 230000005856 abnormality Effects 0.000 description 3
- 230000000740 bleeding effect Effects 0.000 description 3
- 229920001400 block copolymer Polymers 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 230000008614 cellular interaction Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- UHZZMRAGKVHANO-UHFFFAOYSA-M chlormequat chloride Chemical compound [Cl-].C[N+](C)(C)CCCl UHZZMRAGKVHANO-UHFFFAOYSA-M 0.000 description 3
- 238000004140 cleaning Methods 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- 238000005520 cutting process Methods 0.000 description 3
- 210000004292 cytoskeleton Anatomy 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 210000004443 dendritic cell Anatomy 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000006196 drop Substances 0.000 description 3
- 229920002549 elastin Polymers 0.000 description 3
- 150000002148 esters Chemical group 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000003889 eye drop Substances 0.000 description 3
- 229940012356 eye drops Drugs 0.000 description 3
- 239000000835 fiber Substances 0.000 description 3
- 102000034240 fibrous proteins Human genes 0.000 description 3
- 108091005899 fibrous proteins Proteins 0.000 description 3
- 210000001650 focal adhesion Anatomy 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000001476 gene delivery Methods 0.000 description 3
- 210000004209 hair Anatomy 0.000 description 3
- 125000001475 halogen functional group Chemical group 0.000 description 3
- 210000003128 head Anatomy 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 230000002779 inactivation Effects 0.000 description 3
- 238000007373 indentation Methods 0.000 description 3
- 238000009540 indirect ophthalmoscopy Methods 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 230000008595 infiltration Effects 0.000 description 3
- 238000001764 infiltration Methods 0.000 description 3
- 210000001821 langerhans cell Anatomy 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 230000004807 localization Effects 0.000 description 3
- 229920002521 macromolecule Polymers 0.000 description 3
- 230000003547 miosis Effects 0.000 description 3
- 210000000066 myeloid cell Anatomy 0.000 description 3
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 3
- 230000017074 necrotic cell death Effects 0.000 description 3
- 238000010899 nucleation Methods 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 235000016709 nutrition Nutrition 0.000 description 3
- 230000001717 pathogenic effect Effects 0.000 description 3
- ACNHBCIZLNNLRS-UBGQALKQSA-N paxilline Chemical compound N1C2=CC=CC=C2C2=C1[C@]1(C)[C@@]3(C)CC[C@@H]4O[C@H](C(C)(O)C)C(=O)C=C4[C@]3(O)CC[C@H]1C2 ACNHBCIZLNNLRS-UBGQALKQSA-N 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 108090000102 pigment epithelium-derived factor Proteins 0.000 description 3
- 229920003023 plastic Polymers 0.000 description 3
- 239000004033 plastic Substances 0.000 description 3
- 229920001610 polycaprolactone Polymers 0.000 description 3
- 229920000728 polyester Polymers 0.000 description 3
- 229920001296 polysiloxane Polymers 0.000 description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 235000019833 protease Nutrition 0.000 description 3
- 230000007115 recruitment Effects 0.000 description 3
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 3
- 230000000717 retained effect Effects 0.000 description 3
- 230000002207 retinal effect Effects 0.000 description 3
- 210000003786 sclera Anatomy 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007790 solid phase Substances 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 230000004936 stimulating effect Effects 0.000 description 3
- 230000035882 stress Effects 0.000 description 3
- 239000003106 tissue adhesive Substances 0.000 description 3
- 230000007704 transition Effects 0.000 description 3
- 210000005048 vimentin Anatomy 0.000 description 3
- 229920002818 (Hydroxyethyl)methacrylate Polymers 0.000 description 2
- BFUUJUGQJUTPAF-UHFFFAOYSA-N 2-(3-amino-4-propoxybenzoyl)oxyethyl-diethylazanium;chloride Chemical compound [Cl-].CCCOC1=CC=C(C(=O)OCC[NH+](CC)CC)C=C1N BFUUJUGQJUTPAF-UHFFFAOYSA-N 0.000 description 2
- IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical group NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 description 2
- 208000035404 Autolysis Diseases 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 108010081589 Becaplermin Proteins 0.000 description 2
- OXJGJKIURHREKH-UHFFFAOYSA-O CC(=C)C(=O)OCCP(=O)=C(O)C[N+](C)(C)C Chemical compound CC(=C)C(=O)OCCP(=O)=C(O)C[N+](C)(C)C OXJGJKIURHREKH-UHFFFAOYSA-O 0.000 description 2
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 2
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 2
- 206010057248 Cell death Diseases 0.000 description 2
- 102000019034 Chemokines Human genes 0.000 description 2
- 108010012236 Chemokines Proteins 0.000 description 2
- 229920001661 Chitosan Polymers 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010051625 Conjunctival hyperaemia Diseases 0.000 description 2
- 206010010726 Conjunctival oedema Diseases 0.000 description 2
- 206010010741 Conjunctivitis Diseases 0.000 description 2
- 102000001045 Connexin 43 Human genes 0.000 description 2
- 108010069241 Connexin 43 Proteins 0.000 description 2
- 206010010984 Corneal abrasion Diseases 0.000 description 2
- 206010010996 Corneal degeneration Diseases 0.000 description 2
- 102100036912 Desmin Human genes 0.000 description 2
- 108010044052 Desmin Proteins 0.000 description 2
- 108010022355 Fibroins Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 108010076876 Keratins Proteins 0.000 description 2
- 102000011782 Keratins Human genes 0.000 description 2
- 150000008575 L-amino acids Chemical class 0.000 description 2
- 108010064548 Lymphocyte Function-Associated Antigen-1 Proteins 0.000 description 2
- 231100000002 MTT assay Toxicity 0.000 description 2
- 206010025421 Macule Diseases 0.000 description 2
- 108010072582 Matrilin Proteins Proteins 0.000 description 2
- 102000055008 Matrilin Proteins Human genes 0.000 description 2
- 241000237536 Mytilus edulis Species 0.000 description 2
- 108010077077 Osteonectin Proteins 0.000 description 2
- 102100037602 P2X purinoceptor 7 Human genes 0.000 description 2
- 101710189965 P2X purinoceptor 7 Proteins 0.000 description 2
- 108010016731 PPAR gamma Proteins 0.000 description 2
- 102100038825 Peroxisome proliferator-activated receptor gamma Human genes 0.000 description 2
- 229930182556 Polyacetal Natural products 0.000 description 2
- 239000004642 Polyimide Substances 0.000 description 2
- 229920001710 Polyorthoester Polymers 0.000 description 2
- 239000004721 Polyphenylene oxide Substances 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 108010071563 Proto-Oncogene Proteins c-fos Proteins 0.000 description 2
- 102000007568 Proto-Oncogene Proteins c-fos Human genes 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 2
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 2
- 208000037111 Retinal Hemorrhage Diseases 0.000 description 2
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 2
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 2
- 102000040945 Transcription factor Human genes 0.000 description 2
- 108091023040 Transcription factor Proteins 0.000 description 2
- 102000013127 Vimentin Human genes 0.000 description 2
- 108010065472 Vimentin Proteins 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 206010047513 Vision blurred Diseases 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 108091006088 activator proteins Proteins 0.000 description 2
- 208000038016 acute inflammation Diseases 0.000 description 2
- 230000006022 acute inflammation Effects 0.000 description 2
- 230000004430 ametropia Effects 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 230000003444 anaesthetic effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 201000009310 astigmatism Diseases 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- 229960000397 bevacizumab Drugs 0.000 description 2
- 230000002146 bilateral effect Effects 0.000 description 2
- 229920002988 biodegradable polymer Polymers 0.000 description 2
- 239000004621 biodegradable polymer Substances 0.000 description 2
- 238000001574 biopsy Methods 0.000 description 2
- 230000002051 biphasic effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 201000004781 bullous keratopathy Diseases 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000021164 cell adhesion Effects 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000024245 cell differentiation Effects 0.000 description 2
- 230000032823 cell division Effects 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 229920002301 cellulose acetate Polymers 0.000 description 2
- 210000004240 ciliary body Anatomy 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000004624 confocal microscopy Methods 0.000 description 2
- 239000000356 contaminant Substances 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 230000001054 cortical effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 210000005045 desmin Anatomy 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 2
- 229960002986 dinoprostone Drugs 0.000 description 2
- 230000009429 distress Effects 0.000 description 2
- 210000003717 douglas' pouch Anatomy 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000005038 ethylene vinyl acetate Substances 0.000 description 2
- 239000003885 eye ointment Substances 0.000 description 2
- 230000009746 freeze damage Effects 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 238000010166 immunofluorescence Methods 0.000 description 2
- 238000010874 in vitro model Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 230000031146 intracellular signal transduction Effects 0.000 description 2
- 230000009545 invasion Effects 0.000 description 2
- 230000001788 irregular Effects 0.000 description 2
- 239000004816 latex Substances 0.000 description 2
- 229920000126 latex Polymers 0.000 description 2
- 210000003041 ligament Anatomy 0.000 description 2
- 210000001232 limbus corneae Anatomy 0.000 description 2
- 229920006008 lipopolysaccharide Polymers 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 210000003622 mature neutrocyte Anatomy 0.000 description 2
- 210000002752 melanocyte Anatomy 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 230000001617 migratory effect Effects 0.000 description 2
- 230000011278 mitosis Effects 0.000 description 2
- 230000009456 molecular mechanism Effects 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 210000001616 monocyte Anatomy 0.000 description 2
- 230000004899 motility Effects 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 229940069265 ophthalmic ointment Drugs 0.000 description 2
- 238000000879 optical micrograph Methods 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 238000010647 peptide synthesis reaction Methods 0.000 description 2
- 239000010702 perfluoropolyether Substances 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 230000002085 persistent effect Effects 0.000 description 2
- 206010034754 petechiae Diseases 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 2
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 2
- 229920002627 poly(phosphazenes) Polymers 0.000 description 2
- 229920001281 polyalkylene Polymers 0.000 description 2
- 239000004632 polycaprolactone Substances 0.000 description 2
- 239000004417 polycarbonate Substances 0.000 description 2
- 229920000515 polycarbonate Polymers 0.000 description 2
- 229920000570 polyether Polymers 0.000 description 2
- 229920001721 polyimide Polymers 0.000 description 2
- 229920006324 polyoxymethylene Polymers 0.000 description 2
- 229920001451 polypropylene glycol Polymers 0.000 description 2
- 229920002635 polyurethane Polymers 0.000 description 2
- 239000004814 polyurethane Substances 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002203 pretreatment Methods 0.000 description 2
- 238000001314 profilometry Methods 0.000 description 2
- 230000000770 proinflammatory effect Effects 0.000 description 2
- 229960001371 proparacaine hydrochloride Drugs 0.000 description 2
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 2
- 230000004439 pupillary reactions Effects 0.000 description 2
- 230000001696 purinergic effect Effects 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 239000012966 redox initiator Substances 0.000 description 2
- 230000001172 regenerating effect Effects 0.000 description 2
- 230000008521 reorganization Effects 0.000 description 2
- 230000008263 repair mechanism Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 210000003583 retinal pigment epithelium Anatomy 0.000 description 2
- 229960004586 rosiglitazone Drugs 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 230000028043 self proteolysis Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000013517 stratification Methods 0.000 description 2
- 210000003518 stress fiber Anatomy 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000008719 thickening Effects 0.000 description 2
- 210000001578 tight junction Anatomy 0.000 description 2
- 229940075469 tissue adhesives Drugs 0.000 description 2
- 230000001052 transient effect Effects 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 238000002834 transmittance Methods 0.000 description 2
- 230000001960 triggered effect Effects 0.000 description 2
- 230000004304 visual acuity Effects 0.000 description 2
- 230000004393 visual impairment Effects 0.000 description 2
- 210000002395 vitreous cell Anatomy 0.000 description 2
- NNRFRJQMBSBXGO-CIUDSAMLSA-N (3s)-3-[[2-[[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]-4-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-oxobutanoic acid Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O NNRFRJQMBSBXGO-CIUDSAMLSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- FBFNMTGUOBUGFQ-UHFFFAOYSA-M 2-(2,5-diphenyltetrazol-1-ium-1-yl)-4,5-dimethyl-1,3-thiazole;bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=C(C=2C=CC=CC=2)N=NN1C1=CC=CC=C1 FBFNMTGUOBUGFQ-UHFFFAOYSA-M 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- SXGZJKUKBWWHRA-UHFFFAOYSA-N 2-(N-morpholiniumyl)ethanesulfonate Chemical compound [O-]S(=O)(=O)CC[NH+]1CCOCC1 SXGZJKUKBWWHRA-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 229940044192 2-hydroxyethyl methacrylate Drugs 0.000 description 1
- NJNWCIAPVGRBHO-UHFFFAOYSA-N 2-hydroxyethyl-dimethyl-[(oxo-$l^{5}-phosphanylidyne)methyl]azanium Chemical group OCC[N+](C)(C)C#P=O NJNWCIAPVGRBHO-UHFFFAOYSA-N 0.000 description 1
- UPXRTVAIJMUAQR-UHFFFAOYSA-N 4-(9h-fluoren-9-ylmethoxycarbonylamino)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound C1C(C(O)=O)N(C(=O)OC(C)(C)C)CC1NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 UPXRTVAIJMUAQR-UHFFFAOYSA-N 0.000 description 1
- PCCVCJAQMHDWJY-UHFFFAOYSA-N 5-(2-ethyl-1,3-dihydroinden-2-yl)-1h-imidazole;hydrochloride Chemical compound Cl.C1C2=CC=CC=C2CC1(CC)C1=CN=CN1 PCCVCJAQMHDWJY-UHFFFAOYSA-N 0.000 description 1
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 230000005730 ADP ribosylation Effects 0.000 description 1
- 102100032814 ATP-dependent zinc metalloprotease YME1L1 Human genes 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102100040069 Aldehyde dehydrogenase 1A1 Human genes 0.000 description 1
- 101710133479 Aldehyde dehydrogenase 1A1 Proteins 0.000 description 1
- 102000004888 Aquaporin 1 Human genes 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- 102100036597 Basement membrane-specific heparan sulfate proteoglycan core protein Human genes 0.000 description 1
- 101001065614 Bos taurus Lumican Proteins 0.000 description 1
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 description 1
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 description 1
- 102100036301 C-C chemokine receptor type 7 Human genes 0.000 description 1
- 206010006895 Cachexia Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 101710132601 Capsid protein Proteins 0.000 description 1
- 102000003727 Caveolin 1 Human genes 0.000 description 1
- 108090000026 Caveolin 1 Proteins 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 108010029240 Cell-Tak Proteins 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 102000009410 Chemokine receptor Human genes 0.000 description 1
- 108050000299 Chemokine receptor Proteins 0.000 description 1
- 229920001287 Chondroitin sulfate Polymers 0.000 description 1
- 208000032544 Cicatrix Diseases 0.000 description 1
- 102000012422 Collagen Type I Human genes 0.000 description 1
- 108010022452 Collagen Type I Proteins 0.000 description 1
- 102000001187 Collagen Type III Human genes 0.000 description 1
- 108010069502 Collagen Type III Proteins 0.000 description 1
- 102000004510 Collagen Type VII Human genes 0.000 description 1
- 108010017377 Collagen Type VII Proteins 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 1
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 1
- 102000010970 Connexin Human genes 0.000 description 1
- 108050001175 Connexin Proteins 0.000 description 1
- 206010061788 Corneal infection Diseases 0.000 description 1
- 206010011039 Corneal perforation Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 241000238424 Crustacea Species 0.000 description 1
- 108010064003 Crystallins Proteins 0.000 description 1
- 102000014824 Crystallins Human genes 0.000 description 1
- 229920001651 Cyanoacrylate Polymers 0.000 description 1
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 1
- 150000008574 D-amino acids Chemical class 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 101100206935 Danio rerio tll1 gene Proteins 0.000 description 1
- 241000238557 Decapoda Species 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 206010015866 Extravasation Diseases 0.000 description 1
- 208000031969 Eye Hemorrhage Diseases 0.000 description 1
- 208000001860 Eye Infections Diseases 0.000 description 1
- 206010015946 Eye irritation Diseases 0.000 description 1
- 108091008794 FGF receptors Proteins 0.000 description 1
- 102100031509 Fibrillin-1 Human genes 0.000 description 1
- 108010030229 Fibrillin-1 Proteins 0.000 description 1
- 108010080379 Fibrin Tissue Adhesive Proteins 0.000 description 1
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 1
- 208000005422 Foreign-Body reaction Diseases 0.000 description 1
- 102000039539 Fos family Human genes 0.000 description 1
- 108091067362 Fos family Proteins 0.000 description 1
- 201000001925 Fuchs' endothelial dystrophy Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Polymers OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- VPNYRYCIDCJBOM-UHFFFAOYSA-M Glycopyrronium bromide Chemical compound [Br-].C1[N+](C)(C)CCC1OC(=O)C(O)(C=1C=CC=CC=1)C1CCCC1 VPNYRYCIDCJBOM-UHFFFAOYSA-M 0.000 description 1
- 229920002971 Heparan sulfate Polymers 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 101800001649 Heparin-binding EGF-like growth factor Proteins 0.000 description 1
- 102400001369 Heparin-binding EGF-like growth factor Human genes 0.000 description 1
- 208000003923 Hereditary Corneal Dystrophies Diseases 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101000716065 Homo sapiens C-C chemokine receptor type 7 Proteins 0.000 description 1
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 1
- 101001076407 Homo sapiens Interleukin-1 receptor antagonist protein Proteins 0.000 description 1
- 101000829980 Homo sapiens Ral guanine nucleotide dissociation stimulator Proteins 0.000 description 1
- 101001050288 Homo sapiens Transcription factor Jun Proteins 0.000 description 1
- 101000798130 Homo sapiens Tumor necrosis factor receptor superfamily member 11B Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- 208000031354 Hyphema Diseases 0.000 description 1
- 102000038455 IGF Type 1 Receptor Human genes 0.000 description 1
- 108010031794 IGF Type 1 Receptor Proteins 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102000048143 Insulin-Like Growth Factor II Human genes 0.000 description 1
- 108090001117 Insulin-Like Growth Factor II Proteins 0.000 description 1
- 108090000965 Insulin-like growth factor binding protein 3 Proteins 0.000 description 1
- 102100022708 Insulin-like growth factor-binding protein 3 Human genes 0.000 description 1
- 102100022338 Integrin alpha-M Human genes 0.000 description 1
- 108010030506 Integrin alpha6beta4 Proteins 0.000 description 1
- 102000012355 Integrin beta1 Human genes 0.000 description 1
- 108010022222 Integrin beta1 Proteins 0.000 description 1
- 102000012334 Integrin beta4 Human genes 0.000 description 1
- 108010022238 Integrin beta4 Proteins 0.000 description 1
- 229940119178 Interleukin 1 receptor antagonist Drugs 0.000 description 1
- 102000051628 Interleukin-1 receptor antagonist Human genes 0.000 description 1
- 101710144554 Interleukin-1 receptor antagonist protein Proteins 0.000 description 1
- 102100026018 Interleukin-1 receptor antagonist protein Human genes 0.000 description 1
- 102000003814 Interleukin-10 Human genes 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 101710107944 Isopenicillin N synthase Proteins 0.000 description 1
- 102000039537 Jun family Human genes 0.000 description 1
- 108091067369 Jun family Proteins 0.000 description 1
- 229920000288 Keratan sulfate Polymers 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 208000034693 Laceration Diseases 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- IXAQOQZEOGMIQS-ORRYEOPJSA-N Lipoxin A Natural products CCCCCC(O)C=CC=C/C=C/C=C/C(O)C(O)CCCC(=O)O IXAQOQZEOGMIQS-ORRYEOPJSA-N 0.000 description 1
- 108090000542 Lymphotoxin-alpha Proteins 0.000 description 1
- 102000004083 Lymphotoxin-alpha Human genes 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 102100037611 Lysophospholipase Human genes 0.000 description 1
- 102000043131 MHC class II family Human genes 0.000 description 1
- 108091054438 MHC class II family Proteins 0.000 description 1
- 101150014058 MMP1 gene Proteins 0.000 description 1
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- MWCLLHOVUTZFKS-UHFFFAOYSA-N Methyl cyanoacrylate Chemical compound COC(=O)C(=C)C#N MWCLLHOVUTZFKS-UHFFFAOYSA-N 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 241000282341 Mustela putorius furo Species 0.000 description 1
- 101001055320 Myxine glutinosa Insulin-like growth factor Proteins 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical group CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 208000021957 Ocular injury Diseases 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 102000004264 Osteopontin Human genes 0.000 description 1
- 108010081689 Osteopontin Proteins 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 108010035766 P-Selectin Proteins 0.000 description 1
- 102100023472 P-selectin Human genes 0.000 description 1
- 102100034925 P-selectin glycoprotein ligand 1 Human genes 0.000 description 1
- 108010054395 P-selectin ligand protein Proteins 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 108010058864 Phospholipases A2 Proteins 0.000 description 1
- 229920001305 Poly(isodecyl(meth)acrylate) Polymers 0.000 description 1
- 229920002319 Poly(methyl acrylate) Polymers 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 229920000331 Polyhydroxybutyrate Polymers 0.000 description 1
- 229920000388 Polyphosphate Polymers 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- LRJOMUJRLNCICJ-JZYPGELDSA-N Prednisolone acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O LRJOMUJRLNCICJ-JZYPGELDSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 101800000795 Proadrenomedullin N-20 terminal peptide Proteins 0.000 description 1
- 102100041026 Procollagen C-endopeptidase enhancer 1 Human genes 0.000 description 1
- 101710087172 Procollagen C-endopeptidase enhancer 1 Proteins 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- 108700020978 Proto-Oncogene Proteins 0.000 description 1
- 102000052575 Proto-Oncogene Human genes 0.000 description 1
- 102000000033 Purinergic Receptors Human genes 0.000 description 1
- 108010080192 Purinergic Receptors Proteins 0.000 description 1
- 102000014128 RANK Ligand Human genes 0.000 description 1
- 108010025832 RANK Ligand Proteins 0.000 description 1
- 102100023320 Ral guanine nucleotide dissociation stimulator Human genes 0.000 description 1
- 208000029091 Refraction disease Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- YIQKLZYTHXTDDT-UHFFFAOYSA-H Sirius red F3B Chemical compound C1=CC(=CC=C1N=NC2=CC(=C(C=C2)N=NC3=C(C=C4C=C(C=CC4=C3[O-])NC(=O)NC5=CC6=CC(=C(C(=C6C=C5)[O-])N=NC7=C(C=C(C=C7)N=NC8=CC=C(C=C8)S(=O)(=O)[O-])S(=O)(=O)[O-])S(=O)(=O)O)S(=O)(=O)O)S(=O)(=O)[O-])S(=O)(=O)[O-].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+] YIQKLZYTHXTDDT-UHFFFAOYSA-H 0.000 description 1
- 102100028848 Stromelysin-2 Human genes 0.000 description 1
- 101710108792 Stromelysin-2 Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 102000002938 Thrombospondin Human genes 0.000 description 1
- 108060008245 Thrombospondin Proteins 0.000 description 1
- 102000011154 Tight junction protein ZO-1 Human genes 0.000 description 1
- 108050001370 Tight junction protein ZO-1 Proteins 0.000 description 1
- 102000008233 Toll-Like Receptor 4 Human genes 0.000 description 1
- 108010060804 Toll-Like Receptor 4 Proteins 0.000 description 1
- 102000014172 Transforming Growth Factor-beta Type I Receptor Human genes 0.000 description 1
- 108010011702 Transforming Growth Factor-beta Type I Receptor Proteins 0.000 description 1
- 108010009583 Transforming Growth Factors Proteins 0.000 description 1
- 102000009618 Transforming Growth Factors Human genes 0.000 description 1
- 102000014701 Transketolase Human genes 0.000 description 1
- 108010043652 Transketolase Proteins 0.000 description 1
- BGDKAVGWHJFAGW-UHFFFAOYSA-N Tropicamide Chemical compound C=1C=CC=CC=1C(CO)C(=O)N(CC)CC1=CC=NC=C1 BGDKAVGWHJFAGW-UHFFFAOYSA-N 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 108010040002 Tumor Suppressor Proteins Proteins 0.000 description 1
- 102000001742 Tumor Suppressor Proteins Human genes 0.000 description 1
- 102100032236 Tumor necrosis factor receptor superfamily member 11B Human genes 0.000 description 1
- 238000011111 UV-scan method Methods 0.000 description 1
- 206010064996 Ulcerative keratitis Diseases 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 1
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 1
- 206010047571 Visual impairment Diseases 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000010398 acute inflammatory response Effects 0.000 description 1
- 230000033289 adaptive immune response Effects 0.000 description 1
- 230000004721 adaptive immunity Effects 0.000 description 1
- 102000035181 adaptor proteins Human genes 0.000 description 1
- 108091005764 adaptor proteins Proteins 0.000 description 1
- 210000002867 adherens junction Anatomy 0.000 description 1
- 238000004026 adhesive bonding Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000036626 alertness Effects 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 229920005603 alternating copolymer Polymers 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 210000001691 amnion Anatomy 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 210000000612 antigen-presenting cell Anatomy 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 108010072041 arginyl-glycyl-aspartic acid Proteins 0.000 description 1
- 238000003491 array Methods 0.000 description 1
- 108010045569 atelocollagen Proteins 0.000 description 1
- 229960001352 atipamezole hydrochloride Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- 229940125717 barbiturate Drugs 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 238000005452 bending Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000000227 bioadhesive Substances 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 239000010796 biological waste Substances 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000004420 blood-aqueous barrier Effects 0.000 description 1
- 210000002164 blood-aqueous barrier Anatomy 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 230000003848 cartilage regeneration Effects 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000011712 cell development Effects 0.000 description 1
- 238000002701 cell growth assay Methods 0.000 description 1
- 230000008619 cell matrix interaction Effects 0.000 description 1
- 230000009087 cell motility Effects 0.000 description 1
- 230000017455 cell-cell adhesion Effects 0.000 description 1
- 230000035289 cell-matrix adhesion Effects 0.000 description 1
- 210000003570 cell-matrix junction Anatomy 0.000 description 1
- 210000003850 cellular structure Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940059329 chondroitin sulfate Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 108700004333 collagenase 1 Proteins 0.000 description 1
- 229940047120 colony stimulating factors Drugs 0.000 description 1
- 210000001520 comb Anatomy 0.000 description 1
- 238000010835 comparative analysis Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000004154 complement system Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000002153 concerted effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- 231100000269 corneal opacity Toxicity 0.000 description 1
- 230000004453 corneal transparency Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000002380 cytological effect Effects 0.000 description 1
- 230000003229 cytophilic effect Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 210000001047 desmosome Anatomy 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- HRLIOXLXPOHXTA-NSHDSACASA-N dexmedetomidine Chemical compound C1([C@@H](C)C=2C(=C(C)C=CC=2)C)=CN=C[N]1 HRLIOXLXPOHXTA-NSHDSACASA-N 0.000 description 1
- 229960004253 dexmedetomidine Drugs 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 235000012489 doughnuts Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 230000005584 early death Effects 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 208000026500 emaciation Diseases 0.000 description 1
- 230000036040 emmetropia Effects 0.000 description 1
- 238000007720 emulsion polymerization reaction Methods 0.000 description 1
- 210000003989 endothelium vascular Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 230000009786 epithelial differentiation Effects 0.000 description 1
- 230000008472 epithelial growth Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- BHBPJIPGXGQMTE-UHFFFAOYSA-N ethane-1,2-diol;2-methylprop-2-enoic acid Chemical compound OCCO.CC(=C)C(O)=O.CC(=C)C(O)=O BHBPJIPGXGQMTE-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 230000036251 extravasation Effects 0.000 description 1
- 231100000013 eye irritation Toxicity 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 230000003619 fibrillary effect Effects 0.000 description 1
- 230000003328 fibroblastic effect Effects 0.000 description 1
- 230000001497 fibrovascular Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 230000007849 functional defect Effects 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 230000006251 gamma-carboxylation Effects 0.000 description 1
- 210000003976 gap junction Anatomy 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 230000009477 glass transition Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- SYUXAJSOZXEFPP-UHFFFAOYSA-N glutin Natural products COc1c(O)cc2OC(=CC(=O)c2c1O)c3ccccc3OC4OC(CO)C(O)C(O)C4O SYUXAJSOZXEFPP-UHFFFAOYSA-N 0.000 description 1
- 229940015042 glycopyrrolate Drugs 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 229940015043 glyoxal Drugs 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 229920000578 graft copolymer Polymers 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 238000009499 grossing Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- KIUKXJAPPMFGSW-MNSSHETKSA-N hyaluronan Chemical class CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H](C(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-MNSSHETKSA-N 0.000 description 1
- 230000000887 hydrating effect Effects 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 239000000416 hydrocolloid Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 229920001480 hydrophilic copolymer Polymers 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 230000000544 hyperemic effect Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 238000002991 immunohistochemical analysis Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 210000005007 innate immune system Anatomy 0.000 description 1
- 230000008611 intercellular interaction Effects 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 239000003407 interleukin 1 receptor blocking agent Substances 0.000 description 1
- 229940076144 interleukin-10 Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 230000010262 intracellular communication Effects 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000003447 ipsilateral effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 108010028309 kalinin Proteins 0.000 description 1
- KXCLCNHUUKTANI-RBIYJLQWSA-N keratan Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@H](COS(O)(=O)=O)O[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@H](O[C@@H](O[C@H]3[C@H]([C@@H](COS(O)(=O)=O)O[C@@H](O)[C@@H]3O)O)[C@H](NC(C)=O)[C@H]2O)COS(O)(=O)=O)O[C@H](COS(O)(=O)=O)[C@@H]1O KXCLCNHUUKTANI-RBIYJLQWSA-N 0.000 description 1
- 229960004184 ketamine hydrochloride Drugs 0.000 description 1
- 238000011005 laboratory method Methods 0.000 description 1
- 238000000608 laser ablation Methods 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- IXAQOQZEOGMIQS-SSQFXEBMSA-N lipoxin A4 Chemical compound CCCCC[C@H](O)\C=C\C=C/C=C/C=C/[C@@H](O)[C@@H](O)CCCC(O)=O IXAQOQZEOGMIQS-SSQFXEBMSA-N 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 238000003754 machining Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 238000013178 mathematical model Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 210000003632 microfilament Anatomy 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 230000002297 mitogenic effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 230000004118 muscle contraction Effects 0.000 description 1
- 235000020638 mussel Nutrition 0.000 description 1
- 210000001640 nerve ending Anatomy 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 210000000933 neural crest Anatomy 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 230000003076 paracrine Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 108010049224 perlecan Proteins 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 1
- 229960001802 phenylephrine Drugs 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- DCWXELXMIBXGTH-UHFFFAOYSA-N phosphotyrosine Chemical compound OC(=O)C(N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-UHFFFAOYSA-N 0.000 description 1
- 230000000886 photobiology Effects 0.000 description 1
- 210000000608 photoreceptor cell Anatomy 0.000 description 1
- 108091008695 photoreceptors Proteins 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 108010000685 platelet-derived growth factor AB Proteins 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920002006 poly(N-vinylimidazole) polymer Polymers 0.000 description 1
- 229920001490 poly(butyl methacrylate) polymer Polymers 0.000 description 1
- 229920000117 poly(dioxanone) Polymers 0.000 description 1
- 239000005014 poly(hydroxyalkanoate) Substances 0.000 description 1
- 239000005015 poly(hydroxybutyrate) Substances 0.000 description 1
- 229920000218 poly(hydroxyvalerate) Polymers 0.000 description 1
- 229920000212 poly(isobutyl acrylate) Polymers 0.000 description 1
- 229920000205 poly(isobutyl methacrylate) Polymers 0.000 description 1
- 229940065514 poly(lactide) Drugs 0.000 description 1
- 229920000196 poly(lauryl methacrylate) Polymers 0.000 description 1
- 229920000184 poly(octadecyl acrylate) Polymers 0.000 description 1
- 239000002745 poly(ortho ester) Substances 0.000 description 1
- 229920002946 poly[2-(methacryloxy)ethyl phosphorylcholine] polymer Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920002721 polycyanoacrylate Polymers 0.000 description 1
- 229920006149 polyester-amide block copolymer Polymers 0.000 description 1
- 229920000129 polyhexylmethacrylate Polymers 0.000 description 1
- 229920000903 polyhydroxyalkanoate Polymers 0.000 description 1
- 229920000197 polyisopropyl acrylate Polymers 0.000 description 1
- 229920001855 polyketal Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920001444 polymaleic acid Polymers 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 229920000098 polyolefin Polymers 0.000 description 1
- 229920000182 polyphenyl methacrylate Polymers 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 229920002620 polyvinyl fluoride Polymers 0.000 description 1
- 238000011886 postmortem examination Methods 0.000 description 1
- 230000001323 posttranslational effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229960002800 prednisolone acetate Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002206 pro-fibrotic effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000007114 proinflammatory cascade Effects 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 230000010344 pupil dilation Effects 0.000 description 1
- 230000001179 pupillary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012372 quality testing Methods 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 238000013102 re-test Methods 0.000 description 1
- 230000036647 reaction Effects 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000008458 response to injury Effects 0.000 description 1
- 210000001210 retinal vessel Anatomy 0.000 description 1
- 239000012313 reversal agent Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 102000000568 rho-Associated Kinases Human genes 0.000 description 1
- 108010041788 rho-Associated Kinases Proteins 0.000 description 1
- 235000019192 riboflavin Nutrition 0.000 description 1
- 229960002477 riboflavin Drugs 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
- 239000011435 rock Substances 0.000 description 1
- 239000005060 rubber Substances 0.000 description 1
- 230000037387 scars Effects 0.000 description 1
- 239000000565 sealant Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 229920000260 silastic Polymers 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 238000013424 sirius red staining Methods 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 230000007847 structural defect Effects 0.000 description 1
- 210000004895 subcellular structure Anatomy 0.000 description 1
- 210000002301 subretinal fluid Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 230000019635 sulfation Effects 0.000 description 1
- 238000005670 sulfation reaction Methods 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000009182 swimming Effects 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229920001169 thermoplastic Polymers 0.000 description 1
- 239000004416 thermosoftening plastic Substances 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229940033618 tisseel Drugs 0.000 description 1
- 230000008467 tissue growth Effects 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 230000007838 tissue remodeling Effects 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000004627 transmission electron microscopy Methods 0.000 description 1
- 239000012780 transparent material Substances 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 229960004791 tropicamide Drugs 0.000 description 1
- 238000007514 turning Methods 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000006496 vascular abnormality Effects 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 208000029257 vision disease Diseases 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 208000016261 weight loss Diseases 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/52—Hydrogels or hydrocolloids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/24—Collagen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/14—Eye parts, e.g. lenses, corneal implants; Implanting instruments specially adapted therefor; Artificial eyes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/16—Materials or treatment for tissue regeneration for reconstruction of eye parts, e.g. intraocular lens, cornea
Definitions
- ametropia an eye whose far point is not at infinity, which is often considered to be an error of refraction; accordingly, ametropias also are referred to as refractive errors, which describes the range of visual defects that are caused by a less than optimal combination of the various optical parameters of the eye.
