WO2013063390A1 - A suturable hybrid superporous hydrogel keratoprosthesis for cornea - Google Patents
A suturable hybrid superporous hydrogel keratoprosthesis for cornea Download PDFInfo
- Publication number
- WO2013063390A1 WO2013063390A1 PCT/US2012/062116 US2012062116W WO2013063390A1 WO 2013063390 A1 WO2013063390 A1 WO 2013063390A1 US 2012062116 W US2012062116 W US 2012062116W WO 2013063390 A1 WO2013063390 A1 WO 2013063390A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- collagen
- hydrogel
- phema
- pmma
- superporous
- Prior art date
Links
- 239000000017 hydrogel Substances 0.000 title claims abstract description 139
- 210000004087 cornea Anatomy 0.000 title claims abstract description 59
- 102000008186 Collagen Human genes 0.000 claims abstract description 112
- 108010035532 Collagen Proteins 0.000 claims abstract description 112
- 229920001436 collagen Polymers 0.000 claims abstract description 112
- 229920003229 poly(methyl methacrylate) Polymers 0.000 claims abstract description 85
- 239000004926 polymethyl methacrylate Substances 0.000 claims abstract description 85
- 239000007943 implant Substances 0.000 claims abstract description 48
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 claims abstract description 26
- 229920001577 copolymer Polymers 0.000 claims abstract description 19
- 238000004519 manufacturing process Methods 0.000 claims abstract description 16
- 229920002338 polyhydroxyethylmethacrylate Polymers 0.000 claims abstract description 15
- 230000008929 regeneration Effects 0.000 claims abstract description 5
- 238000011069 regeneration method Methods 0.000 claims abstract description 5
- 239000000243 solution Substances 0.000 claims description 69
- 239000011148 porous material Substances 0.000 claims description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 41
- 238000000034 method Methods 0.000 claims description 36
- MYWOJODOMFBVCB-UHFFFAOYSA-N 1,2,6-trimethylphenanthrene Chemical compound CC1=CC=C2C3=CC(C)=CC=C3C=CC2=C1C MYWOJODOMFBVCB-UHFFFAOYSA-N 0.000 claims description 22
- 239000000499 gel Substances 0.000 claims description 22
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 16
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 claims description 16
- 239000008367 deionised water Substances 0.000 claims description 14
- 229910021641 deionized water Inorganic materials 0.000 claims description 14
- 238000002156 mixing Methods 0.000 claims description 9
- 229910001870 ammonium persulfate Inorganic materials 0.000 claims description 8
- 238000004132 cross linking Methods 0.000 claims description 8
- 229940044192 2-hydroxyethyl methacrylate Drugs 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 3
- 102100026735 Coagulation factor VIII Human genes 0.000 claims 1
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 claims 1
- 210000004027 cell Anatomy 0.000 description 125
- 229920000642 polymer Polymers 0.000 description 32
- 210000001519 tissue Anatomy 0.000 description 32
- 239000011159 matrix material Substances 0.000 description 30
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
- 230000010354 integration Effects 0.000 description 23
- 239000000463 material Substances 0.000 description 19
- 239000010410 layer Substances 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 14
- 230000012292 cell migration Effects 0.000 description 13
- 210000002950 fibroblast Anatomy 0.000 description 13
- 238000002513 implantation Methods 0.000 description 13
- 102000012422 Collagen Type I Human genes 0.000 description 12
- 108010022452 Collagen Type I Proteins 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 230000021164 cell adhesion Effects 0.000 description 11
- 210000002744 extracellular matrix Anatomy 0.000 description 10
- 238000001727 in vivo Methods 0.000 description 10
- 230000008961 swelling Effects 0.000 description 10
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 9
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000000512 collagen gel Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 241000283973 Oryctolagus cuniculus Species 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 239000012620 biological material Substances 0.000 description 8
- 239000004088 foaming agent Substances 0.000 description 8
- 229940096422 collagen type i Drugs 0.000 description 7
- 238000013461 design Methods 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 229920001477 hydrophilic polymer Polymers 0.000 description 7
- 230000007774 longterm Effects 0.000 description 7
- 230000014759 maintenance of location Effects 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- 229920001223 polyethylene glycol Polymers 0.000 description 7
- -1 polypropylene Polymers 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 6
- 229920002845 Poly(methacrylic acid) Polymers 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000009792 diffusion process Methods 0.000 description 6
- 210000002919 epithelial cell Anatomy 0.000 description 6
- 210000000981 epithelium Anatomy 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 102000006495 integrins Human genes 0.000 description 6
- 108010044426 integrins Proteins 0.000 description 6
- 238000006116 polymerization reaction Methods 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 238000001356 surgical procedure Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 238000005187 foaming Methods 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- 210000004379 membrane Anatomy 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 238000010899 nucleation Methods 0.000 description 5
- 235000015097 nutrients Nutrition 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 230000002093 peripheral effect Effects 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 230000007480 spreading Effects 0.000 description 5
- 238000003892 spreading Methods 0.000 description 5
- 238000010186 staining Methods 0.000 description 5
- 231100000331 toxic Toxicity 0.000 description 5
- 230000002588 toxic effect Effects 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 239000004971 Cross linker Substances 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 229920001222 biopolymer Polymers 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 238000001125 extrusion Methods 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 210000001650 focal adhesion Anatomy 0.000 description 4
- 238000010348 incorporation Methods 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000002356 single layer Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 230000035899 viability Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
- 229930182816 L-glutamine Natural products 0.000 description 3
- 229920002125 Sokalan® Polymers 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 230000004888 barrier function Effects 0.000 description 3
- 238000001574 biopsy Methods 0.000 description 3
- 230000001851 biosynthetic effect Effects 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 210000003239 corneal fibroblast Anatomy 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 208000030533 eye disease Diseases 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 238000001879 gelation Methods 0.000 description 3
- 230000001976 improved effect Effects 0.000 description 3
- 239000003999 initiator Substances 0.000 description 3
- 230000004410 intraocular pressure Effects 0.000 description 3
- 238000011326 mechanical measurement Methods 0.000 description 3
- 239000000178 monomer Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000003361 porogen Substances 0.000 description 3
- 210000000130 stem cell Anatomy 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 238000002054 transplantation Methods 0.000 description 3
- 230000000007 visual effect Effects 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- BGWLYQZDNFIFRX-UHFFFAOYSA-N 5-[3-[2-[3-(3,8-diamino-6-phenylphenanthridin-5-ium-5-yl)propylamino]ethylamino]propyl]-6-phenylphenanthridin-5-ium-3,8-diamine;dichloride Chemical compound [Cl-].[Cl-].C=1C(N)=CC=C(C2=CC=C(N)C=C2[N+]=2CCCNCCNCCC[N+]=3C4=CC(N)=CC=C4C4=CC=C(N)C=C4C=3C=3C=CC=CC=3)C=1C=2C1=CC=CC=C1 BGWLYQZDNFIFRX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229920001661 Chitosan Polymers 0.000 description 2
- 102000029816 Collagenase Human genes 0.000 description 2
- 108060005980 Collagenase Proteins 0.000 description 2
- 108010067306 Fibronectins Proteins 0.000 description 2
- 102000016359 Fibronectins Human genes 0.000 description 2
- 239000012981 Hank's balanced salt solution Substances 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000003466 anti-cipated effect Effects 0.000 description 2
- 210000002469 basement membrane Anatomy 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000013060 biological fluid Substances 0.000 description 2
- 229920001400 block copolymer Polymers 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- BQRGNLJZBFXNCZ-UHFFFAOYSA-N calcein am Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(CN(CC(=O)OCOC(C)=O)CC(=O)OCOC(C)=O)=C(OC(C)=O)C=C1OC1=C2C=C(CN(CC(=O)OCOC(C)=O)CC(=O)OCOC(=O)C)C(OC(C)=O)=C1 BQRGNLJZBFXNCZ-UHFFFAOYSA-N 0.000 description 2
- 210000000845 cartilage Anatomy 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 125000004386 diacrylate group Chemical group 0.000 description 2
- 235000015872 dietary supplement Nutrition 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 238000002091 elastography Methods 0.000 description 2
- 238000005538 encapsulation Methods 0.000 description 2
- 210000003038 endothelium Anatomy 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- STVZJERGLQHEKB-UHFFFAOYSA-N ethylene glycol dimethacrylate Chemical compound CC(=C)C(=O)OCCOC(=O)C(C)=C STVZJERGLQHEKB-UHFFFAOYSA-N 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 238000012744 immunostaining Methods 0.000 description 2
- 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 2
- 238000011068 loading method Methods 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- FRQMUZJSZHZSGN-HBNHAYAOSA-N medroxyprogesterone Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FRQMUZJSZHZSGN-HBNHAYAOSA-N 0.000 description 2
- 229960004616 medroxyprogesterone Drugs 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 210000002901 mesenchymal stem cell Anatomy 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 230000017074 necrotic cell death Effects 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000004814 polyurethane Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 230000001172 regenerating effect Effects 0.000 description 2
- 238000001878 scanning electron micrograph Methods 0.000 description 2
- 238000002791 soaking Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 210000004872 soft tissue Anatomy 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 210000003518 stress fiber Anatomy 0.000 description 2
- 229920002994 synthetic fiber Polymers 0.000 description 2
- 229920001059 synthetic polymer Polymers 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 238000002834 transmittance Methods 0.000 description 2
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 2
- 238000009827 uniform distribution Methods 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 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 1
- UPNUQQDXHCUWSG-UHFFFAOYSA-N 1-[6-(4-azido-2-nitroanilino)hexanoyloxy]-2,5-dioxopyrrolidine-3-sulfonic acid Chemical compound O=C1C(S(=O)(=O)O)CC(=O)N1OC(=O)CCCCCNC1=CC=C(N=[N+]=[N-])C=C1[N+]([O-])=O UPNUQQDXHCUWSG-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 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
- JAHNSTQSQJOJLO-UHFFFAOYSA-N 2-(3-fluorophenyl)-1h-imidazole Chemical compound FC1=CC=CC(C=2NC=CN=2)=C1 JAHNSTQSQJOJLO-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
- VHSHLMUCYSAUQU-UHFFFAOYSA-N 2-hydroxypropyl methacrylate Chemical compound CC(O)COC(=O)C(C)=C VHSHLMUCYSAUQU-UHFFFAOYSA-N 0.000 description 1
- LCSKNASZPVZHEG-UHFFFAOYSA-N 3,6-dimethyl-1,4-dioxane-2,5-dione;1,4-dioxane-2,5-dione Chemical group O=C1COC(=O)CO1.CC1OC(=O)C(C)OC1=O LCSKNASZPVZHEG-UHFFFAOYSA-N 0.000 description 1