- myopia near-sightedness
- hyperopia farsightedness
- astigmatism presbyopia
- presbyopia is generally characterized by a decrease in the eye's ability to increase its power to focus on nearby objects due to, for example, a loss of elasticity in the crystalline lens that occurs over time.
- young people under the age of 40 can easily focus both on distance and near objects. Near objects can be seen clearly due to contraction of the ciliary muscle resulting in increase in lens curvature. The focal length of the lens decreases, and the image of the object is focused on the retina.
- the ciliary muscles progressively weaken and the lens starts to lose elasticity. Accommodation starts decreasing, making it difficult to see intermediate and near objects. This deficiency, which worsens as we age, is known as presbyopia.
- the most common solution to presbyopia is to wear reading glasses.
- IOLs Intraocular Lens
- LASIK multifocal LASIK
- conductive keratoplasty a surgical procedure that uses low level radiofrequency energy to reshape the cornea
- refractive lens exchange a surgical procedure that uses low level radiofrequency energy to reshape the cornea
- Ophthalmic devices and/or procedures e.g., contact lenses, intraocular lenses, LASIK, inlays
- the diopter power of one eye is adjusted to focus distant objects and the power of the second eye is adjusted to focus near objects. The appropriate eye is used to clearly view the object of interest.
- multifocal or bifocal optics are used to simultaneously, in one eye, provide powers to focus both distant and near objects.
- One common multifocal design includes a central zone of higher diopter power to focus near objects, surrounded by a peripheral zone of the desired lower power to focus distant objects.
- the diopter power of one eye is adjusted to focus distance objects, and in the second eye a multifocal optical design is induced by an intracorneal inlay.
- the subject therefore has the necessary diopter power from both eyes to view distant objects, while the near power zone of the multifocal eye provides the necessary power for viewing near objects.
- the multifocal optical design is induced in both eyes.
- Eyeglasses and contact lenses are the most common options for people needing vision correction, these corrective devices may not be suitable for all, particularly for those with highly irregular corneas, and may not be acceptable alternatives for those with specific lifestyle requirements.
- corneal inlays and onlays can be inserted into the cornea to reshape the curvature of the anterior surface of the human eye, as shown in FIG.4 [Taken from Wu, J. et al. Sci China Chem. (2014) 57 (4): 501-9].
- An inlay is an optical device that corrects the refractive error of the eye by changing the anterior corneal curvature by functioning as an intrastromal implant.
- Design criteria for such intracorneal materials include chemical inactivity, adequate permeability to maintain the diffusion of intracorneal fluid and metabolites, and avoidance of excessive pressure or tension on the corneal tissue [Id.].
- Materials considered for intrastromal implants also should have a sufficient water content to sustain nutritional transport, an isotropic refractive index to match that of the surrounding tissue, a compliance similar to the native cornea, be optically clear and biostable (meaning resistant to hydrolytic, oxidative and enzymatic degradation) and biocompatible with the stromal tissue [Id., citing McCarey, BE. Refract. Corneal Surg. (1990) 6: 40-46; McCarey, BE. Int. Ophthalmol. Clin.
- An onlay is an optical device placed onto the corneal surface, and therefore is surgically simpler than an inlay. Since an onlay is usually implanted under the epithelium of the cornea, it can be more optically effective and less likely to compromise the nutritional requirements of the cornea. However, onlay implantation, which requires regrowth of the corneal epithelium, may encounter the challenge of epithelial remodeling.
- FIG. 1 is an illustration of a human eye. (Allaboutvision.com/resources/anatomy.htm, Accessed March 2019.)
- the anatomy of the eye includes a conjunctiva, an iris, a lens, a pupil, a cornea, a sclera, a ciliary body, a vitreous body, an anterior chamber, a choroid, a retina, a macula, an optic nerve, and an optic disc.
- the conjunctiva is a clear, thin membrane that covers part of the front surface of the eye and the inner surface of the eyelids.
- the iris is a thin, circular structure made of connective tissue and muscle that surrounds the pupil and regulates the amount of light that strikes the retina.
- the retina is a light-sensitive membrane on which light rays are focused. It is composed of several layers, including one that contains specialized cells called photoreceptors. Photoreceptor cells take light focused by the cornea and lens (a transparent, biconvex structure) and convert it into chemical and nervous signals which are transported to visual centers in the brain by way of the optic nerve.
- the sclera is a dense connective tissue that surrounds the cornea and forms the white part of the eye.
- the ciliary body connects the iris to the choroid and consists of ciliary muscle (which alters the curvature of the lens), a series of radial ciliary processes (from which the lens is suspended by ligaments), and the ciliary ring (which adjoins the choroid).
- the choroid is the pigmented vascular layer of the eye between the retina and the sclera.
- the vitreous body is a transparent, colorless, semisolid mass composed of collagen fibrils and hyaluronic acid that fills the posterior cavity of the eye between the lens and the retina.
- the anterior chamber is an aqueous humor-filled space inside the eye between the iris and the cornea’s innermost surface.
- the macula is an oval- shaped pigmented area near the center of the retina.
- the optic disc is the raised disk on the retina at the point of entry of the optic nerve, which lacks visual receptors, thus creating a blind spot.
- the Cornea [0010]
- the cornea is a clear and transparent layer anterior on the eye. It is the eye's main refracting surface.
- FIG.2 is an illustration showing the cornea, which is avascular and exhibits the following five layers, from the anterior (nearer to the front) to posterior (nearer to the rear) direction: the epithelium, Bowman's layer, stroma, Descemet's membrane, and the endothelium.
- the epithelium is a layer of cells that can be thought of as covering the surface of the cornea.
- the cornea is covered externally by a stratified nonkeratinizing epithelium (5-6 layers of cells, about 50 microns in thickness) with three types of cells: superficial cells, wing cells and basal cells (deepest cell layer). Desmosomes form tight junctions in between the superficial cells.
- the basal cells are the only corneal epithelial cells capable of mitosis; the basement membrane of epithelial cells is 40-60 nm in thickness and is made up of type IV collagen and laminin secreted by basal cells.
- the epithelial layer is highly sensitive due to numerous nerve endings and has excellent regenerative power.
- epithelium of central and peripheral cornea there are differences between epithelium of central and peripheral cornea.
- the epithelium In the central cornea, the epithelium has 5-7 layers, the basal cells are columnar; there are no melanocytes or Langerhans cells, and the epithelium is uniform to provide a smooth regular surface.
- the epithelium In the peripheral cornea, the epithelium is 7-10 layered, the basal cells are cuboidal, there are melanocytes and Langerhans cells, and there are undulating extensions of the basal layer. (Sridhar, M.S., “Anatomy of cornea and ocular surface,” Indian J. Ophthalmol. (2016) 66(2): 190-194). [0012] Bowman’s membrane is structureless and acellular.
- the stroma is the thickest layer of the cornea and gives the cornea much of its strength. Most refractive surgeries involve manipulating stroma cells. Specifically, the substantia basement (stroma) forms 90% of the cornea's thickness and is made up of keratocytes and extracellular matrix. Fibrils of the stroma crisscross at 90o angles; these fibrils are of types I, III, V, and VII collagen. [0014] Descemet's membrane and the endothelium are considered the posterior portion of the cornea. Descemet membrane is structureless, homogeneous, and measures 3- 12 microns; it is composed of the anterior banded zone and the posterior nonbanded zone; the Descemet membrane is rich in type IV collagen fibers.
- the cornea is covered internally by the corneal endothelium, a single layer, 5 microns thick, of simple cuboidal and hexagonal cells with multiple orthogonal arrays of collagen in between.
- the endothelium is derived from the neural crest and functions to transport fluid from the anterior chamber to the stroma. Because the cornea is avascular, its nutrients are derived mainly from diffusion from the endothelium layer. (Duong, H-V. Q. “Eye Globe Anatomy,” https://emedicine.medscape.com/article/1923010-0verview,updated Nov. 9, 2017).
- the shape of the cornea is aspheric, meaning that it departs slightly from the spherical form.
- the central cornea is about 3D steeper than the periphery.
- the cornea is divided into zones that surround fixation and blend into one another.
- the central zone of 1-2 mm closely fits a spherical surface. Adjacent to the central zone is the paracentral zone, a 3-4 mm doughnut with an outer diameter of 7-8 mm that represents an area of progressive flattening from the center. Together, the paracentral and central zones constitute the apical zone.
- the central and paracentral zones are primarily responsible for the refractive power of the cornea.
- Adjacent to the paracentral zone is the peripheral zone, with an outer diameter of approximately 11 mm.
- the peripheral zone is also known as the transitional zone, as it is the area of greatest flattening and asphericity of the normal cornea. Adjoining the peripheral zone is the limbus, with an outer diameter that averages 12 mm.
- the optical zone is the portion of the cornea that overlies the entrance pupil of the iris; it is physiologically limited to approximately 5.4 mm because of the Stiles-Crawford effect (the reduction of the brightness when a light beam's entry into the eye is shifted from the center to the edge of the pupil has from the outset been shown to be due to a change in luminous efficiency of radiation when it is incident obliquely on the retina. (See G. Westheimer, “Directional sensitivity of the retina: 75 years of Stiles-Crawford effect,” Proc. R. Soc. B. (2008) 275 (1653): 2777-86). [0019] The corneal apex is the point of maximum curvature.
- the corneal vertex is the point located at the intersection of a subject’s line of fixation and the corneal surface. .
- the cornea must be clear, smooth and healthy for good vision. If it is scarred, swollen, or damaged, light is not focused properly into the eye.
- Wound Healing Corneal Wound Healing [0021] The term “wound healing” refers to the process by which the body repairs trauma to any of its tissues, especially those caused by physical means and with interruption of continuity. [0022] A wound-healing response often is described as having three distinct phases- injury, inflammation and repair. Injury often results in the disruption of normal tissue architecture, initiating a healing response.
- the body responds to injury with an inflammatory response, which is crucial to maintaining the health and integrity of an organism.
- the closing phase of wound healing consists of an orchestrated cellular re- organization guided by a fibrin (a fibrous protein that is polymerized to form a “mesh” that forms a clot over a wound site)-rich scaffold formation, wound contraction, closure and re- epithelialization.
- fibrin a fibrous protein that is polymerized to form a “mesh” that forms a clot over a wound site
- the response of the anterior segment of the eye to wound healing closely resembles the response of non-CNS tissues. (Friedlander, M. “Fibrosis and diseases of the eye,” J. Clin. Invest. (2007) 117(3): 576-86).
- corneal epithelial healing involves a number of concerted events, including cell migration, proliferation, adhesion and differentiation, with cell layer stratification.
- corneal epithelial healing largely depends on limbal epithelial stem cells (LESCs) stem cells, which, in many species, including humans, exclusively reside in the corneoscleral junction, and remodeling of the basement membrane.
- LSCs limbal epithelial stem cells
- LESCs In response to injury, LESCs undergo few cycles of proliferation and give rise to many transit-amplifying cells (TACS), which appear to make up most of the basal epithelium in the limbus and peripheral cornea.
- TACS transit-amplifying cells
- the LESCs are thought to migrate into the central cornea, proliferate rapidly afterwards, and eventually terminally differentiate into central corneal epithelial cells.
- keratocytes During stromal healing, keratocytes get transformed to motile and contractile myofibroblasts largely due to activation of the transforming growth factor ⁇ system.
- the kinetics of epithelial wound healing includes two distinct phases: an initial latent phase, and a closure phase.
- the initial latent phase includes cellular and subcellular reorganization to trigger migration of the epithelial cells at the wound edge.
- the initial latent phase includes cellular and subcellular reorganization to trigger migration of the epithelial cells at the wound edge.
- the closure phase includes several continuous processes starting with cell migration, which is independent of cell mitosis.
- Id citing Anderson, SC, et al., Rho and Rho-kinase (ROCK) signaling in adherens and gap junction assembly in corneal epithelium. Invest. Ophthalmol. Vis. Sci. (2002) 43: 978–986), followed by cell proliferation and differentiation, and eventually, by stratification to restore the original multicellular epithelial layer (Id., citing Crosson, CE et al., Epithelial wound closure in the rabbit cornea. A biphasic process. Invest. Ophthalmol. Vis. Sci. (1986) 27: 464–473)).
- Wound healing factors in epithelial wound healing [0027] When corneal epithelium is injured, nucleotides and neuronal factors are released to the extracellular milieu, generating a Ca(2+) wave from the origin of the wound to neighboring cells. (Id., citing Lee, A, et al., Hypoxia-induced changes in Ca2+ mobilization and protein phosphorylation implicated in impaired wound healing. Am. J. Physiol. Cell. Physiol. (2014) 306: C972–985).
- TLRs Toll-like receptors
- TLRs are a family of proteins that play a major role in the innate immune system and modulate inflammation via several pathways, such as nuclear factor ⁇ B (NF- ⁇ B), MAP kinases, and activator protein (AP)-1.
- NF- ⁇ B nuclear factor ⁇ B
- MAP kinases MAP kinases
- AP-1 activator protein
- the TLR signaling pathway is activated in response to its ligands, such as pathogen associated molecular patterns (“PAMPs”, for viruses and bacteria) and damage-associated molecular patterns (DAMPs) as a result of tissue injury.
- PAMPs pathogen associated molecular patterns
- DAMPs damage-associated molecular patterns
- EGF and PDGF (Id., citing Tuominen, IS et al, Human tear fluid PDGF-BB, TNF- ⁇ and TGF- ⁇ 1 vs corneal haze and regeneration of corneal epithelium and subbasal nerve plexus after PRK. Exp. Eye Res. (2001) 72: 631–641), which trigger a series of responses leading to epithelial cell migration through ERK, MAP kinases, and/or NF- ⁇ B pathways.
- a number of transcription factors such as c-fos, c-jun, jun-B, and fos-B, which become activated during the lag phase of wound healing before the cells start to migrate (Id., citing Oakdale, Y, Expression of fos family and jun family proto-oncogenes during corneal epithelial wound healing. Curr. Eye Res. (1996) 15: 824–832), can also lead to activation of other parallel pathways in underlying stroma, including IL-1 mediated keratocyte apoptosis via FAS/Fas ligand (Id., citing Wilson SE, et al., Stromal-epithelial interactions in the cornea. Prog. Retin. Eye Res.
- EGFR transactivation has been shown to enhance intracellular signaling in corneal epithelial wound healing in the presence of non-EGF ligands, such as IGF, insulin and HGF, by activating ERK and PI3K/Akt pathways (Id., citing Lyu J, Transactivation of EGFR mediates insulin-stimulated ERK1/2 activation and enhanced cell migration in human corneal epithelial cells. Mol. Vis. (2006) 12: 1403–1410; Spix JK, et al., Hepatocyte growth factor induces epithelial cell motility through transactivation of the epidermal growth factor receptor. Exp. Cell Res. (2007) 313: 3319–3325).
- HGF Hepatocyte growth factor
- KGF keratinocyte growth factor
- PEDF pigment epithelium-derived factor
- MMPs matrix metalloproteinases
- ECM extracellular matrix
- cellular nucleotides e.g., ATP
- EGFR epidermal growth factor receptor
- EGFR and purinergic signaling are also involved in the phosphorylation of paxillin, a focal adhesion-associated phosphotyrosine-containing protein that contains a number of motifs that mediate protein- protein interactions (see Schaller, MD, “Paxillin: a focal adhesion associated adaptor protein,” Oncogene (2001) 20: 6459-72) needed for cell migration (Id., citing Kimura K, et al., Role of JNK-dependent serine phosphorylation of paxillin in migration of corneal epithelial cells during wound closure. Invest. Ophthalmol. Vis. Sci.
- IGF1 Insulin-like growth factor 1
- IGF1 receptor can also be engaged in cross-talk with ⁇ 1 chain-containing integrins important for corneal epithelial cell migration (Id., citing Seomun Y, Joo CK. Lumican induces human corneal epithelial cell migration and integrin expression via ERK 1/2 signaling. Biochem. Biophys. Res. Commun.
- Corneal epithelium makes its own ECM in the form of a specialized epithelial basement membrane that is positioned between basal epithelial cells and the stroma and apposed to the underlying collagenous Bowman’s layer. It provides structural support and regulates, through various receptors, epithelial migration, proliferation, differentiation, adhesion and apoptosis (Id., citing Azar DT, et al., Altered epithelial-basement membrane interactions in diabetic corneas. Arch. Ophthalmol. (1992) 110: 537–40; Kurpakus MA, et al., The role of the basement membrane in differential expression of keratin proteins in epithelial cells.
- Corneal epithelial basement membrane is composed of specialized networks of type IV collagens, laminins, nidogens and perlecan, as are most basement membranes (Id., citing Nakayasu K, et al., Distribution of types I, II, III, IV and V collagen in normal and keratoconus corneas. Ophthalmic Res. (1986) 18: 1–10; Martin GR, Timpl R. Laminin and other basement membrane components. Annu. Rev. Cell Biol.
- Immune system involvement in epithelial wound healing [0033] Immune system cells, such as neutrophils, play a major role in corneal epithelial wound healing, which might be due to their ability to release growth factors that impact the epithelium (Li Z, et al., Lymphocyte function-associated antigen-1-dependent inhibition of corneal wound healing. Am. J. Pathol.
- corneal epithelium The major function of corneal epithelium is to protect the eye interior by serving as a physical and chemical barrier against infection by tight junctions and sustaining the integrity and visual clarity of cornea.
- IL-1 ⁇ The major function of corneal epithelium is to protect the eye interior by serving as a physical and chemical barrier against infection by tight junctions and sustaining the integrity and visual clarity of cornea.
- IL-1RN an IL-1 ⁇ antagonist
- IL-1RN an IL-1 ⁇ antagonist
- Platelets also accumulate in the limbus and migrate to the stroma in response to wounded epithelium, which is necessary for efficient re- epithelialization through cell adhesion molecules such as P-selectin (Id., citing Li Z, et al., Platelet response to corneal abrasion is necessary for acute inflammation and efficient re- epithelialization. Invest. Ophthalmol. Vis. Sci.
- Pal-Ghosh and coworkers demonstrated that removal of the epithelial BM enhances many wound healing processes in the cornea, including keratocyte apoptosis and nerve death.
- Pal-Ghosh S et al, Removal of the basement membrane enhances corneal wound healing. Exp Eye Res. (2011) 93: 927–936.
- Corneal surgery, injury, or infection frequently triggers the appearance of stromal myofibroblasts associated with persistent corneal opacity (haze).
- Talricelli AA et al., Transmission electron microscopy analysis of epithelial basement membrane repair in rabbit corneas with haze. Invest Ophthalmol Vis Sci.
- the opacity develops as a result of diminished transparency of the cells themselves and the production of disordered extracellular matrix components by stromal cells.
- stromal cells The opacity develops as a result of diminished transparency of the cells themselves and the production of disordered extracellular matrix components by stromal cells.
- Jester JV Transforming growth factor (beta)-mediated corneal myofibroblast differentiation requires actin and fibronectin assembly.
- Proc Natl Acad Sci U S A. (1996) 93: 4219–4223; Wilson SE, et al., Stromal-epithelial interactions in the cornea. Prog Retin Eye Res.
- Singh et al. reported that the normally functioning epithelial BM critically modulates myofibroblast development through its barrier function preventing penetration of epithelial TGF- ⁇ 1 and platelet-derived growth factor (PDGF) into the stroma at sufficient levels to drive myofibroblast development and maintain viability once mature myofibroblasts are generated. (Id., citing Singh V, et al., Stromal fibroblast-bone marrow-derived cell interactions: implications for myofibroblast development in the cornea. Exp Eye Res. (2012) 98: 1–8).
- PDGF platelet-derived growth factor
- the epithelial BM likely functions as a corneal regulatory structure that limits the fibrotic response in the stroma by modulating the availability of epithelium-derived TGF- ⁇ 1, PDGF, and perhaps other growth factors and extracellular matrix components, to stromal cells, including myofibroblast precursors. (Id). It may also regulate levels of stromal cell–produced epithelial modulators of motility, proliferation, and differentiation like keratinocyte growth factor (KGF) that transition through the BM in the opposite direction.
- KGF keratinocyte growth factor
- Wilson SE et al., Hepatocyte growth factor, keratinocyte growth factor, their receptors, fibroblast growth factor receptor-2, and the cells of the cornea. Invest Ophthalmol Vis Sci.
- corneal epithelial BM may modulate epithelial-to-stroma and stroma-to-epithelial interactions by regulating cytokines and growth factor movement from one cell layer to the other.
- Latvala et al. observed that the distribution of ⁇ 6 and ⁇ 4 integrins adjacent to the BM changes during epithelial wound healing after epithelial abrasion in the rabbit cornea.
- ⁇ 3(IV) and ⁇ 4(IV) collagen chains may be important for the healthy corneal epithelium.
- the BM is remodeled to include ⁇ 1(IV) and ⁇ 2(IV) collagen, recapitulating corneal epithelial expression during development. (Id).
- Corneal Stromal Wound Healing occurs upon direct damage to the stroma and its cells (as exemplified by photorefractive keratectomy (PRK) and LASIK (used for myopia correction)) and upon death of stromal cells (keratocytes) caused by damage to or removal of corneal epithelium by various physical or chemical factors (Id., citing Nakayasu K. Stromal changes following removal of epithelium in rat cornea. Jpn. J. Ophthalmol. (1988) 32: 113–125; Szerenyi KD, et al., Keratocyte loss and repopulation of anterior corneal stroma after de- epithelialization. Arch. Ophthalmol.
- Wilson SE et al., Epithelial injury induces keratocyte apoptosis: hypothesized role for the interleukin-1 system in the modulation of corneal tissue organization and wound healing. Exp. Eye Res. (1996) 62:325– 327; Wilson SE, et al, The corneal wound healing response: cytokine mediated interaction of the epithelium, stroma, and inflammatory cells. Prog. Retin. Eye Res. (2001) 20: 625–637; Wilson SE, et al., Apoptosis in the initiation, modulation and termination of the corneal wound healing response. Exp. Eye Res. (2007) 85: 305–311).
- Such damage triggers a release of inflammatory cytokines from epithelial cells and/or tears (Id., citing Maycock NJ, Marshall J. Genomics of corneal wound healing: a review of the literature. Acta Ophthalmol. (2014) 92: e170–84), mainly IL-1 ( ⁇ and ⁇ ) that cause rapid apoptosis through Fas/Fas ligand system and later, necrosis of mainly anterior keratocytes. These cells die preferentially directly beneath the epithelial wounds, rather than also beyond their edges.
- the following stromal remodeling with replenishment of these cells from the areas adjacent to the depleted one (Id., citing Zieske JD, et al., Activation of epidermal growth factor receptor during corneal epithelial migration. Invest. Ophthalmol. Vis. Sci. (2000) 41: 1346–1355) also constitutes a wound healing process and may result in fibrotic changes, especially if the epithelial basement membrane was initially damaged (Id., citing Stramer BM, et al., Molecular mechanisms controlling the fibrotic repair phenotype in cornea: implications for surgical outcomes. Invest. Ophthalmol. Vis. Sci. (2003) 44:4237–4246; Fini ME, Stramer BM.
- Fibroblasts downregulate the expression of differentiated keratocyte proteins, such as corneal crystallins (transketolase and aldehyde dehydrogenase 1A1), and keratan sulfate proteoglycans, and start producing proteinases (mostly MMPs) needed to remodel the wound ECM (Id., citing Fini ME. Keratocyte and fibroblast phenotypes in the repairing cornea. Prog. Retin. Eye Res. (1999) 18: 529–551; Jester JV, et al., Corneal stromal wound healing in refractive surgery: the role of myofibroblasts. Prog. Retin. Eye Res.
- fibroblasts After they reach the wound bed, fibroblasts start expressing ⁇ -smooth muscle actin ( ⁇ -SMA) and desmin, upregulate the expression of vimentin (Id., citing Chaurasia SS, et al., “Dynamics of the expression of intermediate filaments vimentin and desmin during myofibroblast differentiation after corneal injury” Exp. Eye Res. (2009) 89: 590–59), and become highly motile and contractile myofibroblasts needed to remodel wound ECM and contract the wound.
- ⁇ -SMA ⁇ -smooth muscle actin
- desmin upregulate the expression of vimentin (Id., citing Chaurasia SS, et al., “Dynamics of the expression of intermediate filaments vimentin and desmin during myofibroblast differentiation after corneal injury” Exp. Eye Res. (2009) 89: 590–59), and become highly motile and contractile myofibroblasts needed to remodel wound ECM and contract
- Myofibroblasts generate contractile forces to close the wound gap, and the expression of ⁇ -SMA directly correlates with corneal wound contraction (Id., citing Jester JV, et al., Expression of alpha-smooth muscle ( ⁇ -SM) actin during corneal stromal wound healing. Invest. Ophthalmol. Vis. Sci. (1995) 36: 809– 819).
- ⁇ -SM alpha-smooth muscle
- PTK phototherapeutic keratectomy
- the appearance of myofibroblasts is delayed, and they start accumulating as late as four weeks after irregular PTK (Id., citing Barbosa FL, et al., Corneal myofibroblast generation from bone marrow-derived cells. Exp. Eye Res.
- TGF- ⁇ transforming growth factor beta
- TGF- ⁇ 1 and TGF- ⁇ 2 are active in this process, since TGF- ⁇ 3 does not transform fibroblasts to myofibroblasts (Id., citing Karamichos D, et al., Reversal of fibrosis by TGF- ⁇ 3 in a 3D in vitro model. Exp. Eye Res. (2014) 124: 31–36). Upon completion of wound healing, myofibroblasts apparently cease to express ⁇ -SMA.
- Immune cells in stromal healing Corneal injury in animal models entails an inflammatory response by immune system cells, including monocytes/macrophages, T cells, polymorphonuclear (PMN) leukocytes and natural killer (NK) cells (Id., citing Gan L, et al., Effect of leukocytes on corneal cellular proliferation and wound healing. Invest.
- Wilson SE et al., The corneal wound healing response: cytokine mediated interaction of the epithelium, stroma, and inflammatory cells. Prog. Retin. Eye Res. (2001) 20: 625–637; Wilson SE, et al., RANK, RANKL, OPG, and M-CSF expression in stromal cells during corneal wound healing.
- Immune cells may come to the injured cornea from the limbal area or are mobilized from circulation (Id., citing Wilson SE, et al., The corneal wound healing response: cytokine mediated interaction of the epithelium, stroma, and inflammatory cells. Prog. Retin. Eye Res.
- a major attracting signal for such cells may be monocyte chemotactic protein-1 (MCP-1), a cytokine, which can be secreted by activated fibroblasts and triggered by IL-1 or TNF- ⁇ (Id., citing Wilson SE, et al., The corneal wound healing response: cytokine mediated interaction of the epithelium, stroma, and inflammatory cells. Prog. Retin. Eye Res. (2001) 20: 625–637).
- MCP-1 monocyte chemotactic protein-1
- TNF- ⁇ TNF- ⁇
- keratocytes may scavenge remnants of apoptotic keratocytes and protect the cornea from possible infection (Id., citing Wilson SE, et al., The corneal wound healing response: cytokine mediated interaction of the epithelium, stroma, and inflammatory cells. Prog. Retin. Eye Res. (2001) 20: 625–637). Some of these cells may become myofibroblasts (Id., citing Barbosa FL, et al., Corneal myofibroblast generation from bone marrow-derived cells. Exp. Eye Res. (2010) 91: 92–96) and thus participate in wound contraction. Direct involvement of immune cells in the wound healing has been also suggested from recent studies.
- Macrophage depletion impaired wound healing after autologous corneal transplantation, with a decrease in wound myofibroblasts (Id., citing Li S, et al., Macrophage depletion impairs corneal wound healing after autologous transplantation in mice. PLoS One. (2013) 8: e61799). These studies emphasize the importance of local and systemic immunity in corneal wound healing, both epithelial and stromal.
- stromal wound healing is accompanied by several events that may be responsible for ECM changes in this location: death of keratocytes, secretion of proinflammatory and profibrotic cytokines including IL-1, TNF- ⁇ , and MCP-1, transient appearance of cells that do not normally form the stroma (PMNs, macrophages, myofibroblasts), and production of ECM-degrading enzymes by activated cells.
- death of keratocytes secretion of proinflammatory and profibrotic cytokines including IL-1, TNF- ⁇ , and MCP-1
- transient appearance of cells that do not normally form the stroma PMNs, macrophages, myofibroblasts
- production of ECM-degrading enzymes by activated cells production of ECM-degrading enzymes by activated cells.
- ECM remodeling including its degradation, expression of ectopic components (provisional matrix formation by new cell types), and reassembly of the new ECM to form a more or less normal structure (Id., citing Zieske JD, et al., Kinetics of keratocyte proliferation in response to epithelial debridement. Exp. Eye Res. (2001) 72: 33– 39; Torricelli AA, Wilson SE. Cellular and extracellular matrix modulation of corneal stromal opacity. Exp. Eye Res. (2014) 129: 151–160). As a result, new ECM formed during wound healing often accumulates aberrant proteins, both in composition and structure.
- These components which are normally scarce in or absent from adult corneal stroma, include type III, VIII, XIV, and XVIII collagen, limbal isoforms of type IV collagen, embryonic fibronectin isoforms, thrombospondin-1 (TSP-1), tenascin-C, fibrillin-1, and hevin (an ECM- associated secreted glycoprotein belonging to the secreted protein acidic and rich in cysteine (SPARC) family of matricellular proteins (Id., citing Saika S, et al., Epithelial basement membrane in alkali-burned corneas in rats. Immunohistochemical study. Cornea.
- Keratocyte activation to fibroblasts is mediated by FGF-2, TGF- ⁇ , and PDGF, and their proliferation by EGF, HGF, KGF, PDGF, IL-1 and IGF-I (Id., citing Stern ME, et al., Effect of platelet-derived growth factor on rabbit corneal wound healing. Wound Repair Regen. (1995) 3: 59–65; Baldwin HC, Marshall J. Growth factors in corneal wound healing following refractive surgery: A review. Acta. Ophthalmol. Scand. (2002) 80: 238–247; Jester JV, Ho-Chang J.
- TGF- ⁇ is key to fibroblast to myofibroblast transformation, it actually inhibits keratocyte proliferation and migration (Id., citing Baldwin HC, Marshall J. Growth factors in corneal wound healing following refractive surgery: A review. Acta. Ophthalmol. Scand. (2002) 80: 238–247).
- Stromal cellular infiltration upon injury was found to be stimulated by such cytokines as MCP-1 and platelet-activating factor (PAF) (Id., citing Wilson SE, et al., The corneal wound healing response: cytokine mediated interaction of the epithelium, stroma, and inflammatory cells. Prog. Retin. Eye Res.
- TGF- ⁇ isoforms 1 and 2 Id., citing Torricelli AA, Wilson SE. Cellular and extracellular matrix modulation of corneal stromal opacity. Exp. Eye Res.
- BMP-1 bone morphogenetic protein 1
- Invest. Ophthalmol. Vis. Sci. (2014) 55: 6712– 6721 may be responsible for myofibroblast emergence, wound contraction and fibrotic scar formation.
- TGF- ⁇ also promotes deposition of excessive ECM in the wound bed that may result in scar formation directly, as well as by stimulating production of other factors including connective tissue growth factor (CTGF) and IGF-I (Id., citing Izumi K, et al., Involvement of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in corneal fibroblasts during corneal wound healing. Invest. Ophthalmol. Vis. Sci. (2006) 47:591–598; Shi L, et al., Activation of JNK signaling mediates connective tissue growth factor expression and scar formation in corneal wound healing. PLoS One.
- CGF connective tissue growth factor
- IGF-I IGF-I
- topical rosiglitazone a ligand of peroxisome proliferator activated receptor ⁇ (PPAR- ⁇ ) reduced ⁇ -SMA expression and scarring in cat corneas upon excimer laser ablation of anterior stroma without compromising wound healing.
- PPAR- ⁇ peroxisome proliferator activated receptor ⁇
- Inhibitors of mechanistic target of rapamycin (mTOR) and p38 MAP kinase signaling were able to markedly reduce the expression of ⁇ -SMA and collagenase in corneal cells and injured corneas (Id., citing Jung JC, et al., Constitutive collagenase-1 synthesis through MAPK pathways is mediated, in part, by endogenous IL-1 ⁇ during fibrotic repair in corneal stroma. J. Cell Biochem. (2007) 102: 453–462; Huh MI, et al., Distribution of TGF- ⁇ isoforms and signaling intermediates in corneal fibrotic wound repair. J. Cell Biochem.
- Corneal endothelial wound healing [0046] Due to the relative inaccessibility of corneal endothelial layer, there are fewer studies of endothelial healing. This process mostly occurs as a consequence of various burns (Id., citing Zhao B, et al., An investigation into corneal alkali burns using an organ culture model. Cornea.
- corneal endothelial cells especially human, have very low proliferation rates (Id., citing Mimura T, et al., Corneal endothelial regeneration and tissue engineering. Prog. Retin. Eye Res. (2013) 35: 1– 17). It is generally considered that corneal endothelium closes the wound gap mainly by migration and increased cell spreading. These two processes are pharmacologically separable and, depending on the wound nature, their relative contribution may vary (Id., citing Joyce NC, et al., In vitro pharmacologic separation of corneal endothelial migration and spreading responses. Invest. Ophthalmol. Vis. Sci.
- FGF-2-induced wound healing in corneal endothelial cells requires Cdc42 activation and Rho inactivation through the phosphatidylinositol 3-kinase pathway.
- Invest. Ophthalmol. Vis. Sci. (2006) 47:1 376–1386) although this view is challenged by the fact that healing corneal endothelial cells mostly divide amitotically, with formation of binuclear cells (Id., citing Landshman N, et al., Cell division in the healing of the corneal endothelium of cats. Arch. Ophthalmol. (1989) 107: 1804–1808).
- Endothelial wound healing is associated with a transient acquisition of fibroblastic morphology and actin stress fibers by migrating cells, which is consistent with endothelial-mesenchymal transformation (EnMT) (Id., citing Lee HT, et al., FGF-2 induced by interleukin-1 beta through the action of phosphatidylinositol 3-kinase mediates endothelial mesenchymal transformation in corneal endothelial cells. J. Biol. Chem. (2004) 279: 32325– 32332; Miyamoto T, et al., Endothelial mesenchymal transition: a therapeutic target in retrocorneal membrane. Cornea.
- Inducers of EnMT and fibrotic changes in the endothelial layer include FGF-2, which may come from PMNs migrating to the cornea during epithelial and stromal wound healing (Id., citing Lee HT, et al., FGF-2 induced by interleukin-1 beta through the action of phosphatidylinositol 3-kinase mediates endothelial mesenchymal transformation in corneal endothelial cells. J. Biol. Chem.
- IL- 1 ⁇ citing Lee JG, et al., Endothelial mesenchymal transformation mediated by IL-1 ⁇ - induced FGF-2 in corneal endothelial cells. Exp. Eye Res. (2012) 95: 35–39
- TGF- ⁇ Id. citing Sumioka T, et al., Inhibitory effect of blocking TGF- ⁇ /Smad signal on injury-induced fibrosis of corneal endothelium. Mol. Vis. (2008) 14: 2272–2281).
- EnMT may lead to fibrotic complications of healing, such as the formation of retrocorneal fibrous membrane, (Id., citing Ichijima H, et al., In vivo confocal microscopic studies of endothelial wound healing in rabbit cornea. Cornea. (1993) 12: 369–378.), some ways of attenuating EMT have been proposed. These include inhibiting the expression of connexin 43 (Id., citing Nakano Y, et al., Connexin 43 knockdown accelerates wound healing but inhibits mesenchymal transition after corneal endothelial injury in vivo. Invest. Ophthalmol. Vis. Sci.
- TGF- ⁇ type I receptor Id., citing Okumura N, et al., Inhibition of TGF- ⁇ signaling enables human corneal endothelial cell expansion in vitro for use in regenerative medicine. PLoS One. (2013) 8: e58000). The latter technique also facilitates endothelial cell propagation in culture. [0048] Migration and spreading of corneal endothelial cells during wound healing is stimulated by a number of factors.
- ECM proteins fibronectin and transpondin 1 were shown to facilitate cell migration (Id., citing Munjal ID, et al., Thrombospondin: biosynthesis, distribution, and changes associated with wound repair in corneal endothelium. Eur. J. Cell Biol. (1990) 52:252–263; Gundorova RA, et al., Stimulation of penetrating corneal wound healing by exogenous fibronectin. Eur. J. Ophthalmol. (1994) 4: 202–210; Blanco-Mezquita JT, et al., Role of thrombospondin-1 in repair of penetrating corneal wounds. Invest. Ophthalmol. Vis. Sci.
- Growth factors known to promote endothelial migration and wound healing include EGF, FGF-2, IL-1 ⁇ , PDGF-BB, TGF- ⁇ 2, and VEGF, whereas IGF-I and IGF-II are ineffective, and IL-4 reduces migration (Id., citing Joyce NC, et al., In vitro pharmacologic separation of corneal endothelial migration and spreading responses. Invest. Ophthalmol. Vis. Sci. (1990) 31: 1816–1826; Raphael B, et al., Enhanced healing of cat corneal endothelial wounds by epidermal growth factor. Invest. Ophthalmol. Vis. Sci.
- Prostaglandin E2 acting through cAMP pathway, ERK1/2 and p38 MAP kinase have been shown to participate in endothelial migration and wound healing (Id., citing Joyce NC, Meklir B. PGE2: a mediator of corneal endothelial wound repair in vitro. Am. J. Physiol. (1994) 266: C269–275; Sumioka T, et al., Inhibitory effect of blocking TGF- ⁇ /Smad signal on injury-induced fibrosis of corneal endothelium. Mol. Vis. (2008) 14: 2272–2281; Chen WL, et al., ERK1/2 activation regulates the wound healing process of rabbit corneal endothelial cells. Curr.
- FGF-2 stimulates migration through several pathways including p38, PI3K/Akt, and protein kinase C/phospholipase A2 (Id., citing Rieck PW, et al., Intracellular signaling pathway of FGF-2-modulated corneal endothelial cell migration during wound healing in vitro. Exp. Eye Res.
- IL-1 ⁇ stimulates migration through induction of FGF-2 (Id., citing Lee JG, et al., Endothelial mesenchymal transformation mediated by IL-1 ⁇ -induced FGF-2 in corneal endothelial cells. Exp. Eye Res. (2012) 95: 35–39), as well as induction of Wnt5a that activate Cdc42 and inactivate RhoA (Id., citing eLe JG, Kay EP. FGF-2-induced wound healing in corneal endothelial cells requires Cdc42 activation and Rho inactivation through the phosphatidylinositol 3-kinase pathway. Invest. Ophthalmol. Vis. Sci.
- a diseased cornea may be replaced surgically with a clear, healthy cornea from a human donor (corneal transplantation) by a number of methods.
- Phototherapeutic keratectomy (“PTK”) is a type of laser eye surgery that is used to treat corneal dystrophies (meaning abnormal buildup of foreign material in the cornea), corneal scars, and some corneal infections. The surgeon uses a laser to remove thin layers of diseased cornea tissue microscopically, allowing new tissue to grow on the smooth surface.
- DALK deep anterior lamellar keratoplasty
- partial thickness corneal transplant is performed; only the front and middle layers of the cornea are removed, with the endothelial layer kept in place.
- Healing time after DALK is shorter than after a full corneal transplant. There is also less risk of having the new cornea rejected.
- DALK is commonly used to treat keratoconus or bulging of the cornea.
- penetrating keratoplasty (PK) or full thickness corneal transplant is performed to remove and replace the damaged cornea. PK has a longer recovery period than other types of corneal transplants. Getting complete vision back after PK may take up to 1 year or longer.
- Endothelial keratoplasty is a surgery to replace this layer of the cornea with healthy donor tissue. It is known as a partial transplant since only the endothelium is replaced.
- types of endothelial kertoplasty include DSEK (or DSAEK) — Descemet's Stripping (Automated) Endothelial Keratoplasty, and DMEK — Descemet's Membrane Endothelial Keratoplasty.
- the lens [0055]
- the eye lens is a flexible transparent biconvex structure embedded in the anterior segment of the eye and held in place by a ring of ciliary muscle.
- the main function of the lens alongside the cornea is to refract incoming light to be focused on the retina.
- the ciliary muscles help the lens change its shape, thereby changing its focal length. This process, which is generally referred to as accommodation, enables objects at various distances to be focused on the retina, producing sharp images.
- the refractive power of the human eye is measured in diopters, which is a unit of measurement of the optical power of a lens and is equal to the reciprocal of the focal length measured in meters.
- the total refractive power (optical power) of the relaxed eye is approximately 60 diopters.
- the cornea accounts for approximately two-thirds of the refractive power (i.e., 40 diopters) and the lens accounts for the remaining one-third of the refractive power (i.e., 20 diopters).
- Corneal Inlay Structure and Function [0058] A variety of devices and procedures have been developed to attempt to provide vision correction.
- LASIK Laser-assisted in situ keratomileusis
- Corneal inlays are one of the options used to correct a decrease in near vision in people with presbyopia.
- a corneal inlay is an implant that is surgically inserted within the cornea beneath a portion of corneal tissue. These tiny devices are surgically placed in the cornea to increase the depth of focus or the refractive power of the central or paracentral cornea. Corneal inlays do not restore the ability to accommodate. Corneal inlays can be positioned by, for example, cutting a flap in the cornea and positioning the inlay beneath the flap.
- the corneal flap is created by making an incision in the corneal tissue and separating the corneal tissue from the underlying stroma, with one segment remaining attached, which acts like a hinge.
- the corneal inlay can also be positioned within a pocket (meaning a sac- like cavity) formed in the cornea.
- Corneal inlays can alter the refractive power of the cornea by changing the shape of the anterior surface of the cornea, by creating an optical interface between the cornea and an implant by having an index of refraction different from that of the cornea (i.e., has intrinsic power), or both.
- the cornea is the strongest refracting optical element in the eye, and altering the shape of the anterior surface of the cornea can therefore be a particularly useful method for correcting vision impairments caused by refractive errors.
- Corneal Inlay Procedures [0061] Regardless of the vision correction procedure and/or devices implanted, it is important to understand the cornea's natural response to the procedure to understand how the cornea will attempt to reduce or minimize the impact of the vision correction procedure. [0062] In a simple biomechanical model proposed by Watsky et al., Investigative Ophthalmology and Visual Science, vol. 26, pp. 240-243 (1985) (“Watsky model”), the anterior corneal surface radius of curvature is assumed to be equal to the thickness of the lamellar corneal material (i.e., flap) between the anterior corneal surface and the anterior surface of a corneal inlay plus the radius of curvature of the anterior surface of the inlay.
- the lamellar corneal material i.e., flap
- Huang does not address correcting for presbyopia, nor does it accurately predict changes to the anterior surface, which create a center near portion of the cornea for near vision while allowing distance vision in an area of the cornea peripheral to the center near portion. Additionally, Huang reports on removing cornea tissue by ablation as opposed to adding material to the cornea, such as an intracorneal inlay. [0065] An understanding of the cornea's response to the correction of presbyopia, using, for example, a corneal inlay, allows the response to be compensated for when performing the procedure on the cornea. Corneal Haze [0066] The idea of using corneal reshaping inlays for presbyopia correction dates back to about 50 years.
- BioMaterials for Onlays and Inlays Materials that have been evaluated for use in corneal inlays and corneal onlays can be characterized as biological, synthetic and biosynthetic.
- Biological polymers are natural biocompatible materials that comprise a whole or a part of a living structure or biomedical device that performs, augments, or replaces a natural function. In recent years there has been a push to investigate natural materials for tissue engineering, especially those natural polymers that are present in the body.
- Naturally- occurring biopolymers include, but are not limited to, protein polymers, polysaccharides, and photopolymerizable compounds.
- Protein polymers have been synthesized from self-assembling protein polymers such as, for example, silk fibroin, elastin, collagen, and combinations thereof.
- Naturally-occurring polysaccharides include, but are not limited to, chitin and its derivatives, hyaluronic acid, dextran and cellulosics (which generally are not biodegradable without modification), and sucrose acetate isobutyrate (SAIB).
- SAIB sucrose acetate isobutyrate
- Chitin is composed predominantly of 2-acetamido-2-deoxy-D-glucose groups and is found in yeasts, fungi and marine invertebrates (shrimp, crustaceans) where it is a principal component of the exoskeleton.
- Chitin is not water soluble and the deacetylated chitin, chitosan, only is soluble in acidic solutions (such as, for example, acetic acid).
- acidic solutions such as, for example, acetic acid.
- chitin derivatives that are water soluble, very high molecular weight (greater than 2 million daltons), viscoelastic, non-toxic, biocompatible and capable of crosslinking with peroxides, gluteraldehyde, glyoxal and other aldehydes and carbodiamides, to form gels.
- Synthetic materials have an advantage over natural materials because they can be produced with a fully defined composition and designed features and structures. Many synthetic materials, mostly polymers, have been investigated to act as templates for cartilage regeneration.
- a scaffold should have the following characteristics: (i) three-dimensional and highly porous with an interconnected pore network for cell growth and flow transport of nutrients and metabolic waste; (ii) biocompatible and bioresorbable with a controllable degradation and resorption rate to match cell/tissue growth in vitro and/or in vivo; (iii) suitable surface chemistry for cell attachment, proliferation, and differentiation and (iv) mechanical properties to match those of the tissues at the site of implantation.
- Biosynthetic polymers are materials that combine synthetic components with biopolymers or moieties prepared as mimics of those found in nature [Carlini, AS set al. Macromolecules (2016) 49: 4379-94]. These materials consist of (a) synthetically modified biopolymers, such as functionalized hyaluronic acid derivatives [Id., citing Vasi, A-M, et al. Mater. Sci. Eng. C.
- HA hyaluronic acid
- mammalian vitreous humor, synovial fluid, unbiblical cords and rooster combs, from which it is isolated and purified also can be produced by fermentation processes.
- Table 1 Comparison of Materials Used in Development of Onlays, Inlays and Keratoprostheses (taken from Xie, RZ et al. Bioscience Reports (2002) 21 (4): 513-36). The cited references are below.
- Bioadhesive polymers include bioerodible hydrogels [see Sawhney et al Macromolecules (1993) 26, 581-587].