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-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
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical class O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 108020004491 Antisense DNA Proteins 0.000 description 1
- 108020005544 Antisense RNA Proteins 0.000 description 1
- 241001436672 Bhatia Species 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 102000000503 Collagen Type II Human genes 0.000 description 1
- 108010041390 Collagen Type II Proteins 0.000 description 1
- 102000001187 Collagen Type III Human genes 0.000 description 1
- 108010069502 Collagen Type III Proteins 0.000 description 1
- 102000004266 Collagen Type IV Human genes 0.000 description 1
- 108010042086 Collagen Type IV Proteins 0.000 description 1
- 102000004427 Collagen Type IX Human genes 0.000 description 1
- 108010042106 Collagen Type IX Proteins 0.000 description 1
- 102000012432 Collagen Type V Human genes 0.000 description 1
- 108010022514 Collagen Type V Proteins 0.000 description 1
- 102000002734 Collagen Type VI Human genes 0.000 description 1
- 108010043741 Collagen Type VI Proteins 0.000 description 1
- 102000004510 Collagen Type VII Human genes 0.000 description 1
- 108010017377 Collagen Type VII Proteins 0.000 description 1
- 102000001191 Collagen Type VIII Human genes 0.000 description 1
- 108010069526 Collagen Type VIII Proteins 0.000 description 1
- 102000030746 Collagen Type X Human genes 0.000 description 1
- 108010022510 Collagen Type X Proteins 0.000 description 1
- 102000009736 Collagen Type XI Human genes 0.000 description 1
- 108010034789 Collagen Type XI Proteins 0.000 description 1
- 102000014870 Collagen Type XII Human genes 0.000 description 1
- 108010039001 Collagen Type XII Proteins 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- 206010063560 Excessive granulation tissue Diseases 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 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
- 241001441571 Hiodontidae Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102100023967 Keratin, type I cytoskeletal 12 Human genes 0.000 description 1
- 102100025759 Keratin, type II cytoskeletal 3 Human genes 0.000 description 1
- 108010065086 Keratin-12 Proteins 0.000 description 1
- 108010070918 Keratin-3 Proteins 0.000 description 1
- 102000007547 Laminin Human genes 0.000 description 1
- 108010085895 Laminin Proteins 0.000 description 1
- 241000145847 Moria Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical group ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 108010020346 Polyglutamic Acid Proteins 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 208000002158 Proliferative Vitreoretinopathy Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 108010067787 Proteoglycans Proteins 0.000 description 1
- 102000016611 Proteoglycans Human genes 0.000 description 1
- 206010038848 Retinal detachment Diseases 0.000 description 1
- 206010038934 Retinopathy proliferative Diseases 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000000150 Sympathomimetic Substances 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 206010060872 Transplant failure Diseases 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 206010064996 Ulcerative keratitis Diseases 0.000 description 1
- 108010006886 Vitrogen Proteins 0.000 description 1
- 108010031318 Vitronectin Proteins 0.000 description 1
- 102100035140 Vitronectin Human genes 0.000 description 1
- 206010048031 Wound dehiscence Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 210000001691 amnion Anatomy 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000000507 anthelmentic effect Effects 0.000 description 1
- 239000000921 anthelmintic agent Substances 0.000 description 1
- 229940124339 anthelmintic agent Drugs 0.000 description 1
- 230000002456 anti-arthritic effect Effects 0.000 description 1
- 230000003367 anti-collagen effect Effects 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 229940124346 antiarthritic agent Drugs 0.000 description 1
- 239000012984 antibiotic solution Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000000729 antidote Substances 0.000 description 1
- 229940075522 antidotes Drugs 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 229940125683 antiemetic agent Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 229940033495 antimalarials Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 229940005529 antipsychotics Drugs 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 229940125716 antipyretic agent Drugs 0.000 description 1
- 239000003816 antisense DNA Substances 0.000 description 1
- 229940064004 antiseptic throat preparations Drugs 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 229940121357 antivirals Drugs 0.000 description 1
- 210000001742 aqueous humor Anatomy 0.000 description 1
- 210000001188 articular cartilage Anatomy 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 238000006065 biodegradation reaction Methods 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 238000009530 blood pressure measurement Methods 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000000799 cathartic agent Substances 0.000 description 1
- 230000004956 cell adhesive effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000010382 chemical cross-linking Methods 0.000 description 1
- 229940112822 chewing gum Drugs 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 210000001612 chondrocyte Anatomy 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 239000003184 complementary RNA Substances 0.000 description 1
- 208000021921 corneal disease Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 239000005549 deoxyribonucleoside Substances 0.000 description 1
- 210000002555 descemet membrane Anatomy 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- NJDNXYGOVLYJHP-UHFFFAOYSA-L disodium;2-(3-oxido-6-oxoxanthen-9-yl)benzoate Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=CC(=O)C=C2OC2=CC([O-])=CC=C21 NJDNXYGOVLYJHP-UHFFFAOYSA-L 0.000 description 1
- 108010007093 dispase Proteins 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000013013 elastic material Substances 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- 229940066493 expectorants Drugs 0.000 description 1
- 230000035557 fibrillogenesis Effects 0.000 description 1
- 230000001497 fibrovascular Effects 0.000 description 1
- 238000012632 fluorescent imaging Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229920000370 gamma-poly(glutamate) polymer Polymers 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 210000001126 granulation tissue Anatomy 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000002706 hydrostatic effect Effects 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000008629 immune suppression Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000007373 indentation Methods 0.000 description 1
- 238000009540 indirect ophthalmoscopy Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000030214 innervation Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 210000003963 intermediate filament Anatomy 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000001459 lithography Methods 0.000 description 1
- 229940083747 low-ceiling diuretics xanthine derivative Drugs 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- LVHBHZANLOWSRM-UHFFFAOYSA-N methylenebutanedioic acid Natural products OC(=O)CC(=C)C(O)=O LVHBHZANLOWSRM-UHFFFAOYSA-N 0.000 description 1
- 210000003632 microfilament Anatomy 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000001089 mineralizing effect Effects 0.000 description 1
- 235000013379 molasses Nutrition 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- 210000000107 myocyte Anatomy 0.000 description 1
- ZEMHQYNMVKDBFJ-UHFFFAOYSA-N n-(3-hydroxypropyl)prop-2-enamide Chemical compound OCCCNC(=O)C=C ZEMHQYNMVKDBFJ-UHFFFAOYSA-N 0.000 description 1
- 208000021971 neovascular inflammatory vitreoretinopathy Diseases 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 239000000734 parasympathomimetic agent Substances 0.000 description 1
- 230000001499 parasympathomimetic effect Effects 0.000 description 1
- 229940005542 parasympathomimetics Drugs 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- CTRLRINCMYICJO-UHFFFAOYSA-N phenyl azide Chemical group [N-]=[N+]=NC1=CC=CC=C1 CTRLRINCMYICJO-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 210000005152 placental membrane Anatomy 0.000 description 1
- 229940012957 plasmin Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 108010064470 polyaspartate Proteins 0.000 description 1
- 108010077051 polycysteine Proteins 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 239000002685 polymerization catalyst Substances 0.000 description 1
- 239000003505 polymerization initiator Substances 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229920006324 polyoxymethylene Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 108010000222 polyserine Proteins 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229940070017 potassium supplement Drugs 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000006785 proliferative vitreoretinopathy Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000001902 propagating effect Effects 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000011555 rabbit model Methods 0.000 description 1
- 239000002534 radiation-sensitizing agent Substances 0.000 description 1
- 238000011536 re-plating Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000004264 retinal detachment Effects 0.000 description 1
- 108700038288 rhodamine-phalloidin Proteins 0.000 description 1
- 239000002342 ribonucleoside Substances 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000004626 scanning electron microscopy Methods 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 210000004927 skin cell Anatomy 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000007779 soft material Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002195 soluble material Substances 0.000 description 1
- 210000004085 squamous epithelial cell Anatomy 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 229940064707 sympathomimetics Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 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 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229920001187 thermosetting polymer Polymers 0.000 description 1
- 230000025366 tissue development Effects 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/14—Eye parts, e.g. lenses, corneal implants; Implanting instruments specially adapted therefor; Artificial eyes
- A61F2/142—Cornea, e.g. artificial corneae, keratoprostheses or corneal implants for repair of defective corneal tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
-
- 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
-
- 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
- A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
-
- 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
- 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
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
- A61L27/48—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with macromolecular fillers
-
- 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
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/56—Porous materials, e.g. foams or sponges
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N11/00—Carrier-bound or immobilised enzymes; Carrier-bound or immobilised microbial cells; Preparation thereof
- C12N11/02—Enzymes or microbial cells immobilised on or in an organic carrier
- C12N11/04—Enzymes or microbial cells immobilised on or in an organic carrier entrapped within the carrier, e.g. gel or hollow fibres
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/16—Materials or treatment for tissue regeneration for reconstruction of eye parts, e.g. intraocular lens, cornea
Definitions
- the cornea is an avascular and optically transparent tissue that refracts and filters light rays before they enter the eye.