- polyesters polyglycolide, polylactic acid and combinations thereof
- polyester polyethylene glycol copolymers polyamino- derived biopolymers, polyanhydrides, polyorthoesters, polyphosphazenes, sucrose acetate isobutyrate (SAIB)
- photopolymerizable biopolymers naturally-occurring biopolymers, protein polymers, collagen, polysaccharides, photopolymerizable compounds, polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl
- Hydrogel compositions have been used in the medical industry for a variety of purposes, including fabrication of medical devices. Such hydrogel compositions may include high water content or certain elements that can have a detrimental effect on biocompatibility, particularly when medical devices fabricated from traditional hydrogel compositions are implanted onto or into the cornea of a patient.
- the present disclosure provides a biocompatible hydrogel composition of water content ranging from 78% to 92% (w/w), inclusive, and high biocompatibility.
- the water content (lower than the water content of previous devices) provides for increased stiffness (as compared to medical devices formed from traditional hydrogel compositions), providing improved handling during fabrication and surgical implantation of the medical devices. use in making corneal onlays and inlays.
- the described invention provides a hydrogel composition and a method of forming the hydrogel composition.
- the hydrogel composition has a water content ranging from 78% to 92%, inclusive, and can be used to fabricate a variety of medical devices, such as (but not limited to) corneal inlays, corneal onlays, implant scaffolds, dermal fillers, wound dressing, drug delivery devices, biosensor coatings, or the like.
- the hydrogels can be synthesized using a combination of biopolymers and synthetic monomers and/or polymers.
- hydrogel-based corneal inlay was implanted in animals and has remained clear without any inflammatory reactions after more than three years, as indicated by the animal studies discussed in International Patent Application No. PCT/US2020/044266, which is incorporated herein by reference in its entirety.
- the hydrogel composition of the present disclosure therefore provides improved biocompatibility.
- the described invention also provides biocompatible hydrogel compositions, methods of making and characterization as medical devices (e.g., inlays for correcting presbyopia).
- the hydrogel compositions can include collagen-synthetic polymer hydrogels.
- a synthetic polymer not only improves the mechanical properties of the medical device, but also minimizes swelling, improves manufacturability/processability, and minimizes in-vivo degradation of the medical device.
- the collagen-synthetic inlays have shown promising results, with no haze observed after being implanted in animals for more than a year (data not shown).
- the described invention provides a hydrogel composition
- a hydrogel composition comprising an interpenetrating polymer network containing a biopolymer and two synthetic polymers, wherein the biopolymer is a collagen; the synthetic polymers are 2- methacryloyloxyethyl phosphorylcholine (MPC) and poly(ethylene glycol)diacrylate (PEGDA), wherein initiation of polymerization and cross-linking of the two synthetic polymers is by an ultraviolet light initiator (wavelength range); and wherein time available for completion of polymerization and cross-linking is between 5 and 30 minutes, inclusive.
- a weight ratio of collagen:PEGDA is about 4:1.
- a weight ratio of PEGDA/MPC ranges from about 1:3 to about 1:1, inclusive.
- a water content of the IPN ranges from about 78% to about 88% inclusive.
- a weight ratio of collagen: PEGDA ranges from about 1:3 to about 1:10, inclusive.
- a weight ratio of PEGDA/MPC ranges from 1:0.5 to 0.05:1, inclusive.
- a water content of the IPN ranges from about 78% (w/w) to about 92% (w/w), inclusive.
- the collagen is crosslinked by a crosslinking agent.
- the collagen is a natural collagen, a synthetic collagen, a recombinant collagen, or a collagen mimic.
- the collagen is porcine collagen.
- the cross-linking agent is Poly(ethylene glycol) diacrylate (PEGDA).
- the cross-linking agent is any multi arm PEG acrylate or methacrylate (e.g., 3 or 4 or 8 arm PEG acrylate or methacrylate).
- the UV initiator is at least one of Lithium phenyl-2,4,6- trimethylbenzoylphosphinate (LAP), 2,2-Dimethoy-2-phenylacetophenone (DMPA), or Irgacure.
- the two synthetic polymers are at least partially interlaced on a molecular scale but are not covalently bonded to each other and cannot be separated.
- the hydrogel composition comprises at least 1%, at least 2%, at least 3%, at least 4%, or at least 5% by weight of the collagen.
- the hydrogel composition comprises at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of the collagen biopolymer.
- the hydrogel composition is optically transparent, biocompatible, permeable and refractive.
- the described invention provides an implant fabricated from the hydrogel composition of claim 1, wherein the implant is optically transparent, biocompatible, permeable and refractive.
- the implant is an optical inlay implant.
- the implant is an optical onlay implant.
- the described invention provides use of a hydrogel composition with low water content to fabricate a medical device.
- the described invention provides a method of treating presbyopia comprising implanting in a cornea of a mammalian subject a corneal inlay device of water content ranging from 78% to 92%, inclusive, the corneal inlay device comprising a thickness, a diameter, a flat or flat-like base and a dome-shaped top, 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.
- the implanting of the corneal inlay device is by cutting a flap in the cornea and positioning the corneal inlay device beneath the flap. According to one embodiment, the implanting of the corneal inlay device is by positioning the corneal inlay device within a pocket formed in the cornea. According to one embodiment, the implanting of the corneal inlay device is in the cornea at a depth of about 100 microns to about 200 microns, inclusive. According to one embodiment, the implanting of the corneal inlay device is in the cornea at a depth of about 130 microns to about 160 microns, inclusive.
- the thickness of the corneal inlay device 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 micron
- 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.
- a 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.
- the corneal inlay device is molded from a hydrogel.
- the corneal inlay device comprises water, a natural polymer (e.g., collagen) and two synthetic polymers, wherein the two synthetic polymers form an interpenetrating polymer network wherein the synthetic polymers are at least partially interlaced on a molecular scale but not covalently bonded to each other and cannot be separated
- the collagen is a porcine collagen.
- a hydrogel for fabricating the corneal inlay device comprises at least 1%, at least 2%, at least 3%, at least 4%, or at least 5% by weight of the collagen.
- a hydrogel for fabricating the corneal inlay device comprises at least 1%, at least 2%, at least 3%, at least 4%, or at least 5% by weight of the natural polymer.
- one of the two synthetic polymers is poly(2-methacryloyloxyethyl phosphorylcholine) (MPC).
- one of the two synthetic polymers is poly(ethylene glycol) diacrylate (PEGDA).
- the water content of the device is effective to sustain nutritional transport.
- the corneal inlay device is optically transparent, biocompatible, permeable and refractive.
- the described invention also provides use of a corneal inlay device with water content ranging from 78% to 92%, inclusive, to treat presbyopia in a mammalian subject, the corneal device comprising a thickness, a diameter, a flat or flat-like base and a dome-shaped top, 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.
- the described invention also provides a corneal inlay device for treating presbyopia, comprising: a body defining a thickness, a diameter, a flat or flat-like base, and a dome-shaped top, wherein the corneal inlay device is fabricated from a hydrogel composition comprising an interpenetrating polymer network of two polymers at least partially interlaced on a molecular scale but not covalently bonded to each other that cannot be separated, comprising a water content of between 78%-92%, inclusive.
- the described invention provides a corneal onlay device of water content ranging from about 78% to about 92% (w/w), inclusive to treat presbyopiathat can be removed and replaced without invasive surgical intervention while decreasing or eliminating the risk of a patient developing corneal haze.
- the corneal onlay implant is fabricated or formed from a hydrogel.
- the hydrogels can be synthesized using a combination of biopolymers and synthetic monomers and/or polymers. The addition of a synthetic polymer not only improves the mechanical properties of the onlay, but also minimizes swelling, improves manufacturability/processability, and minimizes in-vivo degradation of corneal onlays.
- the present disclosure also provides methods of making and characterization of the molded onlays for correcting presbyopia.
- the present disclosure also describes an in- vitro method to confirm biocompatibility of the exemplary onlays and their ability to support epithelial growth.
- the present disclosure also provides a method of treating presbyopia comprising placing on top of Bowman’s membrane of a mammalian subject a corneal onlay device comprising a water content ranging from about 78% to about 92% (w/w), inclusive.
- the present disclosure provides a method of making the corneal onlay.
- the present disclosure provides a method for providing visual correction for presbyopia without damaging the cornea/leaving cornea substantially intact, comprising exposing a surface of Bowman’s membrane by removing the corneal epithelium cell layer; gently cleaning the exposed surface of Bowman’s membrane; placing the corneal implant device and a material effective to adhere the corneal onlay onto the clean exposed surface of Bowman’s membrane; placing a protective contact lens over the onlay; allowing the epitheliallayer to regrow on top of the onlay; and removing the contact lens without disturbing placement of the onlay once the epithelial layer is restored by the regrowth.
- the method may provide correction of presbyopia without invasive surgical intervention.
- the describe invention provides a method of treating presbyopia comprising implanting on a corneal surface of a mammalian subject a corneal onlay device of water content ranging from 78% to 92% % (w/w), the corneal onlay device comprising a thickness, a diameter, a flat or flat-like base and a dome-shaped top, wherein the corneal onlay device, is effective to alter a shape of the anterior surface of a cornea, and to increase an eye's ability to increase its power to focus on nearby objects, with a reduced risk of development of corneal haze compared to a control.
- the implanting of the corneal onlay device is by removing a portion of an epithelial layer of the cornea and positioning the corneal onlay device on a cleaned surface of Bowman’s membrane of the cornea beneath the epithelial layer.
- the portion of the epithelial layer is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.
- the implanting of the corneal onlay device is by positioning the corneal onlay device on a cleaned surface of a Bowman’s membrane of the cornea.
- the cleaned surface is a surface of the Bowman’s membrane of the cornea cleaned with a composition comprising mitomycin C (MMC) and isotonic sterile saline.
- the cleaned surface is a surface of the Bowman’s membrane of the cornea cleaned with a composition comprising mitomycin C (MMC) and isotonic sterile saline.
- the thickness of the corneal onlay device is at least 10 microns, at least 11 microns, at least 12 microns, at least 13 microns, at least 14 microns, at least 15 microns, at least 16 microns, at least 17 microns, at least 18 microns, at least 19 microns, at least 20 microns, at least 21 microns, at least 22 microns, at least 23 microns, at least 24 microns, at least 25 microns, at least 26 microns, at least 27 microns, at least 28 microns, at least 29 microns, or at least 30 microns.
- the thickness of the corneal onlay ranges from at least 20 microns, at least 21 microns, at least 22 microns, at least 23 microns, at least 24 microns, at least 25 microns, at least 26 microns, at least 27 microns, at least 28 microns, at least 29 microns, to 30 microns.
- a diameter of the corneal onlay device is at least 1 mm, at least 1.1 mm, at least 1.2 mm, at least 1.3 mm, at least 1.4 mm, at least 1.5 mm, at least 1.6 mm, at least 1.7 mm, at least 1.8 mm, at least 1.9 mm, at least 2.0 mm, at least 2.1 mm, at least 2.2 mm, at least 2.3 mm, at least 2.4 mm, at least 2.5 mm, at least 2.6 mm, at least 2.7 mm, at least 2.8 mm, at least 2.9 mm, or at least 3.0 mm.
- the corneal onlay device is molded from a hydrogel.
- the corneal onlay device comprises water, a natural polymer, and two synthetic polymers, the two synthetic polymers forming an interpenetrating polymer network, wherein the synthetic polymers and the natural polymer are at least partially interlaced on a molecular scale but not covalently bonded to each other and cannot be separated, comprising.
- the natural polymer is a collagen.
- the collagen is a porcine collagen.
- a hydrogel for fabricating the corneal onlay device comprise at least 1%, at least 2%, at least 3%, at least 4%, or at least 5% by weight of the natural polymer.
- one of the two synthetic polymers is poly(2-methacryloyloxyethyl phosphorylcholine) (MPC).
- one of the two synthetic polymers is Poly(ethylene glycol) diacrylate (PEGDA).
- the water content of the corneal onlay device ranges from about 70% to about 90%, inclusive.
- the water content of the corneal onlay device ranges from about 78% to about 88%, inclusive.
- the water content of the corneal onlay device ranges from about 78% to about 84%, inclusive.
- the corneal onlay device is optically transparent, biocompatible, gas permeable and refractive.
- the described invention provides a method for providing vision correction for presbyopia without damaging the cornea/leaving cornea substantially intact, the method comprising exposing a surface of Bowman’s membrane by removing a corneal epithelium cell layer, gently cleaning the exposed surface of the Bowman’s membrane, implanting a corneal implant device and optionally an adhesive material effective to adhere the corneal implant device onto the clean exposed surface of the Bowman’s membrane, wherein the corneal implant device is a corneal onlay, placing a protective contact lens over the corneal implant device in situ for at least 24 hr allowing the corneal epithelium cell layer to regrow over the corneal implant device, and removing the protective contact lens without disturbing placement of the corneal implant device, wherein the method may provide correction of presbyopia without invasive surgical intervention.
- the described invention provides use of a corneal onlay device with low water content to treat presbyopia in a mammalian subject, the corneal device comprising a thickness, a diameter, a flat or flat-like base and a dome-shaped top, wherein the corneal onlay device when placed on a surface of the cornea is effective to alter a shape of the anterior surface of a cornea and to increase an eye's ability to increase its power to focus on nearby objects with a reduced risk of development of corneal haze, compared to a control.
- the described invention provides a corneal onlay device for treating presbyopia, comprising a body defining a thickness, a diameter, a flat or flat-like base, and a dome-shaped top, wherein thickness is from 10 microns to 30 microns, inclusive, wherein the corneal onlay device is fabricated from a hydrogel composition comprising an interpenetrating polymer network of two polymers at least partially interlaced on a molecular scale but not covalently bonded to each other that cannot be separated, comprising a low water content of between 78%-92%, inclusive; and wherein in vitro, the hydrogel composition remains stable for at least two years.
- FIG. 1 shows an illustrative view of the human eye; (from Allaboutvision.com/resources/anatomy.htm, Accessed March 2019).
- FIG.2 shows an illustrative view of the five layers of the cornea.
- FIG. 3 shows an illustrative view of the effects of presbyopia on the human eye.
- FIG. 4A-4B show an illustrative view of corneal refractive procedures involving a corneal onlay (FIG.4A) and a corneal inlay (FIG.4B).
- FIG. 5 shows an illustrative embodiment of the corneal inlay device of the present disclosure.
- FIG. 6 is a diagram showing the corneal inlay of the present disclosure implanted in a cornea.
- FIG.7 shows an example of how a corneal inlay can provide near vision to a subject's eye while retaining some distance vision according to an embodiment of the present disclosure.
- FIG.8 is a graph showing a change in anterior corneal surface height and the corresponding induced added power.
- FIG. 9 is a diagram showing a preoperative optical coherence tomography (“OCT”) and a postoperative OCT including an example location for the corneal inlay of the present disclosure.
- FIG. 10 is a perspective view of an exemplary mold assembly for fabricating an exemplary hydrogel inlay in accordance with the present disclosure.
- FIG.11 is a side view of the exemplary mold assembly of FIG.9.
- FIG.12 is a cross-sectional view of the exemplary mold assembly of FIG.9.
- FIG. 13 is a detailed view of the exemplary mold assembly of FIG. 11 showing a cavity formed between a first and second mold section.
- FIG.14 is a detailed view of the exemplary mold assembly of FIG.12. [00112] FIG.
- FIG. 15 is a perspective view of a first mold section of the exemplary mold assembly of FIG.10.
- FIG.16 is a top view of a first mold section of FIG.15.
- FIG.17 is a side view of a first mold section of FIG.15.
- FIG.18 is a cross-sectional view of a first mold section of FIG.17.
- FIG.19 is a detailed view of a first mold section of FIG.18 showing a cavity formed in a top surface of the first mold section.
- FIG.20 is a perspective view of a second mold section of an exemplary mold assembly of FIG.10.
- FIG.21 is a top view of a second mold section of FIG.20.
- FIG.22 is a side view of a second mold section of FIG.20.
- FIG.23 is a cross-sectional view of a second mold section of FIG.22.
- FIG.24 is a detailed view of a second mold section of FIG.23.
- FIG. 25 is a top view of an exemplary hydrogel inlay in accordance with the present disclosure.
- FIG.26 is a side view of the exemplary hydrogel inlay of FIG.25.
- FIG.27 is a cross-sectional view of the exemplary hydrogel inlay of FIG.25.
- FIG. 28 is a detailed cross-sectional view of the exemplary hydrogel inlay of FIG.27.
- FIG.29 is a side view of an exemplary hydrogel meniscus inlay in accordance with the present disclosure.
- FIG.30 is a cross-sectional view of the exemplary hydrogel inlay of FIG.29.
- FIG. 31 is a detailed cross-sectional view of the exemplary hydrogel inlay of FIG.30.
- FIG. 32 is an image of cell coverage on a biocompatible material after seven days.
- FIG. 33 is an image of cell coverage on a non-biocompatible material after seven days.
- FIGS. 34A, 34B, 34C, 34D, and 34E illustrate guideline haze grading schemes for corneal haze scoring.
- FIG. 34A, 34B, 34C, 34D, and 34E illustrate guideline haze grading schemes for corneal haze scoring.
- FIG. 34A, 34B, 34C, 34D, and 34E illustrate guideline haze grading schemes for corneal haze scoring.
- FIG. 35 is a bar graph showing thickness for different samples tested in the cell attachment assay at day 4.
- FIG. 36 is a bar graph showing thickness for different samples tested in the cell attachment assay at day 7.
- FIG. 37 is a bar graph showing thickness over time for different samples tested in the cell attachment assay.
- FIGS. 38A, 38B, 38C, 38D, 38E, 38F, and 38G are microscopy images for different samples tested in the cell attachment assay at day 4, with FIG. 38A showing a control, FIG. 38B showing Nippi 10%, FIG. 38C showing Nippi 12%, FIG. 38D showing Nippi 15%, FIG. 38E showing Nippon 10%, FIG. 38F showing Ferentis 1823B, and FIG.
- FIGS. 39A, 39B, 39C, 39D, 39E, 39F, and 39G are microscopy images for different samples tested in the cell attachment assay at day 7, with FIG. 39A showing a control, FIG. 39B showing Nippi 10%, FIG. 39C showing Nippi 12%, FIG. 39D showing Nippi 15%, FIG. 39E showing Nippon 10%, FIG. 39F showing Ferentis 1823B, and FIG. 39G showing Ferentis 1837A.
- FIG. 40 is a diagram illustrating placement of materials then seeded with cells during a cell attachment assay.
- FIG. 41 is a bar graph showing thickness over time for different samples tested in the cell attachment assay.
- FIGS. 42A, 42B, 42C, 42D, 42E, 42F, 42G, 42H, and 42I are microscopy images for different samples tested in the cell attachment assay at day 4, with FIG. 42A showing a control, FIG.42B showing Ferentis 1842A, FIG.42C showing Nippi 12%D12%, FIG. 42D showing Nippi 10%D10%, FIG. 42E showing Nippi 12%D10%, FIG. 42F showing Nippon 10%, FIG.42G showing SA-13-31B, FIG.42H showing SA-13-92A edge, and FIG.42I showing SA-13-92A on sample. [00140] FIGS.
- FIG. 43A, 43B, 43C, 43D, 43E, 43F, 43G, 43H, and 43I are microscopy images for different samples tested in the cell attachment assay at day 7, with FIG. 43A showing a control, FIG.43B showing Ferentis 1842A, FIG.43C showing Nippi 12%D12%, FIG. 43D showing Nippi 10%D10%, FIG. 43E showing Nippi 12%D10%, FIG. 43F showing Nippon 10%, FIG.43G showing SA-13-31B, FIG.43H showing SA-13-92A edge, and FIG.43I showing SA-13-92A on sample. [00141] FIG.
- FIGS.45A, 45B, 45C, 45D, 45E, and 45F are microscopy images for control samples tested in the cell attachment assay, with each of FIGS. 45A-45F showing control samples and, in particular, FIGS. 45A-45D showing control sample images for 4/6 samples, 80-100% confluent, and FIGS. 45E-45F showing control sample images for 2/6 samples mostly confluent, and a few patches in center.
- FIGS.45A, 45B, 45C, 45D, 45E, and 45F are microscopy images for control samples tested in the cell attachment assay, with each of FIGS. 45A-45F showing control samples and, in particular, FIGS. 45A-45D showing control sample images for 4/6 samples, 80-100% confluent, and FIGS. 45E-45F showing control sample images for 2/6 samples mostly confluent, and a few patches in center.
- FIGS.45A, 45B, 45C, 45D, 45E, and 45F are microscopy images for control samples tested
- FIGS. 46A, 46B, 46C, 46D, 46E, 46F, 46G, 46H, 46I, and 46J are microscopy images for 1745A samples tested in the cell attachment assay, with FIGS. 46A- 46C showing 1745A sample images for 3/10 confluent at edges and nearly confluent in center, FIGS.46D-46E showing 1745A sample images for 2/1060-70% confluent in center, confluent at edges, and FIGS.46F-46J showing 1745A sample images for 5/10 samples 30- 40% confluent in center, patchy, some holes. [00144]
- FIG. 47 is an image of an MTT plate illustrating the setup for samples tested in the cell attachment assay. [00145] FIG.
- FIG. 48 is a bar graph showing cell numbers for MTT results in the cell attachment assay for a sample and control.
- FIG.49 is a diagram of seeding materials during a cell attachment assay.
- FIGS. 50A-50B are light microscopy images of PC-MPC cells attached to a sample.
- FIG. 51 is a confocal microscopy image of a cross-section of PC-MPC material following incubation with epithelial cells. There are few multi-layer spots on top of the material.
- FIGS.52A-52B are confocal microscopy images of a cross-section of controls showing some multilayered structures as a baseline for comparison. [00150] FIGS.
- FIG. 54 is a perspective view of an exemplary mold assembly for fabricating an exemplary hydrogel inlay having a disc-shaped configuration in accordance with the present disclosure; [00152] FIG.55 is a side view of the exemplary mold assembly of FIG.54; [00153] FIG.56 is a cross-sectional view of the exemplary mold assembly of FIG.54; [00154] FIG.
- FIG. 57 is a perspective view of a first mold section of the exemplary mold assembly of FIG.54; [00155] FIG.58 is a top view of a first mold section of FIG.57; [00156] FIG.59 is a side view of a first mold section of FIG.57; [00157] FIG.60 is a cross-sectional view of a first mold section of FIG.57; [00158] FIG.61 is a detailed view of a first mold section of FIG.60 showing a cavity formed in a top surface of the first mold section; [00159] FIG.62 is a perspective view of a second mold section of an exemplary mold assembly of FIG.54; [00160] FIG.63 is a top view of a second mold section of FIG.54; [00161] FIG.64 is a side view of a second mold section of FIG.54; [00162] FIG.65 is a cross-sectional view of a second mold section of FIG.62; and [00163] FIG.66 is a detailed view of a second
- a “polymer” is a reference to one or more polymers and equivalents thereof known to those skilled in the art, and so forth.
- the term “adaptive immune response” refers to an immune response mediated by uniquely specific recognition or a non-self entity by lymphocytes whose activation leads to elimination of the entity and the production of specific memory lymphocytes. Because these memory lymphocytes forestall disease in subsequent attacks by the same pathogen, the host immune system is said to have “adapted” to copy with the entity.
- the term “adhere” and its other grammatical forms as used herein means to stick fast to a surface or substance.
- admixture or “blend” is generally used herein to refer to a physical combination of two or more different components. In the case of polymers, an admixture is a physical combination of two or more different polymers.
- Anatomical terms [00169] 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.
- proximal On the limbs or other appendages, a point closer to the main body is "proximal”; a point farther away is “distal”.
- proximal 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.
- 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. [00171] 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.
- 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.
- 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.
- collagen refers to a natural, chemically synthesized, or synthetic protein rich in glycine and proline that in vivo is a major component of the extracellular matrix and connective tissues.
- corner apex refers to the point of maximum curvature.
- corner vertex refers to the point located at the intersection of an individual’s line of fixation and the corneal surface.
- curvature refers to a degree of curving of a continuously bending line, without angles.
- cytokine refers to small soluble protein substances secreted by cells which have a variety of effects on other cells. Cytokines mediate many important physiological functions including growth, development, wound healing, and the immune response. They act by binding to their cell-specific receptors located in the cell membrane, which allows a distinct signal transduction cascade to start in the cell, which eventually will lead to biochemical and phenotypic changes in target cells. Generally, cytokines act locally.
- type I cytokines which encompass many of the interleukins, as well as several hematopoietic growth factors
- type II cytokines including the interferons and interleukin-10
- TNF tumor necrosis factor
- IL-1 immunoglobulin super-family members
- chemokines a family of molecules that play a critical role in a wide variety of immune and inflammatory functions.
- the same cytokine can have different effects on a cell depending on the state of the cell. Cytokines often regulate the expression of, and trigger cascades of, other cytokines.
- the term “demolding” as used herein refers to a process of removing a mold from a model or a casting from a mold. The process can be, for example, by mechanical means, by hand, by the use of compressed air, etc.
- the term “diopter” as used herein refers to a unit of measurement of the refractive power of a lens equal to the reciprocal of the focal length in meters.
- 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.
- extracellular matrix refers to a complex network of polysaccharides and proteins secreted by cells that serves as a structural element in tissues and also influences their development and physiology. It is composed of an interlocking mesh of fibrous proteins and glycosaminoglycans (GAGs). Examples of fibrous proteins found in the extracellular matrix include collagen, elastin, fribronectin, and laminin.
- GAGs found in the extracellular matrix include proteoglycans (e.g., heparin sulfate), chondroitin sulfate, keratin sulfate, and non-proteoglycan polysaccharide (e.g., hyaluronic acid).
- proteoglycan refers to a group of glycoproteins that contain a core protein to which is attached one or more glycosaminoglycans.
- the extracellular matrix serves many functions, including, but not limited to, providing support and anchorage for cells, segregating one tissue from another tissue, and regulating intracellular communication.
- fibroblast refers to a common cell type in connective tissue that secretes an extracellular matrix rich in collagen and other extracellular matrix macromolecules and that migrates and proliferates readily in wounded tissue and in tissue culture.
- fixation or “visual fixation” as used herein refers to an optic skill that allows one to sustain gaze at a stationary object.
- growth refers to a process of becoming larger, longer or more numerous, or an increase in size, number, or volume of cells in a cell population.
- growth factor refers to an extracellular polypeptide signal molecule that can stimulate a cell to grow or proliferate. Nonlimiting examples include epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). Most growth factors also have other actions.
- hydrogel refers to a substance resulting in a solid, semisolid, pseudoplastic, or plastic structure containing a necessary aqueous component to produce a gelatinous or jelly-like mass.
- the term “hydrophilic” as used herein refers to a material or substance having an affinity for polar substances, such as water.
- the terms “immune response” and “immune mediated” are used interchangeably herein to refer to any functional expression of a subject’s immune system, against either foreign or self-antigens, whether the consequences of these reactions are beneficial or harmful to the subject.
- the term “immune system” as used herein refers to a complex arrangement of cells and molecules that maintain immune homeostasis to preserve the integrity of the organism by elimination of all elements judged to be dangerous.
- the term “implant” as used herein refers to a material inserted or grafted into a tissue.
- index of refraction refers to a measure of the extent to which a substance/medium slows down light waves passing through it. Its value determines the extent to which light is refracted (bent) when entering or leaving the substance/medium. It is the ratio of the velocity of light in a vacuum to its speed in a substance or medium.