- a clear cornea is essential for clear vision.
- the cornea may become opacified following injuries, degenerations or infections.
- the Vision Share Consortium estimates that corneal blindness affects more than 10 million patients worldwide (Carlsson, et al. (2003) Curr. Opin. Ophthalmol. 14 ( ) : 192-7 ) .
- the gold standard treatment is surgical replacement of the cornea using freshly donated cadaver human corneas. Currently, about 40,000 corneal transplants are performed each year in the United States
- porous polymers including polytetrafluroethylene, poly-urethane, poly (2- hydroxyethyl methacrylate) (Carlsson, et al . (2003) supra), and poly (ethylene glycol) (Myung, et al . (2007) supra) have been investigated. While the pores provide a physical pathway for cellular migration from host to implant, they do not provide biological cues for cells to adhere, survive and secrete extracellular matrix. It is apparent that cells respond differently to extracellular cues presented in a three dimensional (3-D) versus a two dimensional (2-D) context. Cell adhesion is markedly altered in 2-D due to the artificial polarity created by the air-substrate interface.
- a 3-D extracellular environment is a key component contributing to the success of a tissue engineering scaffold.
- tissue engineering scaffolds are largely limited by diffusion capabilities. Therefore, a porous system is necessary to facilitate nutrient and waste exchange throughout the construct (Karande, et al. (2004) Ann. Biomed. Eng. 32 ( 12 ): 1728-43 ; Karageorgiou & Kaplan (2005) Biomaterials 26 (27 ): 5474-91) .
- Pores are also advantageous post-implantation where they can serve as conduits for host cell integration.
- the surrounding tissue including blood vessels and neurons, can migrate into the scaffold via the interconnected pore network further cementing the construct within the tissue.
- US Patent No. 6,960,617 describes the use of hydrogels with improved elasticity and mechanical strength.
- the hydrogels taught are superporous and are used to form a network of polymer chains.
- the patent does not teach or suggest combining any other compound with the hydrogel in order to improve the function or biocompatibility of the polymer .
- the epithelium is the outermost layer of the cornea composed of squamous epithelial cells.
- the main functions of the epithelium are to block foreign materials from entering the eye, and to absorb oxygen and nutrients for the cornea.
- Bowman's layer is an acellular sheet of collagen separating the epithelium from the stroma.
- the stroma located beneath Bowman's layer, is composed of water, collagen, and keratocytes, and is devoid of blood vessels. Below the stroma lies Descemet's membrane, another acellular layer that separates the stroma from the endothelium.
- the endothelium is the innermost layer which serves as a pump to regulate the hydration lever of the cornea .
- Collagen matrices support cell growth and differentiation (Sun, et al. (2004) Tissue Eng. 10(9- 10):1548-57; Yoneno, et al. (2005) J. Biomed. Mater. Res. A 75 (3) : 733-41; Reyes & Garcia (2004) J. Biomed. Mater. Res. A 69 ( 4 ): 591-600 ) .
- Collagen is a natural component of human extracellular matrix and is the most abundant protein in mammalian tissue. In addition, collagen is non-toxic, biodegradable, and inexpensive. As an extracellular matrix (ECM) protein, collagen provides an array of integrin binding sites for cell adhesion.
- ECM extracellular matrix
- biosynthetic matrices are described by others.
- US 2004/0048796 teaches the use of collagen biofabric for medical and surgical applications.
- the collagen biofabric is prepared from a placental membrane preferably human, by decellularizing the amniotic membrane.
- US 2006/0083773 discloses artificial corneal implants designed to replace or augment the cornea.
- the implants disclosed are fabricated from a double network hydrogel that consists of biocompatible polymers, wherein at least one of the network polymers is based on a hydrophilic polymer, wherein the implant has epithelialization promoting biomolecules that are covalently linked to the surface of the double network hydrogel.
- the implant also a physiologic diffusion coefficient to allow passage of nutrients to the adhered cells.
- US 2006/0246113 teaches use of a biosynthetic matrix composed of a hydrogel that is formed by chemically cross- linking a synthetic polymer and a biopolymer.
- EP 1 741 457 discloses a biosynthetic matrix comprising a hydrogel which is formed by cross-linking a synthetic polymer and a biopolymer as well.
- none of the matrices described in the prior art has been successfully used to produce a corneal implant material with sufficient strength and biocompatibility for use in corneal replacement surgery. There remains a need for materials that can be used in corneal replacement surgery.
- the present invention is a hybrid scaffold for cornea regeneration comprising a superporous hydrogel copolymer, wherein said superporous hydrogel copolymer comprises poly (2-hydroxyethyl methacrylate) (PHEMA) and poly (methyl methacrylate) (PMMA) , and collagen in the pores of said superporous hydrogel copolymer.
- PHEMA poly (2-hydroxyethyl methacrylate
- PMMA poly (methyl methacrylate)
- Another object of the present invention is a suturable hybrid implant comprising a PHEMA-PMMA copolymer, and collagen in the pores of said PHEMA-PMMA copolymer.
- the suturable hybrid implant forms the skirt of a core-skirt keratoprosthesis for implanatation into a cornea.
- Another object of the present invention is a method for producing a suturable hybrid implant by mixing, in an aqueous solution, methylmethacrylate, 2-hydroxyethyl methacrylate, deionized water, pentaerythritol tetraacrylate, and diemthylformamide to form a superporous PHEMA-PMMA hydrogel solution; cooling the superporous PHEMA-PMMA hydrogel solution; adding collagen to the cooled superporous PHEMA-PMMA hydrogel solution to form a collagen-hydrogel solution; and incubating the collagen- hydrogel solution at 37 °C to create a suturable hybrid implant .
- Yet another object of the present invention is a method for producing a superporous PHEMA-PMMA hydrogel by mixing, in a solution, methylmethacrylate, 2-hydroxyethyl methacrylate, deionized water, pentaerythritol tetraacrylate (PETA) , and diemthylformamide (DMF) to form a superporous PHEMA-PMMA hydrogel, wherein DMF promotes dissolution of MMA and HEMA into a gel solution and PETA promotes crosslinking of the PHEMA-PMMA copolymer.
- PETA pentaerythritol tetraacrylate
- DMF diemthylformamide
- the solution contains methyl methacrylate at a concentration of 10% v/v, 2-hydroxyethyl methacrylate at a concentration of 45% v/v, 5 mg of PETA, 2 mg ammonium persulfate, 10 ⁇ ⁇ , ⁇ , ⁇ ', ⁇ '- tetramethylethylenediamine, DMF at a concentration of 6% v/v, and 22% deionized water.
- Figure 1 depicts the results of tensile strength testing on polymers of this invention. Porous PHEMA-PMMA copolymer, porous PHEMA-PEGDA copolymer and porous PEGDA polymer were compared in the testing. All materials were tested in their hydrated state. PHEMA-PMMA copolymer showed significantly greater tensile strength as compared to the PEGDA polymer as well as a copolymer of PHEMA-PEGDA.
- Figure 2 depicts the results of tensile strength testing on polymers of this invention. Porous salt porogen PHEMA-PMMA copolymer, porous gas-foamed PHEMA-PMMA copolymer, porous PHEMA-PMMA copolymer and porous PEGDA polymer were compared in the testing. All materials were tested in their hydrated state.
- Figure 3 shows the optimal transparency of polymers of this invention. Porous PHEMA-PMMA copolymers with varying amounts if PMMA (3.5, 7, 14, or 21%) were analyzed. Constructs produced with gas or sodium bicarbonate (salt construct) are indicated.
- the present invention is a hybrid scaffold composed of collagen intertwined in a poly (2-hydroxyethyl methacrylate) or PHEMA-based, or alternatively a poly (methyl methacrylate) or PMMA-based superporous hydrogel (SPH) to provide a method for complete 3-D cell adhesion that also encouraged cell ingrowth, while maintaining the overall mechanical strength of the SPH.
- this invention also includes a suturable hybrid implant.
- the suturable hybrid implant is composed of a PHEMA-PMMA copolymer and collagen.
- the hybrid implant provides for promotion of host integration and mass transport in vivo and can be used as the skirt in a core- skirt keratoprosthesis for corneal implant.
- the skirt-core keratoprosthesis model for corneal implants is one where the core permits vision while the skirt facilitates stable host integration.
- a method for producing a suturable hybrid implant which involves mixing, in an aqueous solution, methylmethacrylate (MMA) , 2-hydroxyethyl methacrylate (HEMA) , deionized water, pentaerythritol tetraacrylate, and diemthylformamide to form a superporous PHEMA-PMMA hydrogel solution; cooling the superporous PHEMA-PMMA hydrogel solution; adding collagen to the cooled superporous PHEMA-PMMA hydrogel solution to form a collagen-hydrogel solution; and incubating the collagen-hydrogel solution at 37 °C to create a suturable hybrid implant .
- MMA methylmethacrylate
- HEMA 2-hydroxyethyl methacrylate
- a device that fails to provide both sufficient host integration and full visual field is the Seoul Type Keratoprosthesis, which is composed of a PMMA optic and a skirt made of either polyurethane or polypropylene. Use of this device has resulted in a 66.7% anatomic retention rate at 68 months. All of these devices developed corneal melt leading to full exposure of the skirt.