- innate immunity or innate immune response
- integrins refers to the principal receptors used by animal cells to bind to the extracellular matrix. They are heterodimers and function as transmembrane linkers between the extracellular matrix and the actin cytoskeleton. A cell can regulate the adhesive activity of its integrins from within.
- interlaced and its other grammatical forms as used herein refers to a state of being united by intercrossing; of being passed over and under each other; of being weaved together; intertwined; or being connected intricately.
- isolated refers to material, such as, but not limited to, a nucleic acid, peptide, polypeptide, or protein, which is: (1) substantially or essentially free from components that normally accompany or interact with it as found in its naturally occurring environment.
- substantially free or “essentially free” are used herein to refer to considerably or significantly free of, or more than about 95% free of, more than about 96% free of, more than about 97% free of, more than about 98% free of, or more than about 99% free of.
- the isolated material optionally comprises material not found with the material in its natural environment; or (2) the material has been synthetically (non-naturally) altered by deliberate human intervention.
- matrix refers to a three dimensional network of fibers that contains voids (or "pores") where the woven fibers intersect.
- the structural parameters of the pores can affect how substances (e.g., fluid, solutes) move in and out of the matrix.
- MPC methacryloyloxyethyl phosphorylcholine.
- miosis means excessive constriction (shrinking) of the pupil. In miosis, the diameter of the pupil is less than 2 millimeters (mm),
- myeloid as used herein means of or pertaining to bone marrow.
- Granulocytes and monocytes are differentiated descendants from common progenitors derived from hematopoietic stem cells in the bone marrow. Commitment to either lineage of myeloid cells is controlled by distinct transcription factors followed by terminal differentiation in response to specific colony-stimulating factors and release into the circulation. Upon pathogen invasion, myeloid cells are rapidly recruited into local tissues via various chemokine receptors, where they are activated for phagocytosis as well as secretion of inflammatory cytokines, thereby playing major roles in innate immunity. [Kawamoto, H., Minato, N. Intl J. Biochem. Cell Biol. (2004) 36 (8): 1374-9].
- myofibroblast refers to a differentiated cell type essential for wound healing that participates in tissue remodeling following an insult. Myofibroblasts are typically activated fibroblasts, although they can also be derived from other cell types, including epithelial cells, endothelial cells, and mononuclear cells.
- PEGDA poly(ethylene glycol)diacrylate.
- permeable as used herein means permitting the passage of substances, such as oxygen, glucose, water and ions, as through a membrane or other structure.
- the term “porosity” as used herein refers to the ratio between the pore volume and the total volume of a material.
- the term “peptide” as used herein refers to a molecule of two or more amino acids chemically linked together. A peptide may refer to a polypeptide, protein or peptidomimetic.
- 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.
- polypeptide and protein are used herein in their broadest sense to refer to a sequence of subunit amino acids, amino acid analogs, or peptidomimetics. The subunits are linked by peptide bonds, except where noted.
- the polypeptides described herein may be chemically synthesized or recombinantly expressed. Polypeptides of the described invention can be chemically synthesized. Synthetic polypeptides, prepared using the well- known techniques of solid phase, liquid phase, or peptide condensation techniques, or any combination thereof, can include natural and unnatural amino acids.
- Amino acids used for peptide synthesis may be standard Boc (N- ⁇ -amino protected N- ⁇ -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- ⁇ -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- ⁇ -amino protected amino acids can be obtained from Sigma, Cambridge Research Biochemical, or other chemical companies familiar to those skilled in the art.
- polypeptides can be synthesized with other N- ⁇ -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., ⁇ -methyl amino acids, C- ⁇ -methyl amino acids, and N- ⁇ -methyl amino acids, etc.) to convey special properties.
- D-amino acids which are resistant to L-amino acid-specific proteases in vivo
- various "designer" amino acids e.g., ⁇ -methyl amino acids, C- ⁇ -methyl amino acids, and N- ⁇ -methyl amino acids, etc.
- synthetic amino acids include ornithine for lysine, and norleucine for leucine or isoleucine.
- the polypeptides can have peptidomimetic bonds, such as ester bonds, to prepare peptides with novel properties.
- a peptide may be generated that incorporates a reduced peptide bond, i.e., R 1 -CH 2 - NH-R 2 , where R 1 and R 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.
- polypeptide also are inclusive of modifications including, but not limited to, glycosylation, lipid attachment, sulfation, gamma- carboxylation of glutamic acid residues, hydroxylation and ADP-ribosylation. It will be appreciated, as is well known and as noted above, that polypeptides may not be entirely linear. For instance, polypeptides may be branched as a result of ubiquitination, and they may be circular, with or without branching, generally as a result of posttranslational events, including natural processing event and events brought about by human manipulation which do not occur naturally.
- Circular, branched and branched circular polypeptides may be synthesized by non-translation natural process and by entirely synthetic methods, as well.
- 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.
- the term “proliferate” and its various grammatical forms as used herein means to increase rapidly in numbers; to multiply.
- 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.
- the term “range” and its various grammatical forms as used herein refers to varying between the stated limits and includes the stated limits and all points or values in between.
- 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.
- 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.
- refraction refers to the deflection of a ray of light when it passes from one medium into another of different optical density.
- a denser medium provides more matter from which the light can scatter, so light will travel more slowly in a dense medium.
- a slower speed means a higher index of refraction.
- Light travels much faster in rarer medium (meaning a less dense medium, for example: air). In passing from a denser into a rarer medium the light is deflected away from a line perpendicular to the surface of the refracting medium.
- RGD motif refers to arginylglycylaspartic acid, the binding motif of fibronectin to cell adhesion molecules, which can serve as a cell adhesion site of extracellular matrix, cell surface proteins, and integrins.
- shape refers to the quality of a distinct object or body in having an external surface or outline of specific form or figure.
- subject or “individual” or “patient” are used interchangeably to refer to a member of an animal species of mammalian origin, including but not limited to, mouse, rat, cat, goat, sheep, horse, hamster, ferret, pig, dog, guinea pig, rabbit and a primate, such as, for example, a monkey, ape, or human.
- 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.
- the term “tolerance limits” as used herein refers to the end points of a tolerance interval.
- the term “transactivation” as used herein refers to stimulating transcription of a gene in a host cell by binding to DNA. Genes can be transactivated naturally (e.g., by a virus or a cellular protein) or artificially.
- the term “viscosity”, as used herein refers to the property of a fluid that resists the force tending to cause the fluid to flow.
- St Stokes
- cSt Centistokes
- 1 St 10-4 m 2 /s
- 1 cSt 0.01 St.
- wt % or “weight percent” or “percent by weight” or “wt/wt%” of a component, unless specifically stated to the contrary, refers to the ratio of the weight of the component to the total weight of the composition in which the component is included, expressed as a percentage.
- the term “Young’s modulus” as used herein refers to a measure of elasticity, equal to the ratio of the stress acting on a substance to the strain produced.
- the term “stress” as used herein refers to a measure of the force put on an object over an area.
- strain as used herein refers to the change in length divided by the original length of the object. Change in length is proportional to the force put on it and depends on the substance from which the object is made. Change in length is proportional to the original length and inversely proportional to the cross-sectional area. Fracture is caused by a strain placed on an object such that it deforms (a change of shape) beyond its elastic limit and breaks.
- Embodiments Hydrogel Composition provides an implant- forming hydrogel composition comprising an interpenetrating polymer network (IPN) containing a biopolymer, a first synthetic polymer and a second synthetic polymer.
- IPPN interpenetrating polymer network
- An IPN is a polymer comprising two or more networks that are at least partially interlaced on a molecule scale but not covalently bonded to each other and cannot be separated unless chemical bonds are broken (Intl Union of Pure & Applied Chemistry Compendium of Chemical Terminology (IUPAC Gold Book, v. 2.3.3 (2014-02-24), page 750). Mixtures of two or more polymers cannot be termed IPNs and are instead multicomponent polymer material.
- the hydrogel polymer composition comprises an interpenetrating network (IPN) which includes two or more polymeric units in the network in which the polymers are interlaced with each other (Maity, S. et al. Green approaches in medicinal chemistry for sustainable drug design.
- IPN interpenetrating network
- the polymers should meet the following criteria. First, there should be one polymer which can be synthesized and/or cross- linked with the other. Second, the polymers should have similar reaction rates. Lastly, there should not be any phase separation between/among the polymers (Id., citing (Bajpai, AK et al. Responsive polymers in controlled drug delivery. Prog. Polym. Sci. (2008) 33: 1088-18).
- IPN hydrogels include their viscoelastic properties and easy swelling behavior without dissolving in any solvent (Id.).
- IPNs can be prepared (i) by chemistry and (ii) by structure [Id., citing Myung, D. et al. Polym. Adv. Technol. (2008) 647-57; Naseri, N. et al. Biomacromolecules (2016) 17: 3714-23. [00231]
- IPN hydrogels can be divided into simultaneous IPNs or sequential IPNs. In simultaneous IPNs, both the networks are prepared simultaneously from the precursors by independent, noninterfering routes that will not interfere with one another.
- IPN hydrogels can be categorized into the following types: [00233] (a) full IPNS which are composed of two networks that are ideally juxtaposed, with many entanglements and interactions between the networks; [00234] (b) homo-IPNs, where the two polymers used in the networks are the same; [00235] (c) Semi- or pseudo-IPNs, which is a way of blending of two polymers, where one is cross-linked in the presence of the other to produce a mixture of fine morphology; additional noncovalent interaction between the two polymers can influence the surface morphology and the thermal properties of the semi-IPN gel; [00236] (d) latex IPNs, which result from emulsion polymerization.
- the hydrogel composition comprises a biopolymer.
- the natural biopolymer is a collagen.
- the natural biopolymer is different from the collagen.
- the percentage by weight of the natural polymer within the hydrogel composition can be substantially equal to the percentage by weight of the collagen.
- the natural polymer can be a collagen.
- the biopolymer is a synthetic self-assembling biopolymer.
- the biopolymer is a naturally-occurring biopolymer.
- Exemplary naturally-occurring biopolymers include, but are not limited to, protein polymers, collagen, polysaccharides, and photopolymerizable compounds.
- Exemplary protein polymers synthesized from self-assembling protein polymers include, for example, silk fibroin, elastin, collagen, and combinations thereof.
- the biopolymer comprises a collagen.
- the collagen is a porcine collagen.
- the collagen is a recombinant collagen.
- a synthetic self-assembling biopolymer is a synthetic collagen.
- the synthetic self-assembling biopolymer is a recombinant human collagen.
- the collagen is a collagen mimetic peptide.
- 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.
- the hydrogel composition comprises a synthetic polymeric material.
- the synthetic material is an optically transparent material.
- the synthetic material is a biocompatible material.
- the synthetic material is a biodegradable material. In some embodiments, the synthetic material is a hydrophilic material. In some embodiments, the synthetic materials is a material permeable to low molecular weight nutrients so as to maintain corneal health. In some embodiments, the synthetic materials is a refractive material. In some embodiments, the synthetic material is moldable, optically transparent, biocompatible, hydrophilic, permeable and refractive. [00240] In some embodiments, the first synthetic polymer and the second synthetic polymer are the same. In some embodiments, the first synthetic polymer and the second synthetic polymer are different. [00241] In some embodiments, the first and second synthetic polymer have at least one different property.
- the first and second synthetic polymer have one or more different non-repeating units, such as, for example, an end group, or a non-repeating unit in the backbone of the polymer.
- the first polymer and the second polymer of the polymer matrix have one or more different end groups.
- the first polymer can have a more polar end group than one or more end group(s) of the second polymer.
- the first synthetic polymer and the second synthetic polymer have different molecular weights.
- the molecular weight can have any suitable value, which can, in various aspects, depend on the desired properties of the IPN and the composition.
- the ratio of the first synthetic polymer to the second synthetic polymer can be present in any desired ratio, which is the weight ratio of the first synthetic polymer to the second synthetic polymer.
- more than two synthetic polymers, or biosynthetic polymers can be present in a blend.
- the water content can range from 78%-92% (w/w), inclusive. In some embodiments, the water content can range from 78%-88% inclusive. In some embodiments, the water content is at least 78%. In some embodiments, the water content is at least 79%. In some embodiments, the water content is at least 80%. In some embodiments, the water content is at least 81%. In some embodiments, the water content is at least 82%. In some embodiments, the water content is at least 83%. In some embodiments, the water content is at least 84%. In some embodiments, the water content is at least 85%. In some embodiments, the water content is at least 86%. In some embodiments, the water content is at least 87%.
- the water content is at least 88%. In some embodiments, the water content is at least 89%. In some embodiments, the water content is at least 90%. In some embodiments, the water content is at least 91%. In some embodiments, the water content is at least 92%. In some embodiments, the water content is less than 92%. In some embodiments, the water content is less than 90%. In some embodiments, the water content is less than 88%. In some embodiments, the water content ranges from at least 78%-91%., inclusive In some embodiments, the water content ranges from at least 78%-90% inclusive. In some embodiments, the water content ranges from at least 78%-89% inclusive. In some embodiments, the water content ranges from at least 78%-88% inclusive.
- the water content ranges from at least 78%-87% inclusive. In some embodiments, the water content ranges from at least 78%-86% inclusive. In some embodiments, the water content ranges from at least 78%-85% inclusive. In some embodiments, the water content ranges from at least 78%-85% inclusive. In some embodiments, the water content ranges from at least 78%-84% inclusive. In some embodiments, the water content ranges from at least 78%-83%. inclusive In some embodiments, the water content ranges from at least 78%-82% inclusive. In some embodiments, the water content ranges from at least 78%-81% inclusive. In some embodiments, the water content ranges from at least 78%-80% inclusive. In some embodiments, the water content ranges from at least 78%-79% inclusive.
- the water content ranges from at least 79%-92% inclusive. In some embodiments, the water content ranges from at least 80%-92% inclusive. In some embodiments, the water content ranges from at least 81%-92% inclusive. In some embodiments, the water content ranges from at least 82%-92% inclusive. In some embodiments, the water content ranges from at least 83%-92% inclusive. In some embodiments, the water content ranges from at least 84%-92% inclusive. In some embodiments, the water content ranges from at least 85%-92% inclusive. In some embodiments, the water content ranges from at least 86%-92% inclusive. In some embodiments, the water content ranges from at least 87%-92% inclusive. In some embodiments, the water content ranges from at least 88%-92% inclusive.
- the water content ranges from at least 89%-92% inclusive. In some embodiments, the water content ranges from at least 90%-92% inclusive. In some embodiments, the water content ranges from at least 91%-92% inclusive. In some embodiments, the water content ranges from at least 80%-88% inclusive. In some embodiments, the water content ranges from at least 82%-84% inclusive.
- the water content of the hydrogel composition used to fabricate the medical device, such as the exemplary inlay can allow for ease of handling of the inlay. For example, a water content that is too high (e.g., above 92% w/w) can create more flexibility in the inlay, resulting in potentially greater difficulty for handling and damage to the inlay.
- the water content ranging between 78% and 92%, inclusive, can provide a pliable yet sufficiently strong/stiff material that can be easily handled during manufacturing and surgery.
- the water content range of the hydrogel composition also substantially matches the 78%-80% water content of the cornea, allowing for improved biocompatibility.
- inlays with water content above the 78%-92% range, inclusive, i.e., at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, or 92% can have reduced biocompatibility with the cornea due to the lack of a match between the water content of the inlay and the cornea.
- the substantial match in water content with the cornea results in the same or substantially same refractive index of the inlay and cornea.
- the semi-synthetic composition of the inlay e.g., synthetic and collagen
- the first synthetic polymer is 2-methacryloyloxyethyl phosphorylcholine (MPC) and the second synthetic polymer is poly(ethylene glycol)diacrylate (PEGDA).
- length of the PEGDA polymer is between 200 and 700 Da, inclusive, i.e., about 200 Da, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280 about 290 Da, about 300 Da, about 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380, about 390 Da, about 400 Da, about 410, about 420, about 430, about 440, about 450, about 460, about 470, about 480, about 490 Da, about 500 Da, about 510, about 520, about 530, about 540, about 550, about 560, about 570, about 580, about 590 Da, about 600 Da, about 610,
- length of the PEGDA polymer is greater than about 700 Da.
- initiation of polymerization and cross-linking of the two synthetic polymers is by an ultraviolet light initiator (at a wavelength of about, e.g., 360- 405 nm, inclusive, 360-400 nm inclusive, 360-390 nm inclusive, 360-380 nm inclusive, 360- 370 nm inclusive, 370-405 nm inclusive, 380-405 nm inclusive, 390-405 nm inclusive, 400- 405 nm inclusive, 360 nm inclusive, 370 nm inclusive, 380 nm inclusive, 390 nm inclusive, 400 nm inclusive, 405 nm inclusive, or the like).
- the cross-linking agent is PEGDA.
- the cross-linking agent can be any multi-arm PEG acrylate or methacrylate (i.e., 3 or 4 or 8 arm PEG acrylate or methacrylate).
- time available for completion of polymerization and cross-linking is between 5 and 30 minutes, inclusive.
- the weight ratio of collagen: PEGDA in the composition is about 4:1.
- the weight ratio of PEGDA/MPC ranges from 1:3 to about 1:1, inclusive, i.e., at least 1:3, at least 1:2, or at least 1:1.
- weight ratio of collagen: PEGDA in the composition when the weight ratio of collagen: PEGDA in the composition is about 4:1 and weight ratio of PEGDA/MPC ranges from 1:3 to about 1:1 (i.e.., 1:3, 1:2, or 1:1); water content of the IPN ranges from 90% to about 96% inclusive; [00250] In some embodiments, the weight ratio of collagen:PEGDA ranges from about 1:3 to about 1:10, inclusive; i.e., at least 1:3, at least 1:4, at least 1:5, at least 1:6, at least 1:7, at least 1:8, at least 1:9 or at least 1:10.
- weight ratio of PEGDA/MPC ranges from about , e.g., 1:0.5-0.5:1, 1:0.6-0.5:1, 1:0.7-0.5:1, 1:0.8-0.5:1, 1:0.9-0.5:1, 1:1- 0.5:1, 1:0.5-0.6-:, 1:0.5-0.7:1, 1:0.5-0.8:1, 1:0.5-0.9:1, 1:0.5-1:1, or the like.
- the hydrogel composition of the present disclosure includes a combinations of elements that assist with achieving the discussed biocompatibility and improved handling.
- the percentage by weight of the collagen within the hydrogel composition can be about, e.g., 1%-5%, inclusive 1-4% inclusive, 1-3% inclusive, 1-2%, inclusive 2-5% inclusive, 3-5%, inclusive 4-5% inclusive, 2-4% inclusive, 3-4% inclusive, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9, 2%, 2.1%, 2.2%, 2.3%, 2.4% 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9% , 4%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5%, or the like.
- the percentage by weight of the synthetic polymer within the hydrogel composition can be about, e.g., 1.5-7.2%, inclusive, 1.5-7% inclusive, 1.5-6% inclusive, 1.5- 5% inclusive, 1.5-4% inclusive, 1.5-3% inclusive, 1.5-2% inclusive, 2-7.2% inclusive, 3- 7.2% inclusive, 4-7.2% inclusive, 5-7.2% inclusive, 6-7.2% inclusive, 7-7.2% inclusive, 1.5- 7%, inclusive 2-7% inclusive, 3-7% inclusive, 4-7% inclusive, 5-7% inclusive, 6-7% inclusive, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4% 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9% 4%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.7%, 5.5%
- the collagen can be a porcine atelocollagen, type 1, obtained from Nippi Collagen of North America Inc. However, it should be understood that any similar collagen can be used.
- Polymers used to prepare the described hydrogel composition can be any biocompatible polymer or polymer combination that achieves the desired properties, i.e., moldability, optical transparency, biocompatibility, hydrophilicity, permeability and refractiveness .
- 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
- the water-soluble, biocompatible polymer poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) is a zwitterionic polymer that is able to form a more compact conformation in aqueous solution than poly(ethylene glycol) (PEG).
- non-degradable biocompatible polymers include, without limitation, polysiloxane, polyvinyl alcohol, polyimide a polyacrylate; a polymer of ethylene- vinyl acetate, EVA; cellulose acetate; an acyl-substituted cellulose acetate; a non-degradable polyurethane; a polystyrene; a polyvinyl chloride; a polyvinyl fluoride; a poly(vinyl imidazole); a silicone-based polymer (for example, Silastic® and the like), a chlorosulphonate polyolefin; a polyethylene oxide; polysiloxane, polyvinyl alcohol, and polyimide, or a blend or copolymer thereof.
- Exemplary copolymers may include, hydroxyethyl methacrylate and methyl methacrylate, and hydroxyethyl methacrylate copolymerized with polyvinyl pyrrolidone (PVP, to increase water retention) or ethylene glycol dimethacrylic acid (EGDM).
- PVP polyvinyl pyrrolidone
- EGDM ethylene glycol dimethacrylic acid
- Nexofilcon A (Bausch & Lomb) is a hydrophilic copolymer of 2-hydroxyethyl methacrylate and N-vinyl pyrrolidone.
- Exemplary block polymers comprising blocks of hydrophilic biocompatible polymers or biopolymers or biodegradable polymers may include polyethers, including polyethylene glycol, PEG; polyethylene oxide, PEO; polypropylene oxide, PPO, perfluoropolyethers (PFPEs) and block copolymers comprised of combinations thereof.
- the hydrophilic polymer comprises a hydrogel polymer.
- Hydrogels generally comprise a variety of polymers.
- Exemplary polymers include acrylic acid, acrylamide and 2-hydroxyethylmethacrylate (HEMA).
- HEMA 2-hydroxyethylmethacrylate
- cross- linked poly (acrylic acid) of high molecular weight is commercially available as Carbopol® (B.F.
- Polyethylene glycol diacrylate (PEGDA 400) is a long-chain, hydrophilic, crosslinking monomer.
- Polyoxamers commercially available as Pluronic® (BASF-Wyandotte, USA), are thermal setting polymers formed by a central hydrophobic part (polyoxypropylene) surrounded by a hydrophilic part (ethylene oxide).
- Cellulosic derivatives most commonly used in ophthalmology include: methylcellulose; hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC) and sodium carboxymethylcellulose (CMC Na).
- Photocrosslinked poly(ethylene glycol) diacrylate (PEGDA) hydrogels displaying collagen mimetic peptides (CMPs) that can be further conjugated to bioactive molecules via CMP- CMP triple helix association are described in Stahl, PJ et al. Soft Matter (2012) 8: 10409- 10418.
- a first polymer and a second polymer comprise one or more different non-repeating units, such as, for example, an end group, or a non-repeating unit in the backbone of the polymer.
- the first polymer and the second polymer comprise one or more different end groups.
- the first polymer can have a more polar end group than one or more end group(s) of the second polymer.
- the first polymer will be more hydrophilic, relative to a second polymer (with the less polar end group) alone.
- the first polymer comprises one or more carboxylic acid end groups
- the second polymer comprises one or more ester end groups.
- the hydrogel composition material comprises a polymer matrix.
- the polymer matrix does not necessarily, but can, comprise cross-linked or intertwined polymer chains.
- portions of the polymer matrix can comprise only one of the first and second synthetic polymer.
- the hydrogel composition inlay materials comprises an ultraviolet blocker that is added to the hydrogel composition.
- the hydrogel composition may comprise a dye (e.g., for easy handling of medical device formed from hydrogel composition) added to the hydrogel composition before fabrication of the medical device.
- the dye can be a UV dye added to the hydrogel composition to allow for visibility of the device during illumination with UV light.
- the present disclosure relates to a hydrogel composition of a water content ranging from 78-92%, inclusive that can be used for fabrication of a variety of implantable medical devices.
- the implantable medical devices include a corneal inlay or a corneal onlay.
- properties of the implantable corneal device fabricated from the hydrogel composition can be similar to those of the cornea.
- the implantable medical device may be made of a material with a higher index of refraction than the cornea, e.g., >1.376.
- alternative medical devices could be fabricated from the hydrogel composition while providing the same or substantially similar benefits discussed herein.
- FIG. 5 is a diagram showing an example of a corneal inlay 10 of the present disclosure.
- the corneal inlay 10 includes a thickness 12 and a diameter 14.
- the corneal inlay 10 can have a dome or meniscus shape, including a flat or flat-like base and a dome or more or less spherical, convex shaped top.
- the corneal inlay 10 is biocompatible with the eye.
- the corneal inlay 10 can define a diameter 14 dimensioned smaller than the diameter of the pupil and is capable of correcting presbyopia while reducing or eliminating the risk of a patient developing corneal haze.
- the corneal inlay 10 can be 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, wherein 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. Because the corneal inlay 10 is smaller than the diameter of the pupil, light rays from distant objects bypass the inlay and refract through the region of the cornea peripheral to the “effect” zone to create an image of distant objects on the retina.
- FIG.6 is a diagram showing the corneal inlay 10 implanted in a cornea 20.
- the corneal inlay 10 can have a substantially dome shape with an anterior surface 22 and a posterior surface 24.
- the corneal inlay 10 can be implanted in the cornea at a depth of about 50% or less of the cornea (approximately 250 ⁇ m or less), and is placed on the stromal bed 26 of the cornea 20 created by a microkeratome or any other suitable surgical instrument.
- the corneal inlay 10 can be implanted in the cornea 20 by cutting a flap 28 into the cornea 20, lifting the flap 28 to expose an interior of the cornea 20, placing the corneal inlay 10 on the exposed area of the interior, and repositioning the flap 28 over the corneal inlay 10.
- the flap 28 can be cut using a laser (e.g., a femtosecond laser, a mechanical keratome, etc.) or manually by an ophthalmic surgeon.
- a laser e.g., a femtosecond laser, a mechanical keratome, etc.
- the cornea 20 heals around the flap 28 and seals the flap 28 back to the uncut peripheral portion of the anterior corneal surface.
- a pocket or well having side walls or barrier structures may be cut into the cornea 20, and the corneal inlay 10 inserted between the side walls or barrier structures through a small opening or “port” in the cornea 20.
- the corneal inlay 10 changes the refractive power of the cornea by altering the shape of the anterior corneal surface.
- the pre-operative anterior corneal surface is represented by dashed line 30 and the post-operative anterior corneal surface induced by the underlying corneal inlay 10 is represented by solid line 32.
- 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. In some embodiments, the inlay 10 is positioned at depth of 100 microns.
- the inlay 10 is positioned at depth of 101 microns. In some embodiments, the inlay 10 is positioned at depth of 102 microns. In some embodiments, the inlay 10 is positioned at depth of 103 microns. In some embodiments, the inlay 10 is positioned at depth of 104 microns. In some embodiments, the inlay 10 is positioned at depth of 105 microns. In some embodiments, the inlay 10 is positioned at depth of 106 microns. In some embodiments, the inlay 10 is positioned at depth of 107 microns. In some embodiments, the inlay 10 is positioned at depth of 108 microns. In some embodiments, the inlay 10 is positioned at depth of 109 microns.
- the inlay 10 is positioned at depth of 110 microns. In some embodiments, the inlay 10 is positioned at depth of 111 microns. In some embodiments, the inlay 10 is positioned at depth of 112 microns. In some embodiments, the inlay 10 is positioned at depth of 113 microns. In some embodiments, the inlay 10 is positioned at depth of 114 microns. In some embodiments, the inlay 10 is positioned at depth of 115 microns. In some embodiments, the inlay 10 is positioned at depth of 116 microns. In some embodiments, the inlay 10 is positioned at depth of 117 microns. In some embodiments, the inlay 10 is positioned at depth of 118 microns.