- the Stanford Keratoprosthesis which is composed of a hybrid network of poly (ethylene glycol) and poly (acrylic acid) (PEG/PAA) in its central optic component.
- Alphacor retention at the 2 year follow up has been reported to be up to 62%, and topical use of medroxyprogesterone (MPG) post-operatively was found to be associated with fewer corneal stromal melts, the most frequent complication (Gomaa (2010) Clin. Exp. Ophthalmol . 38:211-224).
- MPG medroxyprogesterone
- other Alphacor complications have included retroprosthetic membrane formation, optic damage, and poor biointegration (Sheardown (2008) In Regenerative Medicine in the Cornea, pp. 1060-1071).
- wound dehiscence due to Alphacor' s inability to hold sutures was a common mode of failure during preclinical trials (Hicks, (1997) Austral. NZ J. Ophthalmol.
- the invention was developed by first investigating the use of a hybrid scaffold composed of collagen intertwined in a polyethylene glycol diacrylate (PEGDA)- based superporous hydrogel (SPH) .
- PEGDA polyethylene glycol diacrylate
- SPH superporous hydrogel
- the invention includes use of other SPH polymers to provide a method for complete 3-D cell adhesion that also encourages cell ingrowth, while maintaining the overall mechanical strength of the SPH.
- the hybrid scaffold is produced by dehydrating the SPH, then reswelling in a collagen-cell solution to create a hybrid scaffold without covalent bonding or close interactions between the materials. This method results in better 3-D cell adhesion compared to scaffolds created with intimate entangling of collagen and PEGDA polymer chains.
- the scaffold produced by the method of the invention is one with strong bulk properties, yet natural 3-D cell adhesive properties.
- the natural and synthetic gels of the instant hybrid scaffold are intertwined in a noncovalent, nonadherent fashion.
- the collagen of the hybrid scaffold is not attached to the walls of the superporous hydrogel, thereby allowing the collagen gel to contract.
- cells embedded within collagen are immersed in 3-D in the collagen gel and are not exposed to the walls of the superporous hydrogel. While collagen increases cell adhesion, retention, and ingrowth, the overall mechanics of the hybrid are not dependent on collagen and greatly resembles the superporous hydrogel.
- the hybrid superporous hydrogel provides mechanical stability and interconnected pores while the 3-D collagen matrix provides 3-D adhesive binding sites.
- the initial hybrid scaffold was composed of collagen and PEGDA, it was contemplated that this versatile method could be adapted to incorporate many different natural and synthetic materials as appropriate to a specific tissue type. Indeed, the instant hybrid scaffold is anticipated to be used effectively with or without preseeding cells based on the desired application.
- the implant with a peripheral skirt containing the hybrid material was less noticeable in the eye after 2 weeks.
- the hybrid skirt implant was well tolerated and biocompatible. Further, the results indicated that the hybrid skirt implant was better integrated with the surrounding eye tissue as compared to the implant without collagen .
- the present invention is a superporous hydrogel composed of a PHEMA-PMMA copolymer.
- This copolymer has now been shown to have unexpected improved properties when incorporated into a keratoprosthesis as compared to a PEGDA-based superporous hydrogel.
- This invention also provides for a novel method for forming a superporous hydrogel for application as a keratoprosthesis.
- the superporous hydrogel is formulated as a PHEMA-PMMA hybrid copolymer.
- the method of the invention involves mixing methyl methacrylate (MMA) , 2-hydroxyethyl methacrylate (HEMA) , pentaerythritol tetraacrylate (PETA) , ammonium persulfate, N, N, ' , ' -tetramethylethylenediamine (TEMED) , dimethylformamide (DMF) , and deionized water to form a gel solution.
- MMA methyl methacrylate
- HEMA 2-hydroxyethyl methacrylate
- PETA pentaerythritol tetraacrylate
- TEMED ammonium persulfate
- DMF dimethylformamide
- deionized water deionized water
- the use of DMF to dissolve PHEMA-PMMA in the gel solution is another novel feature of the present method of forming the superporous hydrogel of the present invention as it provides for dissolution of the PHEMA and PMMA while not destroying large pores that are an important feature of the PHEMA-PMMA copolymer.
- Stirring during the polymerization is a key step that leads to formation of large pores.
- the pores can be made larger by stirring the mixture up to a threshold temperature. Once the threshold temperature has been reached, the gel solution that results from the method of this invention develops a viscosity that is flexible enough to be placed into a contact lens-shaped mold, mimicking the curvature of the cornea.
- the formation of an inter-penetrating collagen network in the porous PHEMA-PMMA copolymer can take up to 36 hours due to the slow expansion of PHEMA-PMMA in aqueous solution.
- the construct that results is a suturable hybrid keratoprosthesis for implantation.
- the suturability of the copolymer of the instant invention is an important advance over other materials.
- the PHEMA-PMMA copolymer is mechanically stable in solution such as deionized water and phosphate-buffered saline (PBS) , while the copolymer is elastic enough to allow for pulling on the material with moderate force.
- the collagen network of the hybrid suturable keratoprosthesis of this invention facilitates migration of cells into the construct from the host.
- collagen fibers were shown to have formed within the pores of the PHEMA-PMMA implant.
- live cells calcein-AM staining
- dead cells ethidium homodimer-1
- PHEMA- PMMA copolymer maintains its integrity under moderate-to- mildly forceful tension, and also resists rupture following the insertion of a needle and the subsequent application of force.
- the PHEMA-PMMA copolymer of the invention provides for a suturable keratoprosthesis that is also capable of stable host integration.
- the porous PHEMA-PMMA copolymer with a collagen type I network embedded in the construct of the present invention represents a vastly improved artificial cornea (keratoprosthesis) .
- This invention satisfies the two major criteria that are not met by existing artificial corneas, i.e., cell migration/host integration and structural/mechanical stability that allows for suturing of the prosthesis.
- Data shows that the hybrid keratoprosthesxs of the present invention promotes cell ingrowth, and also exhibits the tensile strength needed for suturing and implantation.
- this invention provides a novel keratoprosthesis that could support full thickness cornea replacement surgeries.
- the present invention provides hybrid scaffolds composed of collagen and cells incorporated into the pores of a superporous hydrogel and a method for producing the same.
- a superporous hydrogel matrix refers to a semi-solid three-dimensional structure which is capable of absorbing a substantial amount of water due to the presence of a plurality of inter-connected macropores of average diameter size between about 100 nm and about 300 ⁇ .
- Superporous hydrogels can be produced as disclosed herein, i.e., a foaming reaction optimized for simultaneous polymerization, or any other suitable method employed in the art.
- the size of the macropores can be dependent on a number of factors including, e.g., the nature of the solvent or solvents in which the gel is formed and/or the amount of polymerization initiator or catalyst.
- Superporous is intended to mean that the matrix swells in solution In so far as uptake of material is based on capillary action rather than diffusion (Gemeinhart, et al. (2000) J. Biomater. Sci. Polym. Ed. 11 (12) : 1371-80; Gemeinhart, et al. (2001) J. Biomed. Mater. Res. 55(1) :54- 62), the instant superporous hydrogels can rapidly incorporate a variety of soluble materials, such as cells and proteins, within the pores of the scaffold matrix.
- Superporous hydrogels are composed of polymers that will swell, without dissolving, when placed in water or other biological fluids.
- Hydrogels can generally absorb a great deal of fluid and, at equilibrium, typically are composed of 60-90% fluid and only 10-30% polymer. Hydrogels are particularly useful due to the inherent biocompatibility of the cross-linked polymeric network (Hill-West, et al .
- Hydrogel biocompatibility can be attributed to hydrophilicity and ability to imbibe large amounts of biological fluids
- Hydrogel matrices of the invention are composed of synthetic hydrophilic polymers which have been synthetically produced and which are hydrophilic, but not necessarily water-soluble.
- synthetic hydrophilic polymers which can be used in the practice of the present invention are polyethylene glycol (PEG) ; polyoxyethylene; polymethylene glycol; polytrimethylene glycols; polyvinylpyrrolidones; poly(acrylic acid); poly (itaconic acid); poly (methacrylic acid); poly (hydroxypropyl acrylamide) (HPMA) ; poly (peptides ) such as polyglutamate, polylysine, polyaspartate, polyserine, polythreonine, polycysteine; and polyoxyethylene- polyoxypropylene block polymers; and copolymers, and derivatives and mixtures thereof.
- PEG polyethylene glycol
- polyoxyethylene polymethylene glycol
- polytrimethylene glycols polyvinylpyrrolidones
- the hydrophilic matrix is not a naturally occurring polymer such as a protein, starch, cellulose, heparin, or hyaluronic acid.
- the hydrogel matrix is a poly (methacrylic acid) polymer.
- the poly (methyacrylic acid) polymer is a PHEMA-PMMA copolymer
- the polymer must be biocompatible and hydrophilic, but crosslinked physically or chemically to prevent dissolution.
- Particularly suitable polymers include those which are extensively used in the modification of biologically active molecules because they lack toxicity, antigenicity, and immunogenicity; have a wide range of solubilities; are generally non-biodegradable and are easily excreted from most living organisms including humans .
- Superporous hydrogels of the present invention can be further modified to possess high mechanical strength by incorporating a cross-linked hydrophilic agent such as sodium alginate, pectin, chitosan, or (polyvinyl) alcohol that can crosslink after the matrix is formed (Omidian, et al. (2006) Macromol. Biosci. 6:703-10). Hydrogels can also be made degradable in vivo by incorporating PLA, PLGA or PGA polymers.
- a cross-linked hydrophilic agent such as sodium alginate, pectin, chitosan, or (polyvinyl) alcohol that can crosslink after the matrix is formed (Omidian, et al. (2006) Macromol. Biosci. 6:703-10).
- Hydrogels can also be made degradable in vivo by incorporating PLA, PLGA or PGA polymers.
- superporous hydrogels can be modified with fibronectin, laminin, vitronectin, or, for example, RGD for surface modification, which can promote cell adhesion and proliferation (Heungsoo Shin (2003) Biomaterials 24:4353-4364; Hwang, et al. (2006) Tissue Eng. 12:2695-706).
- RGD for surface modification
- altering molecular weights, block structures, degradable linkages, and cross-linking modes can influence strength, elasticity, and degradation properties of the instant hydrogels (Nguyen & West (2002) Biomaterials 23 (22 ): 4307-14 ; Ifkovits & Burkick (2007) Tissue Eng. 13 ( 10 ): 2369-85 ) .
- Superporous hydrogels can also be modified with functional groups for covalently attaching a variety of proteins (e.g., collagen) or compounds such as therapeutic agents.
- Therapeutic agents which can be linked to the matrix include, but are not limited to, analgesics, anesthetics, antifungals, antibiotics, anti-inflammatories , anthelmintics, antidotes, antiemetics, antihistamines, antihypertensives, antimalarials, antimicrobials, antipsychotics, antipyretics, antiseptics, antiarthritics , antituberculotics, antitussives, antivirals, cardioactive drugs, cathartics, chemotherapeutic agents, a colored or fluorescent imaging agent, corticoids (such as steroids) , antidepressants, depressants, diagnostic aids, diuretics, enzymes, expectorants, hormones, hypnotics, minerals, nutritional supplements, parasympathomimetics, potassium supplements, radiation sensitizers
- the therapeutic agent can also be other small organic molecules, naturally isolated entities or their analogs, organometallic agents, chelated metals or metal salts, peptide-based drugs, or peptidic or non-peptidic receptor targeting or binding agents. It is contemplated that linkage of the therapeutic agent to the matrix can be via a protease sensitive linker or other biodegradable linkage.
- the polymers of the instant hydrogels can further contain a means for controlled biodegradation to facilitate removal of the matrix polymer from the subject being treated.
- hydrogels can be made to biodegrade at a faster rate by modification (Sawhney, et al . (1994) J. Biomed. Mater. Res. 28:831-838).
- Hydrogels can be made biodegradable by incorporating a biodegradable cross linker or by utilizing biodegradable copolymers (Sawhney, et al. (1993) Macromolecules 26:581-587; Park, et al . Biodegradable Hydrogels for Drug Delivery. 1993, Lancaster, PA: Technomic Pub.
- telechelic biodegradable block copolymers specifically degraded by either plasmin or crude collagenases , have been used in cross-linked hydrogels (West, et al . (1999) Macromolecules, 32:241-244). The extent and rate or degradation is controlled by the specific degradation mechanism used thereby limiting accumulation of the matrix at the site of implantation.
- hydrogels of the invention can be produced by gas foaming methods, wherein a hydrogel precursor solution is prepared and a foaming agent is added thereto to produce foam, which gels or polymerizes to form a matrix with a plurality of macropores dispersed therein.
- a precursor solution is defined as the mixture of components which are combined to produce the superporous hydrogel structure, but lacks a foaming agent which facilitates foam formation and gelling or polymerization of the hydrogel.
- a precursor solution of the invention can include, but is not limited to, a hydrophilic polymer, an initiator, and a foam stabilizer. Suitable hydrophilic polymers are disclosed herein.
- Suitable initiators include, e.g., APS/TEMED and a suitable foam stabilizer can be a block copolymer such as PLURONIC F-127.
- a foaming agent can be a chemical or physical foaming agent.
- the foaming agent is a salt, such as sodium bicarbonate.
- the foaming agent is a gas, e.g., compressed air or nitrogen. Other foaming agents of use in the gas foaming method are known to those of skill in the art.
- the superporous hydrogel matrix is dehydrated.
- the hydrogel matrix can be dehydrated by any suitable chemical and/or physical means.
- dehydration can be achieved using a combination of alcohol (e.g., ethanol) and a dehydrator.
- the present invention is a method for producing a superporous PHEMA-PMMA hydrogel which comprises mixing in a solution methylmethacrylate
- MMA 2-hydroxyethyl methacrylate
- HEMA 2-hydroxyethyl methacrylate
- PETA pentaerythritol tetraacrylate
- the method of the present invention involves mixing 10% v/v MMA, 45% v/v HEMA, 5 mg PETA, 2 mg ammonium persulfate, 10 ⁇ ⁇ , ⁇ , N' , ⁇ ' -tetramethylethylenedxamxne (TEMED) , 6% v/v DMF, and 22% deionized water.
- the hydrogel matrix is reswelled or rehydrated in a solution containing the molecule of interest with or without the cells.
- Molecules which can be incorporated into the pores of the superporous hydrogel matrix include, but are not limited to, vitamins and other nutritional supplements; glycoproteins (e.g., collagen); fibronectin; peptides and proteins; carbohydrates (both simple and/or complex) ; proteoglycans; antigens; oligonucleotides (sense and/or antisense DNA and/or RNA) ; antibodies (for example, to infectious agents, tumors, drugs or hormones) ; and gene therapy reagents.
- the molecule of interest is collagen.
- the collagen is Type I collagen.
- the molecule of interest is in a biologically compatible solution, i.e., a solution which is non-toxic in vivo. Suitable solutions include, but are not are limited to, water, saline, a buffer and the like.
- Type I collagen is the most abundant collagen of the human body. It is present in scar tissue, tendons, and the organic part of bone. Type II collagen is a component of articular cartilage and is found in association with Type IX collagen, whereas Type III collagen is the collagen of granulation tissue, and is produced quickly by young fibroblasts before the tougher type I collagen is synthesized. Type XII collagen is found to interact with types I and III collagen. Type IV collagen is part of the basal lamina. Type V and Type VI collagen are components of most interstitial tissue and are associated with type I collagen. Type VII collagen is a component of the epithelia as is Type VIII collagen.
- Type X collagen is hypertrophic and part of mineralizing cartilage, whereas Type XI collagen is a component of cartilage. Therefore, depending on the site of implantation and the intended therapeutic result, one or more collagens can be incorporated into the pores of the superporous hydrogel matrix.
- Collagens can be obtained in solution as a pepsin-solubilized collagen dissolved in acid (e.g., Vitrogen; ANGIOTECH® Biomaterials , Palo Alto, CA) .
- the collagen can be neutralized (e.g., to pH 7.0 to pH 7.4 with NaOH) , and directly incorporated into the superporous hydrogel matrix or combined with a cell of interest and be incorporated into the superporous hydrogel matrix.
- the collagen can than be solidified via fibrillogenesis (e.g., at 24°C to 37°C in the presence or absence of .CO 2 ) with cells suspended therein.
- type I collagen is incorporated into the pores of the superporous PHEMA-PMMA hydrogel of the present invention. This is accomplished by adding collagen to a cooled PHEMA-PMMA hydrogel solution (approximately 2-8 °C), wherein the solution remains cooled throughout the collagen absorption process. Once the collagen has incorporated into the PHEMA-PMMA solution, the collagen solution is incubated at 37 °C for one hour in a cell incubator. The resulting product is a suturable hybrid implant or a suturable hybrid keratoprosthesis .
- the cells can be combined with the solution containing the molecule of interest prior or after the solution has be used to reswell or rehydrate the hydrogel .
- the cells are added to the solution prior to reswelling the hydrogel.
- Types of cells of particular use in this invention include, but are not limited to, stem cells, fibroblasts, epithelial cells, endothelial cells, mesenchymal cells, insulin-producing islet cells, hepatocytes, myocytes, neurons, chondrocytes, skin cells, bone marrow cells, and the like.
- the cells can be autogenic, allogenic or xenogenic with respect to the subject receiving the instant hybrid superporous hydrogel.
- Cells can be isolated from biopsy samples or generated by differentiation and expansion of stems cells using conventional methods.
- some embodiments embrace encapsulation of cells within the hydrogel itself, e.g., by adding cells to the hydrogel precursor solution prior to polymerization.
- Cells encapsulated within the hydrogel matrix and hydrogel pores can be the same or different. For example, one could encapsulate stem cells in the hydrogel matrix and encapsulate cells capable of producing growth or differentiation factors in the pores, or vice versa.
- the present invention further embraces coating one or more surfaces of the hybrid superporous hydrogel matrix with one or more of the cell types disclosed herein.
- the present- invention embraces attaching epithelial cells to the surface of the hybrid hydrogel matrix via a layer of collagen.
- the invention embraces the inclusion of a central core in the hybrid hydrogel which is filled with one or more optically clear macromers .
- a macromer is optically clear when it can transmit light at wavelengths ranging from 200 nm to 1000 nm and has a reflective index of more than 1 or more desirably more than 1.3.
- Suitable macromers include, e.g., the hydrophilic polymers disclosed herein.
- the optically clear macromer is PEGDA.
- the components and fabrication method of the invention are not toxic to cells and enables the incorporation of cells within the pores of the superporous hydrogel.
- Such hydrogels find application as biological scaffolds for maintaining and growing cells and in the functional replacement of injured or damaged organs of the body.
- the instant hybrid superporous hydrogel is used in the preparation of a variety of formed implants for use in medical applications.
- the superporous hydrogel is designed to provide cells to a damaged or injured site to facilitate regeneration.
- the instant composition is useful for providing localized delivery of cells to a subject. Such delivery can be used to, e.g., promote wound healing and in tissue regeneration or replacement.
- the hydrogels of the present invention are used in tissue engineering or regenerative medicine, as a model organ system for drug testing, or for use in cell expansion.