- the inlay 10 is positioned at depth of 119 microns. In some embodiments, the inlay 10 is positioned at depth of 120 microns. In some embodiments, the inlay 10 is positioned at depth of 121 microns. In some embodiments, the inlay 10 is positioned at depth of 122 microns. In some embodiments, the inlay 10 is positioned at depth of 123 microns. In some embodiments, the inlay 10 is positioned at depth of 124 microns. In some embodiments, the inlay 10 is positioned at depth of 125 microns. In some embodiments, the inlay 10 is positioned at depth of 126 microns. In some embodiments, the inlay 10 is positioned at depth of 127 microns.
- the inlay 10 is positioned at depth of 128 microns. In some embodiments, the inlay 10 is positioned at depth of 129 microns. In some embodiments, the inlay 10 is positioned at depth of 130 microns. In some embodiments, the inlay 10 is positioned at depth of 131 microns. In some embodiments, the inlay 10 is positioned at depth of 132 microns. In some embodiments, the inlay 10 is positioned at depth of 133 microns. In some embodiments, the inlay 10 is positioned at depth of 134 microns. In some embodiments, the inlay 10 is positioned at depth of 135 microns. In some embodiments, the inlay 10 is positioned at depth of 136 microns.
- the inlay 10 is positioned at depth of 137 microns. In some embodiments, the inlay 10 is positioned at depth of 138 microns. In some embodiments, the inlay 10 is positioned at depth of 139 microns. In some embodiments, the inlay 10 is positioned at depth of 140 microns. In some embodiments, the inlay 10 is positioned at depth of 141 microns. In some embodiments, the inlay 10 is positioned at depth of 142 microns. In some embodiments, the inlay 10 is positioned at depth of 143 microns. In some embodiments, the inlay 10 is positioned at depth of 144 microns. In some embodiments, the inlay 10 is positioned at depth of 145 microns.
- the inlay 10 is positioned at depth of 146 microns. In some embodiments, the inlay 10 is positioned at depth of 147 microns. In some embodiments, the inlay 10 is positioned at depth of 148 microns. In some embodiments, the inlay 10 is positioned at depth of 149 microns. In some embodiments, the inlay 10 is positioned at depth of 150 microns. In some embodiments, the inlay 10 is positioned at depth of 151 microns. In some embodiments, the inlay 10 is positioned at depth of 152 microns. In some embodiments, the inlay 10 is positioned at depth of 153 microns. In some embodiments, the inlay 10 is positioned at depth of 154 microns.
- the inlay 10 is positioned at depth of 155 microns. In some embodiments, the inlay 10 is positioned at depth of 156 microns. In some embodiments, the inlay 10 is positioned at depth of 157 microns. In some embodiments, the inlay 10 is positioned at depth of 158 microns. In some embodiments, the inlay 10 is positioned at depth of 159 microns. In some embodiments, the inlay 10 is positioned at depth of 160 microns. In some embodiments, the inlay 10 is positioned at depth of 161 microns. In some embodiments, the inlay 10 is positioned at depth of 162 microns. In some embodiments, the inlay 10 is positioned at depth of 163 microns.
- the inlay 10 is positioned at depth of 164 microns. In some embodiments, the inlay 10 is positioned at depth of 165 microns. In some embodiments, the inlay 10 is positioned at depth of 166 microns. In some embodiments, the inlay 10 is positioned at depth of 167 microns. In some embodiments, the inlay 10 is positioned at depth of 168 microns. In some embodiments, the inlay 10 is positioned at depth of 169 microns. In some embodiments, the inlay 10 is positioned at depth of 170 microns. In some embodiments, the inlay 10 is positioned at depth of 171 microns. In some embodiments, the inlay 10 is positioned at depth of 172 microns.
- the inlay 10 is positioned at depth of 173 microns. In some embodiments, the inlay 10 is positioned at depth of 174 microns. In some embodiments, the inlay 10 is positioned at depth of 175 microns. In some embodiments, the inlay 10 is positioned at depth of 176 microns. In some embodiments, the inlay 10 is positioned at depth of 177 microns. In some embodiments, the inlay 10 is positioned at depth of 178 microns. In some embodiments, the inlay 10 is positioned at depth of 179 microns. In some embodiments, the inlay 10 is positioned at depth of 180 microns. In some embodiments, the inlay 10 is positioned at depth of 181 microns.
- the inlay 10 is positioned at depth of 182 microns. In some embodiments, the inlay 10 is positioned at depth of 183 microns. In some embodiments, the inlay 10 is positioned at depth of 184 microns. In some embodiments, the inlay 10 is positioned at depth of 185 microns. In some embodiments, the inlay 10 is positioned at depth of 186 microns. In some embodiments, the inlay 10 is positioned at depth of 187 microns. In some embodiments, the inlay 10 is positioned at depth of 188 microns. In some embodiments, the inlay 10 is positioned at depth of 189 microns. In some embodiments, the inlay 10 is positioned at depth of 190 microns.
- the inlay 10 is positioned at depth of 191 microns. In some embodiments, the inlay 10 is positioned at depth of 192 microns. In some embodiments, the inlay 10 is positioned at depth of 193 microns. In some embodiments, the inlay 10 is positioned at depth of 194 microns. In some embodiments, the inlay 10 is positioned at depth of 195 microns. In some embodiments, the inlay 10 is positioned at depth of 196 microns. In some embodiments, the inlay 10 is positioned at depth of 197 microns. In some embodiments, the inlay 10 is positioned at depth of 198 microns. In some embodiments, the inlay 10 is positioned at depth of 199 microns.
- the inlay 10 is positioned at depth of 200 microns. In 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.
- 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. In some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.05 MPa.
- the elastic modulus of the corneal inlay 10 can be at least 0.06 MPa. In some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.07 MPa. In some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.08 MPa. In some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.09 MPa. In some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.10 MPa. In some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.11 MPa. In some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.12 MPa.
- the elastic modulus of the corneal inlay 10 can be at least 0.13 MPa. In some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.14 MPa. In some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.15 MPa. In some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.16 MPa. In some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.17 MPa. In some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.18 MPa. In some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.19 MPa.
- the elastic modulus of the corneal inlay 10 can be at least 0.20 MPa. In some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.21 MPa. In some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.22 MPa. In some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.23 MPa. In some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.24 MPa. In some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.25 MPa. In some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.26 MPa.
- the elastic modulus of the corneal inlay 10 can be at least 0.27 MPa. In some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.28 MPa. In some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.29 MPa. In some embodiments, the elastic modulus of the corneal inlay 10 can be at least 0.30 MPa.
- “Elongation at break”, also called “fracture strain” or “tensile elongation at break” is the percentage increase in length that a material will achieve before breaking. It is a measurement that shows how much a material can be stretched — as a percentage of its original dimensions — before it breaks.
- the elongation at break of the corneal inlay 10 may be 58.30% with a tolerance of ⁇ 4.49%. However, in some embodiments, the elongation at break of the corneal inlay 10 may exceed the tolerance. In some embodiments, the elongation at break of the corneal inlay 10 may be at least 48%. In some embodiments, the elongation at break of the corneal inlay 10 may be at least 49%.
- the elongation at break of the corneal inlay 10 may be at least 50%. In some embodiments, the elongation at break of the corneal inlay 10 may be at least 21%. In some embodiments, the elongation at break of the corneal inlay 10 may be at least 52%. In some embodiments, the elongation at break of the corneal inlay 10 may be at least 53%. In some embodiments, the elongation at break of the corneal inlay 10 may be at least 54%. In some embodiments, the elongation at break of the corneal inlay 10 may be at least 55%. In some embodiments, the elongation at break of the corneal inlay 10 may be at least 56%.
- the elongation at break of the corneal inlay 10 may be at least 57%. In some embodiments, the elongation at break of the corneal inlay 10 may be at least 58%. In some embodiments, the elongation at break of the corneal inlay 10 may be at least 59%. In some embodiments, the elongation at break of the corneal inlay 10 may be at least 60%. In some embodiments, the elongation at break of the corneal inlay 10 may be at least 61%. In some embodiments, the elongation at break of the corneal inlay 10 may be at least 62%. In some embodiments, the elongation at break of the corneal inlay 10 may be at least 63%.
- the elongation at break of the corneal inlay 10 may be at least 64%. In some embodiments, the elongation at break of the corneal inlay 10 may be at least 65%. In some embodiments, the elongation at break of the corneal inlay 10 may be at least 66%. In some embodiments, the elongation at break of the corneal inlay 10 may be at least 67%. In some embodiments, the elongation at break of the corneal inlay 10 may be at least 68%. In some embodiments, the elongation at break of the corneal inlay 10 may be at least 69%. In some embodiments, the elongation at break of the corneal inlay 10 may be at least 70%.
- the tensile strength (meaning the resistance of a material to breaking under tension) of the corneal inlay 10 may be 0.07 MPa with a tolerance of ⁇ 0.02 MPa. In some embodiments, the tensile strength of the corneal inlay may exceed the tolerance. In some embodiments, the tensile strength of the corneal inlay 10 may be at least 0.01 MPa. In some embodiments, the tensile strength of the corneal inlay 10 may be at least 0.02 MPa. In some embodiments, the tensile strength of the corneal inlay 10 may be at least 0.03 MPa. In some embodiments, the tensile strength of the corneal inlay 10 may be at least 0.04 MPa.
- the tensile strength of the corneal inlay 10 may be at least 0.05 MPa. In some embodiments, the tensile strength of the corneal inlay 10 may be at least 0.06 MPa. In some embodiments, the tensile strength of the corneal inlay 10 may be at least 0.07 MPa. In some embodiments, the tensile strength of the corneal inlay 10 may be at least 0.08 MPa. In some embodiments, the tensile strength of the corneal inlay 10 may be at least 0.09 MPa. In some embodiments, the tensile strength of the corneal inlay 10 may be at least 0.10 MPa. In some embodiments, the tensile strength of the corneal inlay 10 may be at least 0.11 MPa.
- the tensile strength of the corneal inlay 10 may be at least 0.12 MPa. In some embodiments, the tensile strength of the corneal inlay 10 may be at least 0.13 MPa. In some embodiments, the tensile strength of the corneal inlay 10 may be at least 0.14 MPa. In some embodiments, the tensile strength of the corneal inlay 10 may be at least 0.15 MPa. [00271] In some embodiments, the backscatter (meaning deflection of radiation or particles through an angle of 180°) of the corneal inlay 10 may be 0.90% with a tolerance of ⁇ 0.17%. However, in some embodiments, the backscatter of the corneal inlay 10 may exceed the tolerance.
- the backscatter of the corneal inlay 10 may be at least 0.65%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.66%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.67%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.68%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.69%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.70%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.71%.
- the backscatter of the corneal inlay 10 may be at least 0.72%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.73%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.74%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.75%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.76%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.77%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.78%.
- the backscatter of the corneal inlay 10 may be at least 0.79%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.80%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.81%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.82%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.83%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.84%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.85%.
- the backscatter of the corneal inlay 10 may be at least 0.86%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.87%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.88%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.89%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.90%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.91%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.92%.
- the backscatter of the corneal inlay 10 may be at least 0.93%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.94%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.95%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.96%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.97%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.98%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 0.99%.
- the backscatter of the corneal inlay 10 may be at least 1.00%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 1.01%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 1.02%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 1.03%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 1.04%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 1.05%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 1.06%.
- the backscatter of the corneal inlay 10 may be at least 1.07%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 1.08%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 1.09%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 1.10%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 1.11%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 1.12%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 1.13%.
- the backscatter of the corneal inlay 10 may be at least 1.14%. In some embodiments, the backscatter of the corneal inlay 10 may be at least 1.15%.
- 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. In some embodiments, the light transmission of the corneal inlay 10 can be at least 85.0%. In some embodiments, the light transmission of the corneal inlay 10 can be at least 86.0%. In some embodiments, the light transmission of the corneal inlay 10 can be at least 87.0%.
- the light transmission of the corneal inlay 10 can be at least 88.0%. In some embodiments, the light transmission of the corneal inlay 10 can be at least 89.0%. In some embodiments, the light transmission of the corneal inlay 10 can be at least 90.0%. In some embodiments, the light transmission of the corneal inlay 10 can be at least 91.0%. In some embodiments, the light transmission of the corneal inlay 10 can be at least 92.0%. In some embodiments, the light transmission of the corneal inlay 10 can be at least 93.0%. In some embodiments, the light transmission of the corneal inlay 10 can be at least 94.0%. In some embodiments, the light transmission of the corneal inlay 10 can be at least 95.0%.
- the light transmission of the corneal inlay 10 can be at least 96.0%. In some embodiments, the light transmission of the corneal inlay 10 can be at least 97.0%. In some embodiments, the light transmission of the corneal inlay 10 can be at least 98.0%. In some embodiments, the light transmission of the corneal inlay 10 can be at least 99.0%. In some embodiments, the light transmission of the corneal inlay 10 can be 100.0%. [00273] In some embodiments, the morphology (meaning form) of the corneal inlay 10 can be that of a fibrillary network with nano-pores. In some embodiments, the nano-pores of the corneal inlay 10 can have a diameter of at least 0.1 ⁇ m.
- the nano-pores of the corneal inlay 10 can have a diameter of at least 0.2 ⁇ m. In some embodiments, the nano-pores of the corneal inlay 10 can have a diameter of at least 0.3 ⁇ m. In some embodiments, the nano-pores of the corneal inlay 10 can have a diameter of at least 0.4 ⁇ m. In some embodiments, the nano-pores of the corneal inlay 10 can have a diameter of at least 0.5 ⁇ m. In some embodiments, the nano-pores of the corneal inlay 10 can have a diameter of at least 0.6 ⁇ m. In some embodiments, the nano-pores of the corneal inlay 10 can have a diameter of at least 0.7 ⁇ m.
- the nano-pores of the corneal inlay 10 can have a diameter of at least 0.8 ⁇ m. In some embodiments, the nano-pores of the corneal inlay 10 can have a diameter of at least 0.9 ⁇ m. In some embodiments, the nano- pores of the corneal inlay 10 can have a diameter of at least 1.0 ⁇ m. In some embodiments, the nano-pores can have a diameter of approximately 0.4 ⁇ m.
- the storage temperature for the corneal inlay 10 may range from about 2° – 8° Celsius, i.e., about 2°C, 2.5°C, 3°C, 3.5°C, 4°C, 4.5°C, 5°C, 5.5°C, 6°C, 6.5°C, 7°C, 7.5°C, 8°C.
- Presbyopic Inlays [00274]
- the diameter of the corneal inlay 10 is small in comparison with the diameter of the pupil for correcting presbyopia.
- a corneal inlay 10 (e.g., 1 mm to 3 mm in diameter, 1.8 mm in diameter, or the like) is implanted substantially 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.
- 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.
- FIG.7 shows an example of how a corneal inlay 10 can provide near vision to a subject's eye while retaining some distance vision according to an embodiment of the invention.
- the eye 40 comprises a cornea 42, a pupil 44, a crystalline lens 46 and a retina 48.
- the corneal inlay 10 (not shown) is implanted substantially centrally in the cornea 42 to create a small diameter “effect” zone 50.
- the corneal inlay 10 has a smaller diameter than the pupil 44 so that the resulting “effect” zone 50 has a smaller diameter than the optical zone of the cornea 42.
- the “effect” zone 50 provides near vision by increasing the curvature of the anterior corneal surface, and therefore the diopter power within the “effect” zone 50.
- the region 52 of the cornea peripheral to the “effect” zone provides distance vision.
- the 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 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.
- presbyopia e.g., about 45 to 55 years of age
- at least 1 diopter is typically required for near vision.
- complete presbyopia e.g., about 60 years of age or older
- between 2 and 3 diopters of additional power are required.
- 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). [00279] 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 FIG.7. This is particularly true with larger pupils.
- 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.
- LASIK Laser in Situ Keratomileusis
- LASEK Laser Epithelial Keratomileusis
- PRK Photorefractive Keratectomy
- FIG. 8 is a plot of anterior corneal surface height (in microns) (y axis) vs. radius from center of inlay (mm) (x-axis). The graph shows the change in anterior corneal surface height (in microns) and the corresponding induced added power (e.g., diopters).
- FIG. 8 is a plot of anterior corneal surface height (in microns) (y axis) vs. radius from center of inlay (mm) (x-axis). The graph shows the change in anterior corneal surface height (in microns) and the corresponding induced added power (e.g., diopters).
- FIG. 9 is a diagram showing a preoperative optical coherence tomography (“OCT”) and a postoperative OCT.
- OCT optical coherence tomography
- postoperative OCT an example location 70 for the corneal inlay 10 is shown.
- Fabrication [00282] The flowability of the hydrogel composition of the present disclosure allows for a variety of potential methods for fabricating medical devices.
- molding can be used to fabricate the hydrogel inlays discussed herein using the hydrogel composition. Due to the softness and presence of water in the pre-mix, molding is used to fabricate the inlay (instead of lathing or machining the inlay into a final shape).
- water content compositions ranging from greater than 94- 98%, inclusive (defined as high water content compositions) and water content compositions ranging from 78%-92%, inclusive (defined as low water content compositions), were used to mold hydrogel inlays for testing.
- un-crosslinked hydrogel composition was cast in a cavity mold assembly made from, e.g., Poly(methyl methacrylate) (PMMA), or the like.
- FIGS.10-24 show perspective, cross-sectional and detailed views of components of an exemplary mold assembly 100 for fabricating or forming the hydrogel inlays discussed herein. [00283] With respect to FIGS.
- the mold assembly 100 generally includes a first mold section 102 (e.g., a male mold section) and a second mold section 104 (e.g., a female mold section).
- the mold assembly 100 can be fabricated for single-use purposes.
- the material of fabrication of the mold assembly 100 can be transparent to UV light, allowing for cross-linking of the hydrogel composition within the mold assembly 100.
- the mold sections 102, 104 are configured to fit complementary to each other to form a cavity 106 therebetween.
- the cavity 106 is in the form of the inlay to be fabricated.
- each of the mold sections 102, 104 includes one or more radial complementary channels that can assist with escape of air during molding. [00284] As illustrated in FIGS.
- the first mold section 102 includes a hemispherical cavity 108 formed in the mating surface, while the second mold section 104 includes a flat cavity 110 formed in the mating surface.
- the cavities 108, 110 align to define the overall shape or form of the hydrogel inlay. Both cavities 108, 110 define a substantially circular shape.
- the diameter of the hemispherical cavity 108 can be about, e.g., 1.8-2.2 mm, inclusive, 1.8-2.1 mm inclusive, 1.8-2.0 mm inclusive, 1.8-1.9 mm inclusive, 1.9-2.2 mm inclusive, 2.0-2.2 mm inclusive, 2.1- 2.2 mm inclusive, 1.8 mm, 1.9 mm, 2.0 mm, 2.1 mm, 2.2 mm, or the like.
- the radius of the hemispherical cavity 108 can be about, e.g., 16.213 mm.
- the diameter of the flat cavity 110 can be about, e.g., 1.8-2.2 mm inclusive, 1.8-2.1 mm inclusive, 1.8-2.0 mm inclusive, 1.8-1.9 mm inclusive, 1.9-2.2 mm inclusive, 2.0-2.2 mm inclusive, 2.1-2.2 mm inclusive, 1.8 mm, 1.9 mm, 2.0 mm, 2.1 mm, 2.2 mm, or the like.
- the depth of the flat cavity 110 can be about, e.g., 0.015 mm.
- the center thickness of the entire cavity can be about, e.g., 40-60 nm inclusive, 40-55 nm inclusive, 40-50 nm inclusive, 40-45 nm inclusive, 45-60 nm inclusive, 50-60 nm inclusive, 55-60 nm inclusive, 45-55 nm inclusive, 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, or the like.
- FIGS. 15-19 are perspective, top, side, cross-sectional and detailed views of the first mold section 102.
- the mold section 102 includes a body 112 defining a substantially cylindrical configuration.
- the body 112 includes a bottom surface 114 and an opposing top surface defining the substantially planar mating surface 116.
- the mold section 102 includes a radial flange 118 extending near the outer perimeter of the body 112 from the top surface, and positioned slightly inwardly offset from the outer perimeter or edge of the body 112.
- the mold section 102 includes a first radial channel 120 inwardly formed in the top surface adjacent to the radial flange 118.
- the mold section 102 includes a second radial channel 122 inwardly formed in the top surface.
- the second radial channel 122 defines a smaller diameter than the first radial channel 120, and is therefore disposed closer to the central longitudinal axis of the mold section 102. As illustrated in FIG.18, the inner walls of the channels 120, 122 taper inwardly.
- FIGS. 20-24 are perspective, top, side, cross-sectional and detailed views of the second mold section 104.
- the mold section 104 includes a body 126 defining a substantially cylindrical configuration complementary to the body 112 of the mold section 102.
- the body 126 includes a bottom surface 128 and an opposing top surface defining the substantially planar mating surface 130.
- the mold section 104 includes a radial edge 132 extending at or near the perimeter of the body 126 from the top surface.
- the mold section 104 includes a first radial channel 134 inwardly formed in the top surface adjacent to the radial edge 132.
- the mold section 104 includes a second radial channel 136 inwardly formed in the top surface.
- the second radial channel 136 defines a smaller diameter than the first radial channel 134, and is therefore disposed closer to the central longitudinal axis of the mold section 104.
- the diameters and edges of the radial channels 134, 136 are dimensioned substantially complementary to the diameters and edges of the respective radial channels 120, 122 of the mold section 102. As illustrated in FIG. 23, the inner walls of the channels 134, 136 taper inwardly.
- the flat cavity 110 is formed in the top surface of the body 126 and is substantially aligned with a central longitudinal axis of the mold section 104.
- a perimeter section 138 surrounds the cavity 110 and forms part of the mating surface 130.
- the mold section 104 includes a transverse channel, cutout or slit extending through the radial flange 132 and the raised section of the body 126 between the channels 134, 136.
- the transverse channel includes channels 140, 142 that extend through the radial flange 132 on opposing sides of the body 126, and channels 144, 146 that extend through the raised section of the body 126 between the channels 134, 136.
- the bottom of the channels 140-146 is substantially aligned with the bottom surface of the channels 134, 136.
- the channels 140- 146 provide a fluidic connection between the channels 134, 136 (and also channels 120, 122 of the mold section 102 when both mold sections 102, 104 are mated to each other).
- the uncrosslinked hydrogel composition can be placed within the cavity 110 of the mold section 104, and the mold section 102 can be aligned with and positioned over the mold section 104 such that the mating surfaces 116, 130 are positioned against each other. As illustrated in FIGS.
- the radial flange 118 of the mold section 102 is configured and dimensioned to fit within the radial edge 132 of the mold section 104, and against the outer wall of the channel 134 of the mold section 104, to ensure alignment and mating of the mold sections 102, 104 relative to each other.
- the cavities 108, 110 are enclosed by the mating surfaces to ensure proper distribution of the hydrogel during formation of the inlay.
- the channels 120, 122, 134, 136 are aligned to allow for escape of air and/or gas from the mold assembly 100.
- a clamp can be used to secure the mold sections 102, 104 to each other prior to crosslinking, as long as the clamp does not obstruct UV light from reaching the hydrogel in the mold cavity.
- the inlay is alloyed to further crosslink at ambient conditions before the inlay is demolded, further processed and characterized.
- FIGS. 25-28 are front, side and cross-sectional views of an exemplary hydrogel inlay 200 fabricated using the mold assembly 100.
- the inlay 200 can define a substantially circular shape of a diameter of about, e.g., 1.8-2.2 mm inclusive, 1.8-2.1 mm inclusive, 1.8-2.0 mm inclusive, 1.8-1.9 mm inclusive, 1.9-2.2 mm inclusive, 2.0-2.2 mm inclusive, 2.1-2.2 mm inclusive, 1.8 mm, 1.9 mm, 2.0 mm, 2.1 mm, 2.2 mm, or the like.
- the inlay 200 can define an edge thickness of about, e.g., 0.015-0.025 mm inclusive, 0.015-0.02 mm inclusive, 0.02-0.025 mm inclusive, 0.015 mm, 0.02 mm, 0.025 mm, or the like.
- the inlay 200 can define a center thickness of about, e.g., 0.04-0.06 mm inclusive, 0.05-0.06 mm inclusive, 0.04-0.05 mm inclusive, 0.04 mm, 0.05 mm, 0.06 mm, or the like.
- the inlay 200 includes a substantially flat perimeter edge 202, a convex top surface 204, and a substantially flat bottom surface 206.
- the body of the inlay 200 is solidly formed from the hydrogel (e.g., no openings or hollow cavities), with the inlay 200 tapering from the thickest area at the central longitudinal axis to the thinnest area at the perimeter edge 202.
- the cavities 108, 110 of the mold assembly 100 can be adjusted to form a hydrogel meniscus inlay 210 shown in FIGS.29-31.
- the inlay 210 can include a substantially circular shape having a diameter of about, e.g., 1.8-2.2 mm inclusive, 1.8-2.1 mm, 1.8-2.0 mm inclusive, 1.8-1.9 mm inclusive, 1.9-2.2 mm inclusive, 2.0-2.2 mm inclusive, 2.1-2.2 mm inclusive, 1.8 mm, 1.9 mm, 2.0 mm, 2.1 mm, 2.2 mm, or the like.
- the inlay 210 can have an edge thickness of about, e.g., 0.018-0.025 mm inclusive, 0.018-0.024 mm inclusive, 0.018-0.023 mm inclusive, 0.018-0.022 mm inclusive, 0.018-0.021 mm inclusive, 0.018-0.02 mm inclusive, 0.018-0.019 mm inclusive, 0.019-0.025 mm inclusive, 0.02-0.025 mm inclusive, 0.021-0.025 mm inclusive, 0.022-0.025 mm inclusive, 0.023-0.025 mm inclusive, 0.024-0.025 mm inclusive, 0.018 mm, 0.019 mm, 0.02 mm, 0.021 mm, 0.022 mm, 0.023 mm, 0.024 mm, 0.025 mm, or the like.
- the inlay 210 can have a center thickness of about, e.g., 0.03-0.055 mm inclusive, 0.03-0.05 mm inclusive, 0.03-0.045 mm inclusive, 0.03-0.04 mm inclusive, 0.03-0.035 mm inclusive, 0.035-0.055 mm inclusive, 0.04-0.055 mm inclusive, 0.045-0.055 mm inclusive, 0.05-0.055 mm inclusive, 0.03 mm, 0.035 mm, 0.04 mm, 0.045 mm, 0.05 mm, 0.055 mm, or the like.
- the inlay 210 can have an outer radius of about 5.773 mm, and an inner radius of about 10 mm.
- the inlay 210 includes a substantially flat perimeter edge 212, a convex top surface 214, and a concave bottom surface 216. As illustrated in FIG.30, the body of the inlay 210 is solidly formed from the hydrogel, with the inlay 210 tapering from the thickest area at the central longitudinal axis to the thinnest area at the perimeter edge 212. [00291] In some embodiments, the inlay can define a substantially disc-shaped configuration.