- the instant hybrid superporous hydrogel is used in the preparation of an artificial cornea.
- specific embodiments embrace the incorporation of collagen and corneal fibroblasts into the pores of the superporous hydrogel .
- the superporous hydrogel of the invention can be used alone or in admixture of a pharmaceutically acceptable carrier in a pharmaceutical composition.
- a pharmaceutically acceptable carrier in a pharmaceutical composition.
- Suitable formulations for use in the present invention are found in Remington: The Science and Practice of Pharmacy, Alfonso R. Gennaro, editor, 20th ed. Lippincott Williams & Wilkins: Philadelphia, PA, 2000.
- Exemplary carriers include, e.g., water, saline, a buffer and the like.
- the compositions can also contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents, detergents and the like.
- compositions of the invention can be formulated for any appropriate manner of administration, including for example, topical, subcutaneous implantation or intramuscular implantation depending on the site at which cells are to be delivered and the disease or condition be treated.
- the present method of producing a hybrid superporous scaffold is simple, inexpensive, and versatile. Therefore, it can be applied to many tissue engineering applications including skeletal and soft tissue applications.
- the hybrid superporous hydrogen can be used in bone tissue engineering.
- Hydrolytic linkages can be incorporated within the SPH to create degradable and non toxic by products over time. Drugs or molecules could be loaded within the SPH for controlled release situations.
- Both natural and synthetic materials can be altered to produce specifically desired properties.
- a PEGDA-based polymer cannot withstand tensile forces including suturing.
- the PHEMA-P A copolymer of the present invention possesses sufficient tensile strength for suturing.
- one of skill would choose the superporous hydrogel of the present invention based on the desired properties.
- MSCs Human mesenchymal stem cells
- FBS fetal bovine serum
- HT-1080 human fibrosarcoma cell line was purchased from ATCC (Manassas, VA) .
- Fibroblasts were bathed in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 1% antibiotics/antimycotics .
- DMEM Dulbecco's Modified Eagle's Medium
- FBS fetal bovine serum
- Rat tail collagen type I (BD Biosciences, San Diego, CA) was mixed with 0.1 N NaOH, 10X Hank's Balanced Salt Solution (HBSS) , and 0.1 N acetic acid at a volume ratio of 3:2:1:1. This created a neutral pH collagen solution at a concentration of 1 mg/mL. If cell seeding was desired, cells were suspended in the collagen solution at a concentration of 1 millions cells/mL to encapsulate them in a 3-D network. Soaking a dehydrated SPH in this solution allowed uptake of cells and collagen within the pores. Collagen gelation was initiated by warming to 37 °C for 30 minutes. If pre-seeding with cells was not desired, the SPH was soaked in the collagen solution without cells. Again gelation occurred by warming to 37 °C for 30 minutes.
- HBSS Hank's Balanced Salt Solution
- the amount of sodium bicarbonate was varied from 100 to 300 mg to create differences in pore architecture. SPHs were rinsed in water to remove unreacted sodium bicarbonate crystals. To prevent pore collapse, the scaffolds were dehydrated in ethanol overnight. Scaffolds were then further dehydrated in a food dehydrator for 45 minutes. Cut sections were placed under UV light for 20 minutes to sterilize.
- the gel solution used to create the porous ⁇ - ⁇ ⁇ copolymer included: 10% v/v methyl methacrylate (MMA) (Aldrich M55909) , 45% v/v 2-hydroxyethyl methacrylate (HEMA) (Aldrich 525464), 5 mg pentaerythritol tetraacrylate (PETA), 2 mg APS, 10 ⁇ . TEMED, 6% v/v dimethylformamide, and 22% deionized water.
- the gel was mixed until a viscosity comparable to soft chewing gum was achieved. Next, the gel was inserted into a mold. The product was polymerized at 37 °C in dry heat for 24 hours. Following polymerization, the gel was rinsed in deionized water ' for up to one week. For long-term storage, water rinsed gels were desiccated at 37 °C in dry heat for 1 day.
- PHEMA sponge US 5,458,819
- PHEMA-PMMA construct dimethylformamide (DMF) and pentaerythritol tetraacrylate were added to the mixture of MMA and HEMA monomers.
- DMF dimethylformamide
- pentaerythritol tetraacrylate was added to the mixture of MMA and HEMA monomers.
- DMF was found to be an important process that facilitated dissolving PHEMA-PMMA polymers. Incorrect use of DMF led to destruction of pores.
- Use of, pentaerythritol tetraacrylate as a crosslinker is unique in that it allowed PHEMA-PMMA crosslinking with desired mechanical properties.
- the gel-like solution develops a viscosity that is comparable to molasses and is flexible enough to be placed into a contact lens-shaped mold, mimicking the curvature of the cornea.
- the process for forming an inter-penetrating collagen network in the porous PHEMA-PMMA can take up to 36 hours due to the slow expansion of PHEMA-PMMA in aqueous solution.
- the polymer construct was sterilized under ultraviolet light for 30 minutes.
- Collagen gel (1-5 mg/ml) was made using rat tail collagen type I (BD Bioscience) according to the BD Bioscience protocol. Human collagen was easily incorporated and concentrations of 1-5 mg/ml of collagen appeared to support cell seeding and attachment.
- the collagen gel solution was added to the cooled and dehydrated PHEMA-PMMA. The sample and an ice pack were covered to maintain cool temperature.
- the PHEMA-PMMA sample must remain cooled, approximately 2-8 °C, throughout the collagen absorption process.
- the construct now referred to as the suturable hybrid implant, was incubated at 37 °C for 1 hour in a cell incubator to create the collagen gel.
- Pore Architecture and Swelling Measurements A scanning electron microscope was used to picture the pore architecture of the SPH. SPHs made with varying amounts of sodium bicarbonate were imaged. Rapid swelling to large volumes is an important feature for this application. A swelling ratio, Q, was determined by comparing the mass of the swollen SPH to the mass of the dehydrated SPH. Dehydrated structures of varying pore sizes were soaked in water for at least 20 minutes. All SPHs were centrifuged at 1000 rpm for 3 minutes to remove air bubbles. SPHs were strained with a sieve, to remove excess water, and weighed. This mass represents the water accumulated in the pores as well as in the hydrogel structure itself.
- QHydrogei Water Weight Hy drogel Water/Weight De hydrated [0053] Cell Staining. SPH constructs with and without collagen were used as 3-D fibroblast scaffolds. Cells were loaded as described above and incubated for 24 and 48 hours. A focal adhesion kit (Chemicon, Temecula, CA) was used to visualize cell adhesion and retention. Rhodamine phalloidin stained microfilaments red and DAPI stained nuclei blue. A live/dead viability kit (Molecular Probes, Eugene, OR) was used to show cells that were alive (green) versus dead (red) . A BIO-RAD confocal microscope was used to image each of these structures.
- Compressive Measurements Compressive modulus of the SPH scaffolds was determined by compressive testing. Water swollen SPHs were sandwiched between two pieces of glass lined with VELCRO (to prevent slippage) and compared to collagen swollen SPHs. Incremental weights were placed atop and the amount of strain that each SPH withstood was recorded. A stress versus strain curve was plotted to determine an estimate of compressive modulus.
- a hydrogel solution was prepared by mixing 5% (w/v) of PEGDA in sterile PBS.
- a photoinitiator, IGRACURE 2959 (CIBA, Tarrytown, NY) was added to the PEGDA solution for a final concentration of 0.025% w/v. Cell viability was assessed in response to photoinitiator, UV light exposure, and PEGDA concentration.
- IGRACURE 2959 was the least toxic photoinitiator to mammalian cells. A concentration of 0.03% (w/v) or less is considered optimal (Williams, et al. (2005) Biomaterials 26 (11) : 1211-8) . Placing this solution under UV light (365 nm, 4 mW) for 10 minutes created a clear, polymerized gel. The gel was soaked in fresh PBS to remove unreacted monomers and initiator.
- the hybrid hydrogel of this invention is more convenient and better mimics natural living systems that generally lack the uniformity imposed by engineered constructs.
- collagen-loaded scaffolds showed cell retention within the scaffold and few if any cells attached to the plate below.
- Collagen within the hydrogel pores greatly enhanced cell spreading and retention in a 3-D manner.
- the microfilament stress fibers were clearly observed, indicating that cell adhesion was mediated by integrin binding sites available in collagen, leading to formation of focal adhesion.
- Corneal fibroblasts have been shown to express a variety of ⁇ family integrins, which can bind to collagen. In scaffolds without collagen, ⁇ - integrin was distributed uniformly around the periphery of the cell. However, in collagen-filled scaffolds, the ⁇ - integrins were punctuated and clustered at sites of focal adhesions. Addition of antibodies against ⁇ -integrins prevented cells from attaching and spreading on the collagens .
- this hybrid scaffold In addition to enhancing cell spreading and retention when embedded in the collagen of the pores, it was demonstrated that this hybrid scaffold also enhanced surrounding cell migration into the scaffold by virtue of an open pore structure and collagen binding.
- Acellular SPH scaffolds with and without collagen were placed on top of a monolayer of fibroblasts. Over 3 weeks, tremendous cellular ingrowth was observed into scaffold with collagen. The scaffold without collagen remained acellular. This demonstrated that pores alone are not sufficient for cellular ingrowth, and the incorporation of collagen greatly enhances this scaffold as an ideal tissue engineering scaffold. Good cell ingrowth is necessary for in vivo implantation so that host cells can migrate into the scaffold and form a strong integration with the surrounding tissue. This is also a conduit for nerve and blood vessel ingrowth which may be necessary for long term survival of the implant .
- the central optic of an artificial cornea should be clear and have an appropriate refractive index.
- qualitative and quantitative analyses of a 5% PEGDA was carried out.
- written text was viewed with and without an overlying hydrogel .
- Optical properties such as light transmission and refractive index of the central core were determined using a UV-Vis spectrophotometer and refractometer, respectively.
- the percent of light transmittance was measured in reference to PBS at wavelengths ranging from 200 nm to 1000 nm. All measurements were made in triplicate.
- the refractive index of the central optic was measured using a refractometer .
- the anterior surface of a hybrid hydrogel matrix is coated with epithelial cells to encourage host epithelialization to regenerate the protective and nutrient absorbing qualities of the epithelium.
- epithelium similar to Bowman's layer, a thin layer of nonporous PEGDA is used to separate the epithelium from the underlying stroma. PEGDA discourages cell binding and keeps cell types localized.
- stromal skirt collagen and cells are surrounded by PEGDA, a hydrogel that is capable of retaining large amounts of water to maintain an appropriate shape and hydration level.
- the hybrid superporous skirt is designed to allow maximal host cell integration through the pores and attachment to cell adhesion sites.
- the central core is kept free of collagen to maintain optical transparency.
- the nonporous PEGDA solution diffused into the immediate periphery and spread along the bottom surface of the SPH and deposited a thin layer of nonporous PEGDA on the anterior surface.
- the nonporous PEGDA was photopolymerized into this irregular shape.
- the anterior surface could then be modified with collagen so that epithelial cells could be attached for proliferation on the top surface.
- a water soluble heterobifunctional cross-linker such as sulfo-SANPAH (PierceNet) can be used to attach collagen type I to the surface of PEGDA.
- the N-hydroxysuccinimide group attaches to collagen proteins while the phenyl azide group photoreactively inserts into PEGDA.
- the presence of covalently bound collagen can be imaged with second harmonic generation using a multiphoton microscope. Compared to the stroma, the collagen on the surface will be a thin layer (1/10 of the concentration) .
- This thin layer of collagen is expected to support the growth of corneal epithelial cells as determined by, e.g., intermediate filament keratin-3 and keratin-12 expression. It is contemplated that this layer can be optimized for sufficient cell attachment while maintaining clarity. Clarity of the collagen layer can be assessed via UV-Vis spectrophotometry.
- Corneal epithelial cultures can obtained from rabbit limbal tissue of approximately 3x2 mm at the time of surgery. The tissue is treated with dispase (10 mg/ml) at 4°C overnight to disrupt the basement membrane. The epithelial sheets are peeled off and digested in 0.25% trypsin-EDTA at 37 °C for 5-10 minutes. Cells are washed and resuspended in keratinocyte serum-free medium (KSFM, Invitrogen) , and plated on collagen-coated tissue culture plates. When cells reach 80% confluency, epithelial cells are trypsinized and plated on the hybrid scaffold.
- KSFM keratinocyte serum-free medium
- the Young's modulus is calculated using Hertz' model : where F is indenting force; R is attached bead radius; ⁇ is indentation, assuming that ⁇ «R; E is Young's modulus, v is Poisson ratio (0.5 for incompressible sample); k is cantilever's spring constant, and d is cantilever's deflection.
- This model assumes a homogeneous, isotropic, semi-infinite elastic material. Also the surface should be flat, a conical or spherical tip should be used, and the indenter material should be much stiffer than the sample.
- the Young's modulus of a human donor cornea was reported as 1.3 MPa (Wollensak, et al. (2003) J. Cataract. Refract. Surg. 29 ( 9) : 1780-5) .
- the Young's modulus of the individual components of the artificial cornea were measured and found to be 2 MPa for a 5% PEGDA gel and ⁇ 1 kPa for a 1 mg/mL collagen gel.
- the contribution of collagens to the overall mechanical properties is expected to be minimal.
- the shear modulus of a hybrid scaffold can be determined using elastography .
- Elastography is a magnetic resonance-based technique that measures mechanical properties by propagating an electromagnetic wave through the material (Zerbe, et al. (2006) supra) .
- the system is ideal for mechanical measurements of soft tissues and complements the AFM measurements.
- This non-destructive 3D imaging technique can also measure the diffusion of water, which is a direct indication of the tissue structure and viability. When cells swell or cell membranes rupture, for example, water diffusion is more rapid due to fewer physical barriers.
- Example 7 Cell Migration into the Porous ⁇ .- ⁇ Hybrid Scaffold
- PHEMA-PMMA constructs were subcutaneously implanted into mice. Interconnected pores were not readily apparent in the SEM image of dehydrated PHEMA-PMMA; however, a small amount of cell ingrowth into the body of the structure was observed following 8 days of implantation under the skin of a mouse. This indicates that the additional pores lead to greater amounts of cell ingrowth.
- Example 8 Biocompatibility of an Artificial Cornea in a Animal Model
- the first step prior to implanting the artificial cornea is to obtain autologous corneal fibroblasts from the rabbit. This is done through a small corneal biopsy from the peripheral cornea. The corneal biopsy tissue is then digested in 1 mg/ml of collagenase overnight at 37 °C. The cells are washed and then plated in DMEM supplemented with 10% FCS (Sigma-Aldrich, St. Louis, MO), 4 mM L-glutamine and 1% antibiotic solution ( Invitrogen-GIBCO) . After a period of 10-14 days in culture, the fibroblasts are trypsinized and dispersed in collagen solution and incorporated into the superporous skirt of the artificial corneas .
- FCS Sigma-Aldrich, St. Louis, MO
- antibiotic solution Invitrogen-GIBCO
- the artificial corneas are surgically implanted into the rabbit cornea in a two stage procedure.
- the artificial cornea is implanted as a partial thickness replacement keeping the anterior cornea of the rabbit as a protective flap.
- a Moria microkeratome designed to make LASIK flaps
- a 130 pm flap of approximately 10 mm diameter is created. This in effect slices the cornea horizontally.
- the posterior aspect of the cornea which is now exposed is trephinated using an 8 mm trephine and the corneal implant composed of a 4 mm core and 2 mm skirt is sutured in place using interrupted 10-0 nylon sutures.
- the control rabbits receive the same implants but without any cells imbedded in the skirt.
- the anterior flap is placed back on top of the implant and sutured to the peripheral cornea using interrupted dissolvable 10-0 vicryl sutures.
- stage two the portion of the anterior flap which covers the clear zone of the implant is removed and the artificial cornea functions as a full-thickness replacement.
- the rationale for this staged procedure is to maintain the integrity of the cornea while allowing time for integration to take place. Specifically, animals are returned to the operating room 2 months after the initial implantation. The rabbits are placed under general anesthesia and the central 4 mm of the anterior flap covering the clear zone of the implant is trephinated and removed.
- the bio-integration and bio-compatibility of the artificial corneas will be evaluated histologically at 1 week, 2 weeks, 6 weeks, 3 months, and 6 months. Three pairs of rabbits (one experimental and one control) will be used for histopathology at each time point. The eyes will be subjected to routine histology and immuno-staining to evaluate the degree of epithelialization over the core, fibroblast ingrowth into the skirts, and capsule formation around the device. Immunostaining against smooth muscle actin will be used to identify fibroblasts in the superporous skirt. The number and extent of fibroblast penetration into the implant will be , graded by masked observers using serial sections starting from the periphery towards the center. The expression of collagen type I, ⁇ - integrin and focal adhesion complexes will likewise be evaluated. The results will be compared between the two groups .
- the integration of the artificial corneas will be mechanically tested according to conventional methods (Lee, et al. (2000) Arch. Ophthalmol. 118 ( 12 ): 1673-8 ) . These measurements will be performed on intact eyes that are enucleated after euthanasia. The intraocular pressure will be progressively increased inside and the pressure at which the host-prosthesis begins to leak will be recorded. These measurements will be done three pairs of eyes (one control, one experimental) for each time point starting at 6 weeks, then 3 months, and 6 months.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Transplantation (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Biomedical Technology (AREA)
- Zoology (AREA)
- Dispersion Chemistry (AREA)
- Biotechnology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Wood Science & Technology (AREA)
- Genetics & Genomics (AREA)
- Virology (AREA)
- Composite Materials (AREA)
- Vascular Medicine (AREA)
- Cell Biology (AREA)
- Developmental Biology & Embryology (AREA)
- Immunology (AREA)
- Ophthalmology & Optometry (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmacology & Pharmacy (AREA)
- Materials Engineering (AREA)
- Biophysics (AREA)
- Microbiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biochemistry (AREA)
- General Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Materials For Medical Uses (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP12842820.8A EP2771042A4 (en) | 2011-10-28 | 2012-10-26 | A suturable hybrid superporous hydrogel keratoprosthesis for cornea |
JP2014539042A JP2014533153A (en) | 2011-10-28 | 2012-10-26 | Sutureable hybrid superporous hydrogel artificial cornea for cornea |
CA2853714A CA2853714A1 (en) | 2011-10-28 | 2012-10-26 | A suturable hybrid superporous hydrogel keratoprosthesis for cornea |
IN3269CHN2014 IN2014CN03269A (en) | 2011-10-28 | 2012-10-26 | |
AU2012328583A AU2012328583A1 (en) | 2011-10-28 | 2012-10-26 | A suturable hybrid superporous hydrogel keratoprosthesis for cornea |
KR1020147014227A KR20140093966A (en) | 2011-10-28 | 2012-10-26 | A suturable hybrid superporous hydrogel keratoprosthesis for cornea |
CN201280060886.8A CN104144716A (en) | 2011-10-28 | 2012-10-26 | A suturable hybrid superporous hydrogel keratoprosthesis for cornea |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/284,301 | 2011-10-28 | ||
US13/284,301 US20120071580A1 (en) | 2008-07-31 | 2011-10-28 | Suturable Hybrid Superporous Hydrogel Keratoprosthesis for Cornea |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2013063390A1 true WO2013063390A1 (en) | 2013-05-02 |
Family
ID=48168545
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2012/062116 WO2013063390A1 (en) | 2011-10-28 | 2012-10-26 | A suturable hybrid superporous hydrogel keratoprosthesis for cornea |
Country Status (9)
Country | Link |
---|---|
US (1) | US20120071580A1 (en) |
EP (1) | EP2771042A4 (en) |
JP (1) | JP2014533153A (en) |
KR (1) | KR20140093966A (en) |
CN (1) | CN104144716A (en) |
AU (1) | AU2012328583A1 (en) |
CA (1) | CA2853714A1 (en) |
IN (1) | IN2014CN03269A (en) |
WO (1) | WO2013063390A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2646804C1 (en) * | 2016-12-28 | 2018-03-07 | федеральное государственное автономное образовательное учреждение высшего образования "Казанский (Приволжский) федеральный университет" (ФГАОУ ВО КФУ) | Ophthalmic agent for regeneration of cornea of the eye |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101617435B1 (en) | 2013-10-29 | 2016-05-02 | 주식회사 티이바이오스 | Method for manufacturing polyhydroxyethyl methacrylate/polymethyl methacrylate membrane |
CN103989553B (en) * | 2014-03-25 | 2017-01-11 | 周辉 | Method for manufacturing and storing corneal injury scar-free repairing device |
US20150308952A1 (en) * | 2014-04-23 | 2015-10-29 | Littelfuse, Inc. | Urea concentration sensor |
EP3490497A4 (en) | 2016-07-26 | 2020-03-25 | Singapore Health Services Pte Ltd | Optical cylinder and method of surface treatment of the same |
CN108727610B (en) * | 2018-06-11 | 2020-09-15 | 浙江大学 | Double-network hydrogel with high toughness, shape memory and self-repairing characteristics and preparation method thereof |
AU2019310647A1 (en) | 2018-07-24 | 2021-02-04 | Newsouth Innovations Pty Limited | Bio-ink for 3D printing |
US11950997B2 (en) * | 2019-05-20 | 2024-04-09 | The Trustees Of The Stevens Institute Of Technology | Artificial cornea with double-side microtextured pHEMA hydrogel |
CN110025402B (en) * | 2019-05-21 | 2021-09-24 | 王丽强 | Artificial cornea containing biological material |
KR102304034B1 (en) | 2019-11-27 | 2021-09-17 | 울산과학기술원 | A method for manufacturing artificial cornea |
WO2021195587A1 (en) * | 2020-03-26 | 2021-09-30 | The Trustees Of The Stevens Institute Of Technology | Artificial cornea with double-side microtextured phema hydrogel |
WO2022124542A1 (en) * | 2020-12-11 | 2022-06-16 | (주)티이바이오스 | Scaffold for artificial organs using acrylic synthetic polymers, and manufacturing method thereof |
KR102646243B1 (en) | 2022-03-07 | 2024-03-11 | 울산과학기술원 | A method and apparatus for manufacturing artificial cornea through image processing |
US20240108454A1 (en) * | 2022-10-03 | 2024-04-04 | EyeYon Medical Ltd. | Patch to treat corneal perforation |
CN117482289B (en) * | 2023-11-29 | 2024-05-28 | 山东第一医科大学附属眼科研究所(山东省眼科研究所、山东第一医科大学附属青岛眼科医院) | Preparation method of double-network multifunctional hydrogel with antibacterial and drug sequential release capabilities |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5300116A (en) * | 1992-08-05 | 1994-04-05 | Lions Eye Institute Of Western Australia | Keratoprosthesis |
US20060287721A1 (en) * | 2004-10-05 | 2006-12-21 | David Myung | Artificial cornea |
US20070233240A1 (en) * | 2004-10-05 | 2007-10-04 | Frank Curtis W | Intraocular lens implant |
US20080089940A1 (en) * | 2006-07-06 | 2008-04-17 | Hossein Omidian | Superporous Hydrogels for Heavy-Duty Applications |
US20100080840A1 (en) * | 2008-07-31 | 2010-04-01 | Michael Cho | Hybrid superporous hydrogel scaffold for cornea regeneration |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1530449A4 (en) * | 2002-06-18 | 2006-05-03 | Univ Leland Stanford Junior | Artificial cornea |
US8029515B2 (en) * | 2005-01-31 | 2011-10-04 | Yichieh Shiuey | Corneal implants and methods and systems for placement |
US9999497B2 (en) * | 2005-01-31 | 2018-06-19 | Yichieh Shiuey | Corneal implants and methods and systems for placement |
-
2011
- 2011-10-28 US US13/284,301 patent/US20120071580A1/en not_active Abandoned
-
2012
- 2012-10-26 AU AU2012328583A patent/AU2012328583A1/en not_active Abandoned
- 2012-10-26 CN CN201280060886.8A patent/CN104144716A/en active Pending
- 2012-10-26 EP EP12842820.8A patent/EP2771042A4/en not_active Withdrawn
- 2012-10-26 IN IN3269CHN2014 patent/IN2014CN03269A/en unknown
- 2012-10-26 WO PCT/US2012/062116 patent/WO2013063390A1/en active Application Filing
- 2012-10-26 CA CA2853714A patent/CA2853714A1/en not_active Abandoned
- 2012-10-26 KR KR1020147014227A patent/KR20140093966A/en not_active Application Discontinuation
- 2012-10-26 JP JP2014539042A patent/JP2014533153A/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5300116A (en) * | 1992-08-05 | 1994-04-05 | Lions Eye Institute Of Western Australia | Keratoprosthesis |
US20060287721A1 (en) * | 2004-10-05 | 2006-12-21 | David Myung | Artificial cornea |
US20070233240A1 (en) * | 2004-10-05 | 2007-10-04 | Frank Curtis W | Intraocular lens implant |
US20080089940A1 (en) * | 2006-07-06 | 2008-04-17 | Hossein Omidian | Superporous Hydrogels for Heavy-Duty Applications |
US20100080840A1 (en) * | 2008-07-31 | 2010-04-01 | Michael Cho | Hybrid superporous hydrogel scaffold for cornea regeneration |
Non-Patent Citations (1)
Title |
---|
See also references of EP2771042A4 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2646804C1 (en) * | 2016-12-28 | 2018-03-07 | федеральное государственное автономное образовательное учреждение высшего образования "Казанский (Приволжский) федеральный университет" (ФГАОУ ВО КФУ) | Ophthalmic agent for regeneration of cornea of the eye |
Also Published As
Publication number | Publication date |
---|---|
CN104144716A (en) | 2014-11-12 |
JP2014533153A (en) | 2014-12-11 |
EP2771042A1 (en) | 2014-09-03 |
IN2014CN03269A (en) | 2015-07-03 |
KR20140093966A (en) | 2014-07-29 |
EP2771042A4 (en) | 2015-08-05 |
AU2012328583A1 (en) | 2014-05-22 |
US20120071580A1 (en) | 2012-03-22 |
CA2853714A1 (en) | 2013-05-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20120071580A1 (en) | Suturable Hybrid Superporous Hydrogel Keratoprosthesis for Cornea | |
US20160144069A1 (en) | Suturable hybrid superporous hydrogel keratoprosthesis for cornea | |
Khosravimelal et al. | Hydrogels as emerging materials for cornea wound healing | |
CN101305052B (en) | Interpenetrating networks, and related methods and compositions | |
Myung et al. | Design and fabrication of an artificial cornea based on a photolithographically patterned hydrogel construct | |
US20100080840A1 (en) | Hybrid superporous hydrogel scaffold for cornea regeneration | |
He et al. | 3D printed biomimetic epithelium/stroma bilayer hydrogel implant for corneal regeneration | |
CA2848405C (en) | Fabrication of gelatin hydrogel sheet for the transplantation of corneal endothelium | |
Liu et al. | Collagen–phosphorylcholine interpenetrating network hydrogels as corneal substitutes | |
Myung et al. | Development of hydrogel‐based keratoprostheses: A materials perspective | |
Lai et al. | Effect of charge and molecular weight on the functionality of gelatin carriers for corneal endothelial cell therapy | |
JP2008093451A (en) | Implant for eye | |
Long et al. | Collagen–hydroxypropyl methylcellulose membranes for corneal regeneration | |
SE1551698A1 (en) | A composite collagen hydrogel material, an implantable ophthalmic device comprising such material and methods of producing the composite collagen hydrogel material and the implantable ophthalmic device | |
Lai et al. | Low Bloom strength gelatin as a carrier for potential use in retinal sheet encapsulation and transplantation | |
US20100303911A1 (en) | Hydrogel systems | |
Wang et al. | Injectable double-network hydrogel for corneal repair | |
Delaey et al. | Tissue engineered scaffolds for corneal endothelial regeneration: a material's perspective | |
Sharifi et al. | Electrospun-reinforced suturable biodegradable artificial cornea | |
Kadakia et al. | Hybrid superporous scaffolds: an application for cornea tissue engineering | |
US20230355844A1 (en) | Electrospun Reinforced Suturable Artificial Cornea and Uses Thereof | |
Polisetti et al. | Biomaterials-enabled regenerative medicine in corneal applications |
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: 12842820 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2853714 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2014539042 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
REEP | Request for entry into the european phase |
Ref document number: 2012842820 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2012842820 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2012328583 Country of ref document: AU Date of ref document: 20121026 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 20147014227 Country of ref document: KR Kind code of ref document: A |