- the disc-shaped inlay can define a diameter of about, e.g., 1.8-2.2 mm inclusive, 1.8-2.1 mm inclusive, 1.8-2.0 mm inclusive, 1.8-1.9 mm inclusive, 1.9-2.2 mm inclusive, 2.0-2.2 mm inclusive, 2.1-2.2 inclusive, 1.8 mm, 1.9 mm, 2.0 mm, 2.1 mm, 2.2 mm, or the like.
- the disc-shaped inlay can define a thickness of about, e.g., 20-50 ⁇ m inclusive, 20-45 ⁇ m inclusive, 20-40 ⁇ m inclusive, 20-35 ⁇ m inclusive, 20-30 ⁇ m inclusive, 20-25 ⁇ m inclusive, 25-50 ⁇ m inclusive, 30-50 ⁇ m inclusive, 35-50 ⁇ m inclusive, 40-50 ⁇ m inclusive, 45-50 ⁇ m inclusive, 20 ⁇ m, 25 ⁇ m, 30 ⁇ m, 35 ⁇ m, 40 ⁇ m, 45 ⁇ m, 50 ⁇ m, or the like.
- an approximately 10 mm diameter cavity mold can be used to fabricate the 10 mm disc.
- a 2 mm biopsy punch can be used to punch out the 2 mm x 40 ⁇ m disc-shaped inlay from the 10 mm disc.
- a similar process can be used to punch out a 15-20 mm diameter disc-shaped inlay.
- a laser beam can be used to create the disc and/or disc-shaped inlays.
- a disc 4 mm in diameter can be implanted into the cornea, and a femtosecond laser can be used to cut out an approximately 2 mm disc-shaped inlay. The peripheral material is subsequently removed from the cornea, leaving the approximately 2 mm disc-shaped inlay implanted in the cornea.
- the mold assembly 300 can be substantially similar in structure and/or function to the mold assembly 100, except for the distinctions noted herein.
- the mold assembly 300 generally includes a first mold section 302 (e.g., a male mold section) and a second mold section 304 (e.g., a female mold section).
- the mold assembly 300 can be fabricated for single-use purposes.
- the material of fabrication of the mold assembly 300 can be transparent to UV light, allowing for cross-linking of the hydrogel composition within the mold assembly 300.
- the mold sections 302, 304 are configured to fit complementary to each other to form a cavity 306 therebetween.
- the cavity 306 is in the form of the disc-shaped inlay to be fabricated.
- each of the mold sections 302, 304 includes one or more radial complementary channels that can assist with escape of air during molding.
- the first mold section 302 includes a flat cavity 308 formed in the mating surface
- the second mold section 304 includes a flat cavity 310 formed in the mating surface.
- the cavities 308, 310 align to define the overall shape or form of the hydrogel disc that can be used to punch out a disc-shaped inlay. Both cavities 308, 310 define a substantially circular shape.
- the diameter of the cavity 308 can be about, e.g., 14-24 mm inclusive, 14-23 mm inclusive, 14-22 mm inclusive, 14-21 mm inclusive, 14-20 mm inclusive, 14-19 mm inclusive, 14-18 mm inclusive, 14-17 mm inclusive, 14-16 mm inclusive, 14-15 mm inclusive, 15-24 mm inclusive, 16-24 mm inclusive, 17-24 mm inclusive, 18-24 mm inclusive, 19-24 mm inclusive, 20-24 mm inclusive, 21-24 mm inclusive, 22-24 mm inclusive, 23-24 mm inclusive, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, 16.67 mm, or the like.
- the depth of the cavity 308 can be about, e.g., 0.4-0.6 mm inclusive, 0.4-0.55 mm inclusive, 0.4-0.5 mm inclusive, 0.4-0.45 mm inclusive, 0.45-0.6 mm inclusive, 0.5-0.6 mm inclusive, 0.55-0.6 mm inclusive, 0.4 mm, 0.45 mm, 0.5 mm, 0.55 mm, 0.6 mm, or the like.
- the diameter of the cavity 310 can be about, e.g., 8-12 mm inclusive, 8-11.5 mm inclusive, 8- 11 mm inclusive, 8-10.5 mm inclusive, 8-10 mm inclusive, 8-9.5 mm inclusive, 8-9 mm inclusive, 8-8.5 mm inclusive, 8.5-12 mm inclusive, 9-12 mm inclusive, 9.5-12 mm inclusive, 10-12 mm inclusive, 10.5-12 mm inclusive, 11-12 mm inclusive, 11.5-12 mm inclusive, 8 mm, 8.5 mm, 9 mm, 9.5 mm, 10 mm, 10.5 mm, 11 mm, 11.5 mm, 12 mm, or the like.
- the depth of the cavity 310 can be about, e.g., 0.3-0.5 mm inclusive, 0.3- 0.45 mm inclusive, 0.3-0.4 mm inclusive, 0.3-0.35 mm inclusive, 0.35-0.5 mm inclusive, 0.4- 0.5 mm inclusive, 0.45-0.5 mm inclusive, 0.3 mm, 0.35 mm, 0.4 mm, 0.45 mm, 0.5 mm, or the like.
- FIGS. 57-61 are perspective, top, side, cross-sectional and detailed views of the first mold section 302.
- the mold section 302 includes a body 312 defining a substantially cylindrical configuration.
- the body 312 includes a bottom surface 314 and an opposing top surface defining the substantially planar mating surface 316.
- the mold section 302 includes a radial flange 318 extending near the outer perimeter of the body 312 from the top surface, and positioned slightly inwardly offset from the outer perimeter or edge of the body 312.
- FIGS. 62-66 are perspective, top, side, cross-sectional and detailed views of the second mold section 304.
- the mold section 304 includes a body 326 defining a substantially cylindrical configuration complementary to the body 312 of the mold section 302.
- the body 326 includes a bottom surface 328 and an opposing top surface defining the substantially planar mating surface 330.
- the mold section 304 includes a radial edge 332 extending at or near the perimeter of the body 226 from the top surface.
- the mold section 204 includes a first radial channel 234 inwardly formed in the top surface adjacent to the radial edge 332.
- the mold section 304 includes a second radial channel 336 inwardly formed in the top surface.
- the second radial channel 336 defines a smaller diameter than the first radial channel 334, and is therefore disposed closer to the central longitudinal axis of the mold section 304.
- the diameters and edges of the radial channels 334, 336 are dimensioned substantially complementary to the diameters and edges of the mold section 302. As illustrated in FIG.65, the inner walls of the channels 334, 336 taper inwardly.
- the flat cavity 310 is formed in the top surface of the body 326 and is substantially aligned with a central longitudinal axis of the mold section 304.
- a perimeter section 338 surrounds the cavity 310 and forms part of the mating surface 330.
- the mold section 304 includes a transverse channel, cutout or slit extending through the radial flange 332 and the raised section of the body 326 between the channels 334, 336.
- the transverse channel includes channels 340, 342 that extend through the radial flange 332 on opposing sides of the body 326, and channels 344, 346 that extend through the raised section of the body 326 between the channels 334, 336.
- the bottom of the channels 340-346 is substantially aligned with the bottom surface of the channels 134, 136.
- the channels 140- 146 provide a fluidic connection between the channels 334, 336.
- the uncrosslinked hydrogel composition can be placed within the cavity 310 of the mold section 304, and the mold section 302 can be aligned with and positioned over the mold section 304 such that the mating surfaces 316, 330 are positioned against each other.
- the radial flange 318 of the mold section 302 is configured and dimensioned to fit within the radial edge 332 of the mold section 304, and against the outer wall of the channel 334 of the mold section 304, to ensure alignment and mating of the mold sections 302, 304 relative to each other.
- the cavities 308, 310 are enclosed by the mating surfaces to ensure proper distribution of the hydrogel during formation of the disc for the inlay.
- the channels 134, 136 allow for escape of air and/or gas from the mold assembly 300.
- a clamp can be used to secure the mold sections 302, 304 to each other prior to crosslinking, as long as the clamp does not obstruct UV light from reaching the hydrogel in the mold cavity.
- the refractive index can range from about, e.g., 1.33-1.36 inclusive, 1.33-1.35 inclusive, 1.33-1.34 inclusive, 1.34-1.36 inclusive, 1.35-1.36 inclusive, 1.34-1.35 inclusive, 1.33, 1.34, 1.35, 1.36, or the like, when measured at about 23 ⁇ 1°C.
- Such exemplary inlay 200 has a percent transmittance ranging from about, e.g., 94-98% inclusive, 94-97% inclusive, 94-96% inclusive, 94-95% inclusive, 95-98% inclusive, 96-98% inclusive, 97-98% inclusive, 95-97% inclusive, 95-96% inclusive, 94%, 95%, 96%, 97%, 98%, or the like, at about 300 nm.
- the hydrogel can be injected into the mold and corneal inlays can then be polymerized by a method appropriate for the particular polymer(s) employed, e.g., chemically, by successive cross-linking of precursors using UV light, cross- linking agents, thermally, or by photopolymerization.
- the inlay can be removed from the mold (demolded), washed and stored in buffer with a preservative until use.
- the hydrogel composition can be formed by initially hydrating the natural polymer, e.g., a collagen, in an acidic medium.
- the dry collagen is mixed with a buffer at a pH of about 3.0, and sits at about 5 ⁇ 3°C for about 10 days (at a minimum 8 days).
- the cross-linker(s), monomer(s) and/or polymer(s), and UV initiator are added to the hydrated collagen.
- the cross-linker for the collagen ranges from about, e.g., 0.25-0.75% inclusive, 0.25-0.65% inclusive, 0.25-0.55% inclusive, 0.25-0.45% inclusive, 0.25-0.35% inclusive, 0.35-0.75% inclusive, 0.45-0.75% inclusive, 0.55-0.75% inclusive, 0.65-0.75% inclusive, 0.25%, 0.35%, 0.45%, 0.55%, 0.65%, 0.75%, or the like, by weight of the hydrogel composition.
- the monomer ranges from about, e.g., 1.2-4.8% inclusive, 1.2-4.0% inclusive, 1.2-3.5% inclusive, 1.2-3.0% inclusive, 1.2-2.5% inclusive, 1.2-2.0% inclusive, 1.2-1.5% inclusive, 1.5-4.8% inclusive, 2.0-4.8% inclusive, 2.5-4.8% inclusive, 3.0-4.8% inclusive, 3.5-4.8% inclusive, 4.0-4.8% inclusive, 4.5-4.8% inclusive, 1.2%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 4.8%, or the like, by weight of the hydrogel composition.
- the cross-linker for the synthetic polymer (after monomer polymerization)ranges from about, 0.2-0.6% inclusive, 0.2-0.5% inclusive, 0.2-0.4% inclusive, 0.2-0.3% inclusive, 0.3-0.6% inclusive, 0.4-0.6% inclusive, 0.5-0.6% inclusive, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, or the like.
- the hydrogel mixture is degassed and then added to the mold prior to cross-linking. UV light is used to crosslink the hydrogel composition for about 15-30 minutes.
- the inlay is then allowed to cross-link in ambient conditions for about 12-20 hours, resulting in complete polymerization of the composition.
- the UV wavelength intensity ranges from about, e.g., 360-405 nm inclusive, 360-400 nm inclusive, 360-390 nm inclusive, 360- 380 nm inclusive, 360-370 nm inclusive, 370-405 nm inclusive, 380-405 nm inclusive, 390- 405 nm inclusive, 400-405 nm inclusive, 360 nm, 370 nm, 380 nm, 390 nm, 400 nm, 405 nm, or the like.
- the crosslinked hydrogel can remain in a chamber overnight.
- the inlay is hydrated in 1x phosphate buffer then washed several times in phosphate buffer to extract unpolymerized material and residual crosslinker and/or UV initiator.
- a single cavity mold e.g., male and female molds
- 2-cavity molding e.g., multi cavity with two or more male and/or two or more female molds
- Such process can render a shape similar to the meniscus inlay 210 lens or dome shape discussed above (e.g., flat on one side, curved on the other side).
- cannula molding can be used to fabricate the medical device (e.g., inlay) from the hydrogel composition.
- One side of a lenticule can be molded against a surface, the other side can be molded in free air.
- the curved side is formed due to surface tension only, and is not in contact with a plastic surface as in 2-cavity molding. The result is a dome-shaped lenticule.
- surface energy molding can be used to fabricate the medical device (e.g., inlay) from the hydrogel composition. Based on the surface energy of a solid surface or substrate, the pre-mix can be dropped onto the surface and forms a shape.
- the shape is a dome geometry meaning flat on one side and curved on the other.
- the surface energy of the substrate and the volume of pre-mix determine the final geometry of the molded article.
- the corneal inlay is cast as a flat, thin, round disc.
- the fabricated inlay is cast as a hemispherical dome.
- the fabricated inlay is cast as a spherical lens.
- the fabricated inlay is cast as a thin sheet.
- the mold can be adjusted as needed depending on the configuration of the desired inlay.
- the corneal inlay improves near vision and decreases dependence on near- vision correction modalities on presbyopic patients.
- the inlay can resemble a small contact lens implanted into the cornea.
- one inlay e.g., lens
- the mode of action is based on displacement of a small section of the corneal stroma. This, in turn, gives rise to a micron size bump anterior to the cornea. This causes a small refractive change giving rise to about 1-3 diopters, inclusive, or 1.5-3 diopters, inclusive, of correction, hence, enabling the patient to view items at near distance. Visual acuity at far distance is still maintained.
- the inlay can have a center thickness of about 40-50 microns inclusive.
- the reported surface area and weight of the inlay can be about 0.063 cm 2 and about 0.0001 gram (100 ⁇ g).
- the inlay is considered to be an optically clear hydrogel with about a 78-92% inclusive water content produced from porcine collagen.
- an 80% water content, collagen-based hydrogel can be used as a corneal or stromal implant.
- Fabrication of the inlay can involve accurate control and consideration of several parameters, e.g., overall geometry, center thickness, edge thickness, surface quality, smoothness/roughness, front radius of curvature, back radius of curvature. [00308]
- the exemplary inlay provides several advantages that alone or in combination provide improved results post-implantation.
- the inlay includes a water content ranging from about 78%-92%, inclusive, or from 78%-80%, inclusive, with collagen hydrogel materials having defined properties.
- the collagen inlay (cytophilic property) and assay yields a biocompatible device in the cornea.
- Such true biocompatibility results in haze-free vision, even after extended periods of time (e.g., beyond 2 years).
- the exemplary inlay has produced positive results showing excellent biocompatibility with the cornea without use of any drugs post-op. No haze has been seen in animal subjects approaching 3 years post-implantation.
- the inlay can be fabricated using cannula molding or surface energy molding, and defines a dome-shaped geometry.
- the corneal implant can be implanted into a deep pocket (e.g., about 180-200 microns) as well as a flap (e.g., about 150 microns similar to a LASIK procedure).
- the highly biocompatible material of the inlay allows for such implantation successfully.
- Traditional corneal implants fail to be truly biocompatible.
- the exemplary inlay solves such issues by providing a truly biocompatible device.
- the inlay has the potential for excellent efficacy together with excellent safety. Future delivery systems or insertion devices can allow quick ease of insertion (as compared to traditional designs). Excellent biocompatibility of the implant can lead to flexibility with surgeons and patients involving specific procedures to be employed (e.g., both flap and pocket procedures can be employed).
- the inlay can be implanted using either a flap or pocket technique formed by a fantosecond laser.
- the inlay can be positioned onto the stromobed and centered against the pupil or visual axis.
- the flap is closed (no closure needed for pocket), and smoothed out.
- the inlay creates a central bump over the cornea, e.g., a 15-20 micron bump. Such bump can provide for correction in vision of about +1.5 to +3 diopters.
- Corneal Onlay Device [00311]
- the described invention provides a corneal onlay device of low water content to treat presbyopia while decreasing or eliminating the risk of a patient developing corneal haze.
- the corneal onlay implant is fabricated or formed from a hydrogel.
- the hydrogel can be synthesized using a combination of biopolymers and synthetic monomers and/or synthetic polymers. The addition of a synthetic polymer not only improves the mechanical properties of the onlays, but also minimizes swelling, improves manufacturability/processability, and minimizes in-vivo degradation of corneal inlays [00312]
- the exemplary hydrogel onlay can define a substantially similar configuration as the inlay 200.
- the exemplary hydrogel onlay can define a configuration substantially similar to the inlay 210.
- the onlay can define a center thickness of about, e.g., 0.010 mm to 0.03 mm inclusive, 0.015 mm to 0.03 mm inclusive, 0.02 mm to 0.03 mm inclusive, 0.025 mm to 0.03 mm inclusive, 0.015 mm to 0.03 mm inclusive, 0.015 mm to 0.025 mm inclusive, 0.015 mm to 0.02 mm inclusive, 0.02 mm to 0.025 mm inclusive, 0.010 mm, 0.015 mm, 0.02 mm, 0.025 mm, 0.03 mm, or the like.
- the present disclosure also provides methods of making and characterization of the molded onlays for correcting presbyopia.
- the onlay is considered to be an optically clear hydrogel with about a 70-92%, inclusive, water content produced from porcine collagen.
- an 80% water content, collagen-based hydrogel can be used as a corneal onlay implant.
- Fabrication of the onlay can involve accurate control and consideration of several parameters, e.g., overall geometry, center thickness, edge thickness, surface quality, smoothness/roughness, front radius of curvature, back radius of curvature.
- the onlay can have a center thickness of about 15-30 microns inclusive, for example, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29, 30 microns.
- the present disclosure provides a method for providing visual correction without damaging the cornea, i.e., leaving cornea substantially intact.
- the method comprises exposing a surface of Bowman’s membrane by removing the corneal epithelium cell layer; gently cleaning the exposed surface of Bowman’s membrane (e.g., with a sterile, neutral buffer); placing the corneal implant device and a material effective to adhere the corneal onlay onto the clean exposed surface of Bowman’s membrane; placing a protective contact lens over the onlay; allowing the epithelial lawyer to regrow on top of the onlay; and removing the contact lens without disturbing placement of the onlay.
- the method may provide correction of presbyopia without invasive surgical intervention.
- the onlay can be adhered to the Bowman’s membrane with, e.g., a biological coating (e.g., fibronectin, collagen, RGDS (Kobayashi, H. and Ikacia, Y., Current Eye Res. (2009) 10 (10): 899-908); or a biocompatible adhesive (e.g., Tisseel) [see Rostron, CK et al. Arch. Ophthalmol. (1988) 106: 1103-6); see also Nam, S. and Mooney, D. Polymeric tissue adhesives. (2021) doi.org/10.102/acs.chemrev.0c00798].
- a biological coating e.g., fibronectin, collagen, RGDS (Kobayashi, H. and Ikacia, Y., Current Eye Res. (2009) 10 (10): 899-908
- a biocompatible adhesive e.g., Tisseel
- PEG is FDA approved in a number of applications and is broadly considered to be nontoxic, biocompatible and nonimmunogenic. [Id., citing Mehdizadeh, M. and Yang, J. Macromol. Biosci. (2013) 13: 271-88].
- DuraSeal Xact Adhesion Barrier and Sealant System utilizes an NHS ester to achieve a hydrogel with adhesive cross-linking and bonding to tissues with reduced swelling [Id., citing Preul, MC et al. J. Neurosurg. Spin (2010) 12: 381-90; Fransen, P. Spine J. (2010) 10: 751-61; Kim, K. D et al.
- photochemical tissue bonding using either Riboflavin or Rose Bengal and UV light may be implemented to secure or glue the onlay in the desired position.
- PTB photochemical tissue bonding
- cyanoacrylate glue typically used for corneal lacerations/perforations and gluing small corneal patches on corneal perforations, corneal melts, and corneal wound leaks
- corneal lacerations/perforations and gluing small corneal patches on corneal perforations, corneal melts, and corneal wound leaks may be used to secure or glue the onlay in the desired position.
- the onlay sticks to the Bowman’s membrane without the use of a biocompatible adhesive.
- the epithelial layer has been repaired (e.g., 24-48 hr) the contact lens can be removed without disturbing placement of the onlay.
- the onlay creates a bump in the cornea that improves presbyopia.
- the exemplary onlay provides several advantages that alone or in combination provide improved results post-implantation. Lower water content results in a stiffer material, which means it may be easier to manufacture and handle.
- the present disclosure also provides a method of treating presbyopia comprising implanting on top of Bowman’s membrane of a mammalian subject a corneal onlay device with a water content ranging from about 70% to about 92% (w/w), inclusive.
- the corneal onlay improves near vision and decreases dependence on near-vision correction modalities on presbyopic patients.
- the onlay may resemble a small contact lens implanted onto the cornea.
- one onlay e.g., lens
- the mode of action is based on addition of the lens to replacement epithelium, which gives rise to a micron size bump anterior to the cornea. This causes a small refractive change giving rise to about 1-5+ to +3 diopters of correction, hence, enabling the patient to view items at near distance. Visual acuity at far distance is still maintained.
- Exemplary polymer hydrogel inlays [00324] Exemplary inlay 1.
- a collagen-synthetic polymer hydrogel inlay was formed from a collagen-2-Methacryloyloxyethyl phosphorylcholine (MPC)-Poly(ethylene glycol) diacrylate (PEGDA) composition.
- the hydrogel composition included an IPN made of a natural polymer (e.g., collagen), and two synthetic polymers (i.e., MPC and PEGDA).
- the water content of the composition ranged from about 94% to about 98% (referred to herein as a “high water content composition”). In some instances the hydrogel composition had a water content of between about 90% to about 96%.
- the IPN for the high water content composition had a collagen/PEGDA weight ratio of about 4:1, and a PEGDA/MPC weight ratio varying from about 1:3 to about 1:1.
- the length of PEGDA was small enough to serve as both a crosslinking agent and a macro-monomer i.e., between about 200 to about 700 Da.
- a crosslinking agent was used to crosslink collagen, while an ultraviolet (UV) initiator was used for simultaneously initiating the polymerization and crosslinking of MPC with PEGDA as a crosslinker.
- UV ultraviolet
- the hydrogel composition was cross-linked with a UV initiator which can extend the mold fabrication time up to about 5 minutes.
- Exemplary inlay 2 A second inlay was formed from a collagen-MPC- PEGDA composition.
- the hydrogel composition included an IPN made of a natural polymer (e.g., collagen), and two synthetic polymers (i.e., MPC and PEGDA).
- the composition had a water content ranging from about 78% to about 92% (referred to herein as a “low water content composition”).
- the IPN for the low water content composition had a collagen/PEGDA weight ratio varying from about 1:3 to about 1:10, and a PEGDA/MPC weight ratio varying from about , e.g., 1:0.5-0.5:1, 1:0.6-0.5:1, 1:0.7-0.5:1, 1:0.8-0.5:1, 1:0.9- 0.5:1, 1:1-0.5:1, 1:0.5-0.6-:, 1:0.5-0.7:1, 1:0.5-0.8:1, 1:0.5-0.9:1, 1:0.5-1:1, or the like.
- the length of PEGDA was greater than about 700 Da.
- a crosslinking agent was used to crosslink collagen, while an initiator (e.g., UV) was used for simultaneously initiating polymerization and crosslinking of MPC and PEDGA.
- Example 2 Method of Making IPN Hydrogels for Corneal Inlay
- the collagen and the non-collagen components of the hydrogel mixture were simultaneously crosslinked in the mold cavity. While collagen was crosslinked only via DMT-MM (4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride), two different crosslinking chemistries can be used to polymerize/crosslink the non-collagen moieties of the hydrogel.
- One crosslinking chemistry can be, e.g., DMT-MM-APS/TMEDA.
- DMT- MM was used to slowly crosslink collagen, while the redox pair, Ammonium Persulfate (APS)/TMEDA was used to polymerize and crosslink MPC, with PEGDA as the crosslinker. The entire process was performed at room temperature.
- Another crosslinking chemistry can be, e.g., DMT-MM-LAP. DMT-MM was used to slowly crosslink collagen, while a UV initiator Lithium phenyl-2,4,6- trimethylbenzoylphosphinate (LAP) was used to polymerize and crosslink MPC, with PEGDA as the crosslinker.
- LAP Lithium phenyl-2,4,6- trimethylbenzoylphosphinate
- DMPA 2,2-Dimethoy-2-phenylacetophenone
- Irgacure Irgacure
- UV polymerization/crosslinking was performed in a UV chamber. After the completion of UV polymerization/crosslinking, the sample was removed from the UV chamber and the crosslinking of collagen was continued for about 12 more hours.
- MES buffer pH 2.90 2-(N-Morpholino)ethanesulfonic acid (MES) buffer pH 2.90 was then added and the tube placed in 5 °C for 7 – 10 days to hydrate the collagen. Once collagen was completely hydrated, 200 mg of MES buffer pH 2.90, 125 mg of 10% w/w MPC in MES buffer pH 2.90 and 4.71 PEGDA, molecular weight (Mw) 575 were added sequentially to the micro centrifuge tube 1. The tube was vortexed after each addition to properly homogenize the mixture. The tube was then centrifuge and placed in 5 °C.
- MES buffer pH 2.90 2-(N-Morpholino)ethanesulfonic acid
- crosslinking/initiating reagents were then prepared; 4% w/w solution of APS in MES buffer pH 2.90, 4% w/w solution of TMEDA solution in MES buffer pH 2.90, and a 12% solution of DMT-MM in MES buffer pH 2.90.
- the tube labeled 1 was removed from 5 °C and 12.19 mg TMEDA solution was added and mixture was homogenized by vortexing. 52 mg of DMT-MM solution and 15.63 mg of APS solution were added to the tube and vortexed to properly mix. The mixture was then centrifuged at 15 °C to remove air bubbles before casting in PMMA cavity molds and allowed to polymerize/crosslink for approximately 12 hours at room temperature, in a humidity chamber.
- Example 4 Method of Making DMT-MM-LAP Hydrogel Inlays With Water Content Ranging From About 92% to About 96%, inclusive for Comparison Testing [00331] 60 mg of collagen powder was weighed into a 2 ml micro-centrifuge tube labeled 1.440 mg of MES buffer pH 2.90 was then added and the tube placed in 5 °C for 7 – 10 days to hydrate the collagen.
- PBS phosphate buffer saline
- the tube labeled 1 was removed from 5 °C and 62.26 mg of DMT-MM solution and 120.0 mg of LAP solution were added to the tube and vortexed to properly mix. The mixture was then centrifuged at 15 °C to remove air bubbles before casting in PMMA cavity molds. The molds were placed in a UV chamber for 30 minutes and then in a humidified chamber for approximately 12 hours at room temperature. After polymerization/crosslinking the inlay was demolded and washed several times in 1x PBS buffer to remove residual reagents. Example 5.
- the weight of the material, W1 is taken by placing material on an analytical balance.
- the inlay is then placed in an oven set at 100 °C for minimum of two and a half hours to completely dry the sample.
- the weight of the dried sample is measured and recorded as W 2 .
- the water content %WC recorded as a percentage is calculated as: Refractive Index [00335]
- a refractometer is used to determine the refractive index. The refractometer is first calibrated with HPLC water and a calibration oil before measurements. To measure the refractive index of the inlay, excess water on the inlay (10 mm diameter by 100 ⁇ m thickness) is blotted with the aid of KimWipes before it is placed on the measuring prism.
- Percent Transmission Percent transmission of a fully hydrated inlay sample is measured using a spectrophotometer, calibrated with HPLC water. The sample (10 mm diameter by 100 ⁇ m thickness) is placed inside the cuvette, along with HPLC water and adjusted so that it is touching the bottom of the cuvette and pressed up against the front side. The cuvette is then inserted into the cell holder compartment for a UV scan. The percent transmission at 300 nm is recorded as the % transmittance of the materials. Example 6.
- MTT assay to quantify cell viability on different material samples.
- Rationale MTT is used to measure cellular metabolic activity as an indicator of cell viability, proliferation and cytotoxicity. The darker the solution, the greater the number of viable metabolically active cells.
- Protocol 12 mm discs are added to cover most of the well area of 24 well plates. The following numbers of rabbit corneal fibroblasts were seeded in duplicate per well: 200K, 100K, 50K, 25K, 12.5K, 6.25K. Cells were cultured in standard culture medium. 10 wells correspond to test samples; 6 wells correspond to controls (no discs).
- An MTT calibration plate is seeded on day 3 with the same cell numbers. The calibration plate is evaluated by microscopy before the assay and confluency estimated. On day 4, water soluble yellow MTT (4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) is added to the cultures. MTT is reduced to purple insoluble formazan by mitochondrial dehydrogenase in the mitochondria of viable cells. The formazan is solubilized with detergent and measured spectrophotometrically. Viable cells with active metabolism convert MTT into a purple colored formazan product with an absorbance maximum near 570 nm.
- FIG.32 shows an image of cell coverage on a biocompatible material
- FIG. 33 shows an image of cell coverage on a non-biocompatible material.
- Table 2 is a list of samples tested in the cell attachment assay, including a Group ID, a description, and the number of samples/size.
- the samples included (1) Nippon 07.14.20, 07.24.20 DMTMM 10%; (2) Nippi 07.24.20, 08.11.20 DMTMM 10%; (3) Nippi 07.24.20, 08.17.20 DMTMM 12%; (4) Nippi 07.24.20, 08.19.20 DMTMM 15%; and (5) Ferentis 1823B, Ferentis 1837A.
- Table 2 Samples for cell attachment assay [00356] FIGS.35 and 36 show the measured thickness of the samples based on cell growth at days 4 and 7, respectively, and FIG.
- FIGS.38A-38G and 98A-39G are microscopy images for days 4 and 7, with FIGS.38A and 39A showing an image of the control, FIGS. 38B and 39B showing images for Nippi 10%, FIGS. 38C and 39C showing images for Nippi 12%, FIGS. 38D and 39D showing images for Nippi 15%, FIGS. 38E and 39E showing images or Nippon 10%, FIGS. 38F and 39F showing images for Ferentis 1823B, and FIGS. 38G and 39G showing images for Ferentis 1837A.
- the first and second row images of FIGS. 38B-38G and 39B-39G are general microscopy images of the samples, and the third row of images of FIGS.38B, 38E, 38G and 39B-39E show bubbles formed.
- Table 3 Microscopy results for different samples tested in cell attachment assay at day 4.
- Table 4. Microscopy results for different samples tested in cell attachment assay at day 7.
- the cell attachment assay provided the following results. With respect to thickness: Nippi 10% and Nippon 10% materials are the thickest (85-98 ⁇ m). Nippi 15% are 76-78 ⁇ m. Nippi 12% and Ferentis 1823B are 55-60 ⁇ m.
- Ferentis 1837A materials are around 40 ⁇ m. Thickness remains steady over culture time. [00360] The cells attached and grew well on all materials, becoming confluent on all samples by day 7 (except one spot on one Nippi 12% sample). Bubbles were observed in the material itself in the following samples: Nippon 10%, Nippi 10% (a few), and Ferentis 1837A (a few) on day 4. Nippon 10%, Nippi 10% (a few), Nippi 12% (a few), and Nippi 15% (a few) on Day 7 [00361] (4) Second Cell Attachment Assay Questions Asked [00362] Can cells grow in the presence of the material/are the materials toxic to cells? [00363] Do cells attach and grow on the materials?
- FIG. 41 is a bar graph showing thickness over time for different samples tested in the cell attachment assay at days 4 and 7 is provided.
- Tables 6 and 7 microscopy results for different samples tested in the cell attachment assay at days 4 and 7, respectively, are provided. The tables include descriptions related to confluency of the cells.
- FIGS. 42A-42I and FIG. 43A-43I show microscopy images for different samples tested in the cell attachment assay at days 4 and 7, respectively.
- FIG.42A and FIG.43A show images for the control
- FIG.42B and FIG.43B show images for Ferentis 1842A
- FIG.42C and FIG. 43C show images for Nippi 12% D12%
- FIG. 43D show images for Nippi 10%D10%
- FIG. 42E and FIG.43E show images for Nippi 12%D10%
- FIG. 42F and FIG.43F show images for Nippon 10%
- FIG. 42G and FIG.43G show images for SA-13-31B
- FIG. 42H and FIG. 43H show images for SA-13- 92A edge
- FIG.42I and FIG.43I show images for SA-13-92A on sample.
- Thickness finding were as follows: Nippi 10%D10% and Nippi 12%12% are thinnest (65-80 ⁇ m). Nippon 10%D10% are 115-120 ⁇ m in thickness. Nippi 12%D10% about are 160 ⁇ m in thickness. Ferentis 1842A and SA-13-31B materials are around 170-200 ⁇ m in thickness. SA-13-92A materials are around 500 ⁇ m in thickness. Thickness remains steady over culture time. [00380] The cells attached and grew well on all materials, becoming confluent on all samples by day 7. [00381] Control non-collagen samples did not support cell growth (but are not toxic to the cells on the plate).
- FIGS. 45A-45F show microscopy images for control samples tested in the cell attachment assay.
- FIGS.46A-46J show microscopy images for 1745A samples tested in the cell attachment assay. At day 3 microscopy imaging, it was hard to image edges due to 24 well plate. Imaged the center of each well to get an idea of cell growth on the materials compared to controls. Controls included: (1) 4/6 samples 70-100% confluent, and (2) 2/6 samples mostly confluent, a few patches in center.
- 1746A samples included: (1) 4/10 confluent at edges and nearly confluent in center, (2) 1/10 about 60% confluent in center, confluent at edges, and (3) 5/10 samples 30-40% confluent in center, patchy, some holes. Controls are more confluent overall than samples, but not a stark difference and might be hard to pick up on MTT assay.
- FIGS. 45A-45D show control sample images for 4/6 samples, 80-100% confluent.
- FIGS. 45E-45F show control sample images for 2/6 samples mostly confluent, a few patches in center.
- FIGS. 46A-46C show 1745A sample images for 3/10 confluent at edges and nearly confluent in center.
- FIGS.46D-46E show 1745A sample images for 2/1060-70% confluent in center, confluent at edges.
- FIGS.46F-46J show 1745A sample images for 5/10 samples 30-40% confluent in center, patchy, some holes.
- FIG. 47 is an image of an MTT plate illustrating the setup for samples tested in the cell attachment assay.
- FIG. 48 is a bar graph showing cell numbers for MTT results in the cell attachment assay for a sample and control. Example 7.
- Test System Species Oryctolagus cuniculus Strain: New Zealand White rabbits (na ⁇ ve) Sex: Male or female (all same sex) Age: Commensurate with weight Weight: Approximately 3.5 to 4.5 kilograms at study start Number: 10 (+ up to 2 extras) Vendor: approved vendor Method of Identification: Ear tag and cage label per ASC SOPs Caging: As per ASC SOPs Minimum Acclimation: 5 days 2. Specialized animal husbandry and/or restraint Fasting – None Restraint – Animals will be manually restrained per ASC SOPs to facilitate ophthalmic examinations and imaging.
- Test Articles are shown in Table 8. [00389] Table 8. Test articles* *ID (Lot #) and Date of Expiry (or retest date) will be recorded in the raw data. 10. Test Article Preparation, Accounting, and Disposition Test articles will be supplied by the Sponsor sterile for implantation and ready to administer. Test material accountability will be maintained according to ASC SOPs. After test article administration has completed, any leftover test articles will be directly transferred to the Sponsor by hand or shipped to the Sponsor on cold packs. 11.
- Pre-Treatment Procedures and Details of Test Article Administration a) Pre-Treatment Examinations Prior to placement on study, each animal will undergo an ophthalmic examination (slit-lamp biomicroscopy and indirect ophthalmoscopy) to be performed by the Study Director or Director of Ophthalmology. Ocular findings will be scored according to a modified McDonald-Shadduck Scoring System per SOP ASC-OC-001. The acceptance criteria for placement on study will be scores of “0” for all variables.
- IM intramuscular
- ketamine hydrochloride up to approximately 50 mg/kg
- xylazine up to approximately 10 mg/kg
- dexmedetomidine approximately 0.25 mg/kg
- Glycopyrrolate approximately 0.01 mg/kg, IM
- Atipamezole hydrochloride up to 1 mg/kg, IM
- Alternative anesthesia regimens may be used as advised by the veterinary staff in consultation with the Study Director and the Sponsor.
- Nictitating membranes will be removed at least 14 days prior to test article administration. Animals will be anesthetized as described herein. A 5% Betadine solution will be used to clean the eye and surrounding area. Betadine will be applied for ⁇ 5 minutes, after which the eye will be rinsed with balanced salt solution (BSS) and the surrounding area wiped with gauze. One to two drops of topical proparacaine hydrochloride anesthetic (0.5%) will be applied to the nictitating membrane of each eye prior to the surgical procedure. The nictitating membrane will be grasped with a pair of forceps and gently clamped at its base with a pair of hemostats. The nictitating membrane will be excised along the clamp line with scissors.
- BSS balanced salt solution
- the excised area will be sealed to stop any further bleeding.
- BSS will be applied to the cauterized area.
- the area may be blotted and medicated with topical gentamicin (0.3%) and/or antibiotic ophthalmic ointment.
- the contralateral eye will have its nictitating membrane removed by the same procedure. Animals will be monitored during anesthesia recovery per ASC SOPs.
- Antibiotic ointment will be applied topically once immediately following nictitating membrane removal and daily for up to 3 days post-operatively.
- One injection of buprenorphine (0.02-0.05 mg/kg, IM/SC) will be given perioperatively.
- Additional buprenorphine injections may be administered in the days after surgery as deemed necessary by the veterinary staff. The day after surgery, animals will be examined to ensure there were no post- surgical complications. 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. d) Group Assignment One animal will be assigned per group. e) Test Article Administration Test articles will be implanted in the corneas of both eyes of all study animals on Day 1 according to the study design in Table 9 (below). All surgical procedures will be performed by the Sponsor’s designated surgeon.
- ASC will provide technician support, anesthesia monitoring, and basic surgical equipment (including a surgical table, surgical microscope, and slit-lamp) and supplies (including sutures, gowns, etc.). Specialized surgical tools and supplies, including the laser and/or microkeratome, will be provided by the Sponsor. Animals will be anesthetized as outlined herein. A 5% Betadine solution will be used to clean the eye and surrounding area. Betadine will be applied for ⁇ 5 minutes, after which the eye will be rinsed with BSS and the surrounding area wiped with gauze. A flap or pocket will be cut into each cornea using a laser or a microkeratome. The surgery type utilized for each eye will be noted in the study data. The appropriate test article for each eye will be inserted into the flap or pocket.
- Test articles will be stained with 10 or 25% fluorescein solution (provided by the Sponsor) to facilitate visualization during the implantation procedure. Further details of surgical procedures may be noted in the raw data. Animals will be monitored during anesthesia recovery per ASC SOPs. One injection of buprenorphine (0.02-0.05 mg/kg IM/SC) will be given for post-surgical analgesia. Additional buprenorphine injections (0.02-0.05 mg/kg, IM/SC, twice daily or sustained-release buprenorphine 0.1 mg/kg, SC, every 72 hours) may be administered in the days after surgery as deemed necessary by the veterinary staff. Antibiotic ophthalmic ointment (e.g. triple antibiotic ointment) or antibiotic eye drops (e.g.
- Baseline examinations will include indirect ophthalmoscopy and assess full set of ocular observation variables; remaining examinations will assess variables related to corneal haze/opacity only.
- #Surgical technique and type laser flap or pocket or microkeratome flap
- #Surgical technique and type will be chosen on the day of surgery at the discretion of the Sponsor and recorded in the raw data for each eye.
- *Additional time points may be added at the discretion of the Sponsor with the approval of the Study Director and Attending Veterinarian. ⁇ May optionally be extended for some or all animals at the Sponsor’s discretion with the agreement of the Study Director and Attending Veterinarian. Alternatively, animals may be euthanized earlier in case of corneal damage developing.
- Slit-Lamp Examinations will be performed on both eyes of all animals at baseline (prior to test article administration) and on Days 8( ⁇ 1), 30( ⁇ 3), 60( ⁇ 5), and 90( ⁇ 7). Additional time points may be added at the Sponsor’s discretion with the agreement of the Study Director and Attending Veterinarian. [00395] Ocular findings will be scored according to a modified McDonald- Shadduck Scoring System per SOP ASC-OC-001. Baseline examinations will include both slit-lamp biomicroscopy and indirect ophthalmoscopy and will assess all ocular observation variables.
- examinations will include slit-lamp biomicroscopy only and will assess only the ocular observation variables related to corneal haze/opacity, namely “Cornea” (severity of corneal haze/opacity) and “Surface Area of Cornea Involvement” (area of corneal haze/opacity).
- corneal haze/opacity namely “Cornea” (severity of corneal haze/opacity) and “Surface Area of Cornea Involvement” (area of corneal haze/opacity).
- corneal haze/opacity namely “Cornea” (severity of corneal haze/opacity) and “Surface Area of Cornea Involvement” (area of corneal haze/opacity).
- examinations will include scoring of corneal haze following a study-specific scoring system. [00397] Examinations will be performed either by the Study Director, the Director of Ophthal
- OCT Corneal Optical Coherence Tomography
- Optical coherence tomography (OCT) of the cornea will be performed at baseline (prior to test article administration) and on Days 8( ⁇ 1) and 90( ⁇ 7). Additional time points may be added at the Sponsor’s discretion with the agreement of the Study Director and Attending Veterinarian.
- Heidelberg Spectralis® Eye Explorer image processing software (HEYEX Software Version 1.9.10.0, Heidelberg Engineering GmbH, Heidelberg, Germany) will be used to measure the thickness of the cornea near the center of the cornea and the depth of the test article implant in the cornea at each time point. Terminal Procedures [00400] 1.
- blood or other specimens will be collected and analyzed as appropriate (e.g., for clinical pathology parameters) to help reveal the cause of malaise/morbidity.
- All unscheduled-sacrifice animals may be necropsied; if so, necropsy will be performed immediately, or, if this cannot be performed, the animal will be refrigerated to minimize autolysis and necropsied no later than 12 hours after death. All tissues listed in this protocol will be preserved.
- the study may be extended for some or all study animals at the Sponsor’s discretion with the agreement of the Study Director and Attending Veterinarian, or animals may be euthanized earlier in case of corneal damage developing; in this case, the day(s) and time(s) when animals are euthanized will be recorded in the study data.
- Animals will be euthanized by an intravenous injection of a commercial barbiturate based euthanasia solution (approximately 150 mg/kg, to effect). The euthanasia procedure will be performed in compliance with the American Veterinary Medical Association (AVMA) Guidelines for Euthanasia of Animals: 2020 Edition.
- AVMA American Veterinary Medical Association
- Tissue Collection Immediately following euthanasia, both eyes will be collected from all animals following on of the below methods. The Sponsor will be contacted before euthanasia to determine which method should be used for each eye of each animal. a) Method 1 A 2% paraformaldehyde (PFA) solution in phosphate-buffered saline (PBS), pH 7.4, will be made fresh on the day of tissue collection. Immediately following euthanasia, the anterior chamber of the eye will be perfused with 2% PFA in PBS for 4 minutes to fix the cornea. Perfusion will be performed using handheld syringes using a push-pull technique (two needles, one for pushing in PFA, one for pulling out aqueous humor).
- PFA paraformaldehyde
- a slow push/pull will be used to maintain the internal pressure of the eye and avoid damage to the cornea.
- the eye will be harvested.
- the cornea plus 1-2 mm limbal tissue will be excised using scalpel puncture and curved corneal scissors. The remaining eye will be discarded.
- the excised cornea will be placed into a chilled container with 2% PFA.
- the container will be sealed to prevent leakage or evaporation and immediately placed on wet ice until being stored refrigerated at 2-8°C. 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.
- Method 2 Immediately following euthanasia, the eye will be harvested.
- the room(s) in which the animals will be kept will be documented in the study records. No other species will be housed in the same room(s).
- the rooms will be well ventilated (greater than 10 air changes per hour) with at least 60% fresh air.
- a 12-hour light/12-hour dark photoperiod will be maintained, except when rooms must be illuminated during the dark cycle to accommodate necessary study procedures.
- Room temperature and humidity will be recorded once daily as per ASC SOPs.
- Food and Water per SOP ASC-HU-012 (Husbandry, Rabbits) Animals will have ad libitum access to species specific chow. No contaminants are known to be present in the diet at levels that would interfere with the results of this study.
- the Sponsor Representative will be contacted via phone and email during normal working hours to discuss appropriate action. If the condition of the animal(s) is such that emergency measures must be taken, the Attending Veterinarian will attempt to consult with the Study Director and Sponsor Representative prior to responding to the medical crisis, but the veterinary staff has authority to act immediately at their discretion to alleviate suffering. The Sponsor Representative will be fully informed of any such events. In the event that an animal dies or is euthanized during the study, terminal procedures will be conducted as described above. [00422] 9. Final Disposition Carcasses of deceased animals will be discarded following post mortem examination in accordance with applicable regulations on biological waste. [00423] 10.
- Unscheduled Treatment Any unscheduled treatment of the animal(s) will be approved by the Study Director and the Sponsor. If the condition of the animal(s) is such that emergency measures must be taken, the Attending Veterinarian will attempt to consult with the Study Director and Sponsor prior to responding to the medical crisis, but the veterinary staff has authority to act immediately at their discretion to alleviate suffering. All unscheduled treatments will be recorded. Records and Reports [00424] A.
- the Sponsor will be responsible for archival of records and tissue specimens that are derived from portions of the study conducted by the Sponsor (or a Sponsor-appointed subcontractor).
- B. Draft Report [00427] The draft report will include test article information and description, materials and methods, results, and conclusions.
- the Sponsor will provide comments based on a review of the summary and data. Report finalization will be conducted on a mutually-agreeable timetable. Upon finalization, a copy of the final report will be provided to the Sponsor as a PDF file.
- C. Corneal Haze Scoring [00430] Haze grading is based on a scale used to grade post-PRK Haze, Arch.
- FIGS.34A-34E illustrate the guideline haze grading schemes for corneal haze scoring to be used during testing of the inlays. The best clinical judgment to grade the level of haze based on slit lamp presentation and associated clinical findings will be used.
- FIGS.34A and 34B show a clear, Grade 0 corneal haze score
- FIG.34C shows a trace, Grade 1 corneal haze score
- FIG. 34D shows a mild, Grade 2 corneal haze score
- FIG.34E shows a moderate, Grade 3 corneal haze score.
- the clear, Grade 0 score reflects a sporadic, peripheral faint haze (clear center), not visible with diffuse slit lamp beam, minimally visible by oblique or slit beam. Vision is not affected.
- the trace haze, Grade 1 score reflects a trace haze covering mid-peripheral and center of inlay. Visible with difficulty using diffuse illumination, visible by broad tangential illumination. May present with myoptic shift, reduced near point, visual symptoms (e.g., glare and halos).
- the mild haze, Grade 2 score reflects a relatively dense, granular confluent haze, covering the entire inlay and outer periphery.
- the haze is easily seen by diffuse and slit beam illumination.
- the haze presents with myoptic shift, greatly reduced near point, and a marked increase in visual symptoms (e.g., glare and halos).
- the moderate haze, Grade 3 score reflects a dense. Reticular, confluent haze presentation. Iris details are obscured with more severe symptoms of Grade 2 possible.
- Appendix A. Modified McDonald-Shadduck Scoring System T. McDonald and J. A.
- Iris Involvement Check the iris for hyperemia of the blood vessels.
- FIG.49 a diagram illustrating seeding materials during a cell attachment assay is provided. Cells were seeded in 100 ⁇ L at edge of plate. The material was a 6-10 mm disc. [00467] Samples were cultured with passaged corneal epithelial cells. [00468] Cells were not seeded on samples to evaluate cell migration onto material. Cells were seeded at an edge in a small volume of media. 4 mL added gently after 30 minutes. [00469] Possible control material: denuded cornea.
- Sample evaluation (1) Migration onto material/attachment to material (light microscopy); and (2) Ability to form cell layers (confocal microscopy).
- Possible addition (1) Stimulate differentiation; and (2) Confocal microscopy for focal adhesion proteins, epithelial cell differentiation markers.
- Microscopy [00472] With respect to FIGS. 50A-50B, light microscopy images of PC-MPC cells attached to a sample are provided. The cells are passaged corneal epithelial cells that have migrated over or attached to the material, PC-MPC (porcine collagen- methacryloyloxyethyl phosphorylCholine). [00473] With respect to FIG.
- FIGS. 52A-52B confocal microscopy images of a cross- section of controls showing some multilayered structures as a baseline for comparison are provided.
- the control was the bare tissue culture plate. Epithelial cells were able to grow over the plate surface.
- Denuded cornea e.g., cornea with the epithelial layer scrapped off
- Denuded cornea could be used as another control, and it is expected that epithelial cells will grow over the deruded cornea.
- FIGS. 53A-53B confocal microscopy images of a cross- section of 3D PEG gelatin material with epithelial cells on a plate and on surface demonstrating the ability of cells to form cell layers. Both have multi-layered spots;
Abstract
L'invention concerne une composition d'hydrogel comprenant un réseau polymère interpénétrant contenant un polymère naturel et deux polymères synthétiques polymérisables par un initiateur UV pour faciliter le moulage de dispositifs d'implant visuel. La composition d'hydrogel peut être utilisée pour fabriquer une variété de dispositifs médicaux, par exemple sans limitation, des dispositifs d'inlay ou d'onlay cornéen qui peuvent être utilisés pour traiter la presbytie, tout en réduisant ou en éliminant le risque qu'un patient développe une opacité cornéenne. La composition d'hydrogel pour des inlays cornéens et des onlays cornéens a une teneur en eau allant d'environ 78 % à environ 92 %, inclus, est optiquement transparente, biocompatible, perméable et réfractive.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202163214687P | 2021-06-24 | 2021-06-24 | |
US63/214,687 | 2021-06-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2022272090A1 true WO2022272090A1 (fr) | 2022-12-29 |
Family
ID=84543918
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2022/034942 WO2022272090A1 (fr) | 2021-06-24 | 2022-06-24 | Composition d'hydrogel et méthodes d'utilisation |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2022272090A1 (fr) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080317818A1 (en) * | 2005-09-09 | 2008-12-25 | May Griffith | Interpenetrating Networks, and Related Methods and Compositions |
US20120321585A1 (en) * | 2009-09-30 | 2012-12-20 | University Of Ottawa | Crosslinked Hydrogels and Related Method of Preparation |
US8591950B2 (en) * | 2010-05-27 | 2013-11-26 | Covidien Lp | Hydrogel implants with varying degrees of crosslinking |
WO2015077439A1 (fr) * | 2013-11-20 | 2015-05-28 | Trustees Of Boston University | Supplément de tissu injectable |
US10166314B2 (en) * | 2013-10-14 | 2019-01-01 | Uab Ferentis | Regenerative prostheses as alternatives to donor corneas for transplantation |
-
2022
- 2022-06-24 WO PCT/US2022/034942 patent/WO2022272090A1/fr unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080317818A1 (en) * | 2005-09-09 | 2008-12-25 | May Griffith | Interpenetrating Networks, and Related Methods and Compositions |
US20120321585A1 (en) * | 2009-09-30 | 2012-12-20 | University Of Ottawa | Crosslinked Hydrogels and Related Method of Preparation |
US8591950B2 (en) * | 2010-05-27 | 2013-11-26 | Covidien Lp | Hydrogel implants with varying degrees of crosslinking |
US10166314B2 (en) * | 2013-10-14 | 2019-01-01 | Uab Ferentis | Regenerative prostheses as alternatives to donor corneas for transplantation |
WO2015077439A1 (fr) * | 2013-11-20 | 2015-05-28 | Trustees Of Boston University | Supplément de tissu injectable |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Trujillo-de Santiago et al. | Ocular adhesives: Design, chemistry, crosslinking mechanisms, and applications | |
Fagerholm et al. | A biosynthetic alternative to human donor tissue for inducing corneal regeneration: 24-month follow-up of a phase 1 clinical study | |
EP2755598B1 (fr) | Fabrication de feuille d'hydrogel de gélatine pour transplantation d'endothélium cornéen | |
KR101298442B1 (ko) | 안과용 장치 및 이와 관련된 방법 및 조성물 | |
JP2002506013A (ja) | 酵素角膜矯正術における角膜硬化剤の使用 | |
US20180228599A1 (en) | Tissue-derived scaffolds for corneal reconstruction | |
Li et al. | Fish-scale collagen membrane seeded with corneal endothelial cells as alternative graft for endothelial keratoplasty transplantation | |
Andreev et al. | A new collagen scaffold for the improvement of corneal biomechanical properties in a rabbit model | |
CN112494729B (zh) | 含药组织移植物及其制备方法、应用 | |
Xeroudaki et al. | A double-crosslinked nanocellulose-reinforced dexamethasone-loaded collagen hydrogel for corneal application and sustained anti-inflammatory activity | |
Lu et al. | A methodology based on the “anterior chamber of rabbit eyes” model for noninvasively determining the biocompatibility of biomaterials in an immune privileged site | |
US20220273422A1 (en) | Corneal inlay design and methods of correcting vision | |
WO2022272090A1 (fr) | Composition d'hydrogel et méthodes d'utilisation | |
Bayoudh et al. | Intraocular silicone implant to treat chronic ocular hypotony: an in vivo trial | |
US20230051595A1 (en) | Corneal implants for treating ectatic corneal disease | |
WO2022272082A1 (fr) | Dispositif médical d'onlay cornéen | |
WO2022272107A1 (fr) | Implant d'incrustation cornéenne | |
Jorge E et al. | In vivo Biocompatibility of Chitosan and Collagen–Vitrigel Membranes for Corneal Scaffolding: a Comparative Analysis | |
Barber | Design of a Retainable Keratoprosthesis: History, Design, and Evaluation in Cats | |
Joepen et al. | Keratin Films in Ocular Surface Reconstruction | |
Xu et al. | Evaluation of new robust silk fibroin hydrogels for posterior scleral reinforcement in rabbits | |
Carriel Araya et al. | Scleral surgical repair through the use of nanostructured fibrin/agarose-based films in rabbits. | |
Akmalin et al. | The Effect of Collagen-Chitosan-Sodium Hyaluronate Implantation Composite on Inflammation Reaction (Flare) In New Zealand Rabbit Corneal Stroma | |
Gorbet et al. | Ocular responses to biomaterials | |
Chae | Investigation of biomaterials-based strategies for corneal reconstruction |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22829407 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |