CN117427215A - Gel type artificial cornea and preparation method thereof - Google Patents
Gel type artificial cornea and preparation method thereof Download PDFInfo
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- CN117427215A CN117427215A CN202311474165.8A CN202311474165A CN117427215A CN 117427215 A CN117427215 A CN 117427215A CN 202311474165 A CN202311474165 A CN 202311474165A CN 117427215 A CN117427215 A CN 117427215A
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- cornea
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- polyethylene glycol
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- 210000004087 cornea Anatomy 0.000 title claims abstract description 178
- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 54
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 54
- 102000008186 Collagen Human genes 0.000 claims abstract description 52
- 108010035532 Collagen Proteins 0.000 claims abstract description 52
- 229920001436 collagen Polymers 0.000 claims abstract description 52
- 150000002334 glycols Chemical class 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 229910052751 metal Inorganic materials 0.000 claims abstract description 26
- 239000002184 metal Substances 0.000 claims abstract description 26
- 239000000243 solution Substances 0.000 claims description 100
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- 230000001954 sterilising effect Effects 0.000 claims description 15
- 210000005252 bulbus oculi Anatomy 0.000 claims description 13
- 238000004659 sterilization and disinfection Methods 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 11
- 239000007853 buffer solution Substances 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 11
- 238000000502 dialysis Methods 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 5
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 4
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 claims description 4
- 229910001424 calcium ion Inorganic materials 0.000 claims description 4
- -1 dimethylsiloxane Chemical class 0.000 claims description 4
- 229910001447 ferric ion Inorganic materials 0.000 claims description 4
- 238000004108 freeze drying Methods 0.000 claims description 4
- 229910021645 metal ion Inorganic materials 0.000 claims description 4
- 238000007493 shaping process Methods 0.000 claims description 4
- SXGZJKUKBWWHRA-UHFFFAOYSA-N 2-(N-morpholiniumyl)ethanesulfonate Chemical compound [O-]S(=O)(=O)CC[NH+]1CCOCC1 SXGZJKUKBWWHRA-UHFFFAOYSA-N 0.000 claims description 3
- 238000005520 cutting process Methods 0.000 claims description 3
- DBLXOVFQHHSKRC-UHFFFAOYSA-N ethanesulfonic acid;2-piperazin-1-ylethanol Chemical compound CCS(O)(=O)=O.OCCN1CCNCC1 DBLXOVFQHHSKRC-UHFFFAOYSA-N 0.000 claims description 3
- 230000005856 abnormality Effects 0.000 claims description 2
- 238000010894 electron beam technology Methods 0.000 claims description 2
- 239000008363 phosphate buffer Substances 0.000 claims description 2
- 230000005855 radiation Effects 0.000 claims description 2
- 239000012266 salt solution Substances 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000028993 immune response Effects 0.000 abstract 1
- 239000000499 gel Substances 0.000 description 58
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 18
- 239000001110 calcium chloride Substances 0.000 description 16
- 229910001628 calcium chloride Inorganic materials 0.000 description 16
- 229910021642 ultra pure water Inorganic materials 0.000 description 15
- 239000012498 ultrapure water Substances 0.000 description 15
- 230000000052 comparative effect Effects 0.000 description 11
- 239000000463 material Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 6
- 239000003431 cross linking reagent Substances 0.000 description 6
- 239000000427 antigen Substances 0.000 description 5
- 102000036639 antigens Human genes 0.000 description 5
- 108091007433 antigens Proteins 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000017 hydrogel Substances 0.000 description 4
- 239000007943 implant Substances 0.000 description 4
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 3
- 101000718529 Saccharolobus solfataricus (strain ATCC 35092 / DSM 1617 / JCM 11322 / P2) Alpha-galactosidase Proteins 0.000 description 3
- NNISLDGFPWIBDF-MPRBLYSKSA-N alpha-D-Gal-(1->3)-beta-D-Gal-(1->4)-D-GlcNAc Chemical compound O[C@@H]1[C@@H](NC(=O)C)C(O)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@@H](CO)O1 NNISLDGFPWIBDF-MPRBLYSKSA-N 0.000 description 3
- 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 3
- 230000000694 effects Effects 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 238000002834 transmittance Methods 0.000 description 3
- BMTZEAOGFDXDAD-UHFFFAOYSA-M 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium;chloride Chemical compound [Cl-].COC1=NC(OC)=NC([N+]2(C)CCOCC2)=N1 BMTZEAOGFDXDAD-UHFFFAOYSA-M 0.000 description 2
- 201000004569 Blindness Diseases 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 230000000735 allogeneic effect Effects 0.000 description 2
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 229910000365 copper sulfate Inorganic materials 0.000 description 2
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 2
- 208000021921 corneal disease Diseases 0.000 description 2
- 229960003280 cupric chloride Drugs 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 230000005847 immunogenicity Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000010413 mother solution Substances 0.000 description 2
- 239000008055 phosphate buffer solution Substances 0.000 description 2
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000004926 polymethyl methacrylate Substances 0.000 description 2
- 230000002980 postoperative effect Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 230000009385 viral infection Effects 0.000 description 2
- ZSZRUEAFVQITHH-UHFFFAOYSA-N 2-(2-methylprop-2-enoyloxy)ethyl 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CC(=C)C(=O)OCCOP([O-])(=O)OCC[N+](C)(C)C ZSZRUEAFVQITHH-UHFFFAOYSA-N 0.000 description 1
- SHKUUQIDMUMQQK-UHFFFAOYSA-N 2-[4-(oxiran-2-ylmethoxy)butoxymethyl]oxirane Chemical compound C1OC1COCCCCOCC1CO1 SHKUUQIDMUMQQK-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 102000012422 Collagen Type I Human genes 0.000 description 1
- 108010022452 Collagen Type I 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
- 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
- 241001391944 Commicarpus scandens Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 101710137510 Saimiri transformation-associated protein Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 125000004386 diacrylate group Chemical group 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 238000001878 scanning electron micrograph Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—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
- A61L27/02—Inorganic materials
- A61L27/025—Other specific inorganic materials not covered by A61L27/04 - A61L27/12
-
- 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
- A61L27/18—Macromolecular materials obtained otherwise than 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
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified 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
- A61L27/50—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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Transplantation (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Dermatology (AREA)
- Public Health (AREA)
- Dispersion Chemistry (AREA)
- Biophysics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Materials For Medical Uses (AREA)
Abstract
The invention relates to a gel type artificial cornea and a preparation method thereof, and relates to the field of medical appliances. The gel type artificial cornea of the invention comprises 0.8-2.5 parts of cornea collagen, 8-15 parts of polyethylene glycol derivative and 5-15 parts of water-soluble metal salt by weight; in the preparation process of the gel type artificial cornea, cornea collagen and polyethylene glycol derivatives are firstly mixed, and then water-soluble metal salt is added. The gel type artificial cornea prepared from the raw materials is not easy to destroy the ocular surface microenvironment, can obviously improve the mechanical property and is not easy to generate immune response in a receptor.
Description
Technical Field
The invention belongs to the field of medical instruments, and particularly relates to a gel type artificial cornea and a preparation method thereof.
Background
Corneal blindness is the second major blindness next to cataracts. The only opportunity for the cornea blind patient to recover is cornea transplantation, which refers to the replacement of the diseased self cornea tissue with foreign material, so as to achieve the purpose of recovering the cornea disease of the patient or controlling the cornea disease.
The cornea mainly includes allogeneic cornea, tissue engineering cornea, and synthetic cornea depending on the donor source. Although allogeneic cornea is the optimal cornea implant, the number of cornea donations does not meet the implant requirements; although the tissue engineering cornea prepared by decellularization can relieve the shortage of cornea donors, the cornea is derived from heterogeneous materials, so that the risks of immune rejection and virus infection exist, the attention of researchers to artificial cornea (artificial cornea for short) is gradually improved, the artificial cornea prepared at present, which takes polymethyl methacrylate (PMMA) as a basic material, is suitable for cornea blind patients, but the mechanical property of the cornea implant product is low, and the cornea implant product is extremely easy to damage in the transplanting process and the later use process, so that the applicability of the artificial cornea is poor.
The hydrogel is a polymer with a three-dimensional network structure, the three-dimensional network structure of the hydrogel is similar to that of a natural extracellular matrix, and the hydrogel can provide adhesion and living environment for the growth of cells. However, the mechanical strength of the cornea with hydrogel as a raw material is far lower than that of a heterogeneous cornea; in addition, the gel cornea is often added with a cross-linking agent in the preparation process, and the residual cross-linking agent can damage the microenvironment of the ocular surface, so that postoperative recovery is affected.
Aiming at the problems in the prior art, there is a great need to develop a gel type artificial cornea with excellent mechanical properties and good safety.
Disclosure of Invention
The invention develops a gel type artificial cornea and a preparation method thereof aiming at the problems in the prior art.
The first aspect of the invention provides a gel-type artificial cornea, which comprises, by weight, 0.8-2.5 parts of cornea collagen, 8-15 parts of polyethylene glycol derivatives and 5-15 parts of water-soluble metal salts; preferably, in the preparation process of the gel type artificial cornea, cornea collagen and polyethylene glycol derivatives are mixed first, and then water-soluble metal salt is added.
Optionally, the cornea collagen is 1.2-2 parts by weight, the polyethylene glycol derivative is 10-13 parts by weight, and the water-soluble metal salt is 7-10 parts by weight.
The inventor has unexpectedly found that after polyethylene glycol derivatives, water-soluble metal salts and cornea collagen are mixed according to a specific proportion, polymer gel with a double-layer network interpenetrating three-dimensional network structure is formed among all substances through the intermolecular and intermolecular attractive force, and cornea collagen with specific content is easy to be matched with the double-layer network to produce interpenetration, so that the three-dimensional network structure of the whole gel artificial cornea is enriched, and the mechanical properties (such as tensile strength and elastic modulus) of the gel artificial cornea are improved. The sequence of firstly mixing cornea collagen with polyethylene glycol derivatives and then adding water-soluble metal salt can help to make the three-dimensional network structure more stable and uniformly distributed in the gel type artificial cornea, thereby being beneficial to further improving the mechanical property of the gel type artificial cornea. In addition, the three-dimensional porous structure is similar to the structure of extracellular matrix in the tissue engineering cornea, can provide a certain space for cell proliferation, and is beneficial to the practical application of the gel artificial cornea in the later stage. Furthermore, the gel type artificial cornea prepared by the invention does not detect antigen components such as alpha-Gal, and the like, which shows that the gel type artificial cornea prepared by the invention has no immune rejection phenomenon and can be well adapted to a receptor. It should be noted that in the preparation process of the gel type artificial cornea, no cross-linking agent (such as 1, 4-butanediol diglycidyl ether (BDDE), carbodiimide (EDC), N-hydroxysuccinimide (NHS) and the like) participates, so that the phenomenon that the cross-linking agent damages the ocular surface microenvironment is effectively avoided, and the selected raw materials are helpful for reducing the risk of postoperative viral infection.
Optionally, the polyethylene glycol derivative comprises polyethylene glycol acetate and/or polyethylene glycol dimethylsiloxane.
Optionally, the metal ion in the water-soluble metal salt is selected from one or more of cupric ion, ferric ion and divalent calcium ion; preferably, the water-soluble metal salt is selected from one or more of copper sulfate, copper chloride, calcium chloride and ferric chloride.
Optionally, the preparation step of the cornea collagen comprises:
(1) Acquiring an eyeball without cornea abnormality;
(2) Cutting the eyeball, and only keeping the cornea as an initial cornea;
(3) Mixing the acid solution with the initial cornea to obtain a solution A; preferably, the mass ratio of the acid solution to the initial cornea is 1:10-25;
(4) And dialyzing the solution A in a buffer solution, and freeze-drying to obtain cornea collagen.
Optionally, in the step (3), mixing the acid solution and the initial cornea for 24-72 hours at a temperature of 4-30 ℃ to obtain a solution A;
in the step (4), the solution A is transferred to a 3.5-12kDa dialysis bag for dialysis for 10-24 hours, the residual solution B in the dialysis bag is collected, and the residual solution B is freeze-dried for 5-15 hours at the temperature of minus 55-minus 30 ℃.
Optionally, the acid solution is selected from one or more of hydrochloric acid solution, acetic acid solution and sulfuric acid solution; the buffer is selected from one or more of 2- (N-morpholino) ethanesulfonic acid buffer (MES), phosphate Buffered Saline (PBS) and 4-hydroxyethylpiperazine ethanesulfonic acid buffer (HEPES).
The invention also provides a preparation method of the gel type artificial cornea, which comprises the following steps:
s1, dissolving cornea collagen in water to obtain cornea collagen solution;
s2, dissolving a polyethylene glycol derivative in water to obtain a polyethylene glycol derivative solution;
s3, mixing the cornea collagen solution with a polyethylene glycol derivative solution to obtain a solution C;
s4, adding water-soluble metal salt into the solution C, stirring for 0.5-1 h, shaping, washing with water, and sterilizing to obtain the gel type artificial cornea.
Optionally, in step S3, the corneal collagen solution and the polyethylene glycol derivative solution are mixed for 3-6 hours at the temperature of 2-15 ℃ to obtain a solution C.
Optionally, in step S4, the sterilization mode includes ethylene oxide sterilization, electron beam sterilization or radiation sterilization.
In summary, the invention has at least one of the following advantages:
after the polyethylene glycol derivative, the water-soluble metal salt and the cornea collagen are mixed according to a specific proportion and a specific sequence, the interaction of the polyethylene glycol derivative, the water-soluble metal salt and the cornea collagen can form a stable network structure which is uniformly penetrated with each other, thereby being beneficial to remarkably improving the mechanical property of the gel-type artificial cornea; the gel type artificial cornea prepared by the invention is not easy to generate immune reaction in a receptor; no cross-linking agent is added in the whole preparation process of the gel type artificial cornea, so that the condition that the cross-linking agent damages the ocular surface microenvironment is effectively reduced.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.
FIG. 1 is a scanning electron microscope (field of view: 100 μm) of both side surfaces of a gel-type artificial cornea prepared in example 1, wherein FIG. 1 a is a scanning electron microscope of one side surface of the gel-type artificial cornea; b in fig. 1 is a scanning electron microscope image of the other side surface of the gel-type artificial cornea;
FIG. 2 is a sectional scanning electron micrograph (field of view: 50 μm) of the gel type artificial cornea obtained in example 1.
Detailed Description
The invention will be further illustrated with reference to the following examples, which are to be understood as merely further illustrating and explaining the invention and are not to be construed as limiting the invention.
Unless defined otherwise, technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the materials and methods are described herein below. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
The test methods, detection methods, and conventional experimental reagent preparation methods employed in the examples of the present invention, unless otherwise specified, were all conducted in accordance with conventional procedures in the art.
For convenience of explanation of the technical scheme of the present invention, the following materials and steps are explained before starting the experiment of the present invention:
(1) Animal eyeballs used in the present invention include, but are not limited to, porcine eyeballs, bovine eyeballs, or ovine eyeballs; as an example, the present invention employs a porcine eyeball.
(2) The polyethylene glycol derivative adopted by the invention can be polyethylene glycol acetate, polyethylene glycol dimethylsiloxane or a mixture of the polyethylene glycol acetate and the polyethylene glycol dimethylsiloxane. As an example, polyethylene glycol acetate is used for polyethylene glycol derivatives in embodiments of the present invention.
(3) The metal ion in the water-soluble metal salt used in the present invention is one or more selected from the group consisting of cupric ion, ferric ion and divalent calcium ion, and for example, the water-soluble metal salt may be cupric sulfate, cupric chloride, calcium chloride, ferric chloride, and at least two of cupric sulfate, cupric chloride, calcium chloride and ferric chloride.
(4) In the process of preparing cornea collagen, after an initial cornea is obtained, an acid solution with the molar concentration of 0.1-2 mol/L is mixed with the initial cornea for 24-72 hours at the temperature of 4-30 ℃ to obtain a solution A. The acid solution is one or more selected from hydrochloric acid solution, acetic acid solution and sulfuric acid solution; the mass ratio of the acid solution to the initial cornea is 1:10-25.
Then transferring the solution A to a 3.5-12kDa dialysis bag, dialyzing for 10-24 h in a buffer solution, collecting the residual solution B in the dialysis bag, placing the residual solution B in a beaker, and freeze-drying at the temperature of-55 to-30 ℃ for 5-15 h to obtain cornea collagen. Wherein the buffer solution is selected from one or more of 2- (N-morpholino) ethane sulfonic acid buffer solution, phosphate buffer salt solution and 4-hydroxyethyl piperazine ethane sulfonic acid buffer solution.
As an example, in an embodiment of the present invention, corneal collagen is prepared by the following preparation example.
Preparation example of cornea collagen:
(1) Repeatedly cleaning the pig eyeballs with ultrapure water, and screening out the pig eyeballs with no abnormal cornea through a slit lamp microscope;
(2) Cutting out the porcine eyeball by using a circular saw, and only keeping the cornea of the porcine eyeball as an initial cornea;
(3) Mixing 0.1mol/L acetic acid solution and initial cornea at 10deg.C for 36 hr, and dissolving porcine cornea into acetic acid solution to obtain solution A; the mass ratio of the acetic acid solution to the initial cornea is 1:15;
(4) Transferring the filtered solution A to a 6.8kDa dialysis bag, dialyzing in phosphate buffer solution for 12h, collecting the residual solution B in the dialysis bag, placing the residual solution B in a beaker, and freeze-drying at-40deg.C for 12h to obtain cornea collagen.
Examples
Example 1
The preparation method of the gel type artificial cornea comprises the following steps:
s1, dissolving 1.5g of cornea collagen prepared in the preparation example in 100mL of ultrapure water to obtain cornea collagen solution;
s2, dissolving 10g of polyethylene glycol acetate in 100mL of ultrapure water to obtain a polyethylene glycol acetate solution;
s3, mixing the cornea collagen solution in 100mLS1 and the polyethylene glycol acetate solution in 100mLS2 for 4.5 hours at 10 ℃ to obtain a solution C.
S4.10 g of calcium chloride is added into the solution C at the temperature of 10 ℃, the initial sample is obtained after continuous stirring for 0.5h, the initial sample is added into a mould, after 8h of shaping, the mould is washed with ultrapure water for 3 times, and sterilization is carried out by an ethylene oxide sterilization mode, thus obtaining the gel type artificial cornea.
Example 2
The preparation method of the gel type artificial cornea comprises the following steps:
the difference from example 1 is that: in step S1, 0.9g of the corneal collagen prepared in the preparation example was dissolved in 100mL of ultrapure water to obtain a corneal collagen solution;
in step S2, 15g of polyethylene glycol acetate was dissolved in 100mL of ultrapure water to obtain a polyethylene glycol acetate solution.
In step S4, 5.6g of calcium chloride was added to solution C. The rest of the procedure is the same as in example 1.
Example 3
The preparation method of the gel type artificial cornea comprises the following steps:
the difference from example 1 is that: in step S1, 2.5g of the corneal collagen prepared in the preparation example was dissolved in 100mL of ultrapure water to obtain a corneal collagen solution;
in step S2, 8g of polyethylene glycol acetate was dissolved in 100mL of ultrapure water to obtain a polyethylene glycol acetate solution.
In step S4, 11g of calcium chloride was added to solution C. The rest of the procedure is the same as in example 1.
Example 4
The preparation method of the gel type artificial cornea comprises the following steps:
the difference from example 1 is that: in step S3, the corneal collagen solution and the polyethylene glycol acetate solution are mixed for 1h at 40 ℃.
In step S4, at 40 ℃, adding calcium chloride with equal mass into the solution C, and stirring for 2.5h. The rest of the procedure is the same as in example 1.
It should be noted that, when the calcium chloride in examples 1-4 is replaced with other metal ion salts of the same mass, specifically, water-soluble metal salts formed by cupric ion, ferric ion or divalent calcium ion (such as copper sulfate, copper chloride and ferric chloride), the results of the related effect experiment verification are similar to those of the corresponding examples, and will not be described separately herein.
Comparative example
Comparative example 1
The preparation method of the gel type artificial cornea comprises the following steps:
the difference from example 1 is that: in step S1, 4g of the corneal collagen prepared in the preparation example was dissolved in 100mL of ultrapure water to obtain a corneal collagen solution;
in step S2, 6g of polyethylene glycol acetate was dissolved in 100mL of ultrapure water to obtain a polyethylene glycol acetate solution.
In step S4, 20g of calcium chloride was added to solution C. The rest of the procedure is the same as in example 1.
Comparative example 2
The preparation method of the gel type artificial cornea comprises the following steps:
the difference from example 1 is that: in step S1, 0.5g of the corneal collagen prepared in the preparation example was dissolved in 100mL of ultrapure water to obtain a corneal collagen solution;
in step S2, 20g of polyethylene glycol acetate was dissolved in 100mL of ultrapure water to obtain a polyethylene glycol acetate solution.
In step S4, 3g of calcium chloride was added to solution C. The rest of the procedure is the same as in example 1.
Comparative example 3
The preparation method of the gel type artificial cornea comprises the following steps:
the difference from example 1 is that: in step S4, 20g of calcium chloride was added to solution C.
Comparative example 4
The preparation method of the gel type artificial cornea comprises the following steps:
the difference from example 1 is that: in step S4, calcium chloride is replaced with polyethylene glycol acetate of equal mass.
Comparative example 5
The preparation method of the gel type artificial cornea comprises the following steps:
the difference from example 1 is that: in step S2, 10g of calcium chloride was dissolved in 100ml of ultrapure water to obtain a calcium chloride solution; in the step S3, the cornea collagen solution in 100mLS1 and the calcium chloride solution in 100mLS are mixed for 4.5 hours at 10 ℃ to obtain a solution C; in step S4, 10g of calcium chloride was added to solution C at a temperature of 10 ℃. The rest of the procedure was the same as in example 1.
Comparative example 6
The preparation method of the gel type artificial cornea comprises the following steps:
the difference from example 1 is that: step S4 is omitted, in step S3, 100mL of the cornea collagen solution in step S1 and 100mL of the polyethylene glycol acetate solution in step S2 are mixed for 4.5 hours at 10 ℃,10 g of calcium chloride is added, and after stirring for 0.5, an initial sample is obtained, the initial sample is added into a mould, after setting for 8 hours, the mould is washed with ultrapure water for 3 times, and sterilization is carried out by an ethylene oxide sterilization mode, so that the gel type artificial cornea is obtained.
Comparative example 7
The preparation method of the gel type artificial cornea comprises the following steps:
the difference from example 1 is that: in step S3, 10g of calcium chloride was added to the corneal collagen solution of 100mLS1 at a temperature of 10℃and stirring was continued for 0.5 hours, thereby obtaining a solution C. In the step S4, the solution C and the polyethylene glycol acetate solution in 100mLS are mixed for 4.5 hours at the temperature of 10 ℃, then are added into a mould for shaping for 8 hours, are washed with ultrapure water for 3 times, and are sterilized by an ethylene oxide sterilization mode, thus obtaining the gel type artificial cornea.
Performance test
Experimental example 1 mechanical Property test
The experimental method comprises the following steps: the gel type artificial corneas and the like prepared in examples 1 to 4 and comparative examples 1 to 7 were placed over a test piece of a transparent plastic mold having a length of 7mm and a width of 5mm, and the test piece was clamped in a jig on an electric 3220-AT type biomechanical testing machine (BOSE company, U.S.A.), and a tensile failure test was performed. The specific test procedure is as follows: humidifying by an air humidifier at normal temperature to simulate a tissue environment, loading with a load of 0.06mm/s, and uniaxially stretching until the test piece breaks; data were collected by WinTest software at a frequency of 0.02 Hz. The preparation method of the similar cornea product comprises the following steps:
(1) Referring to example 2-1 in CN113773379a, a lyophilized preparation was prepared, and the prepared lyophilized preparation was dissolved in MES medium having a concentration of 0.5mol/L and ph6.5, such that the concentration of pegylated collagen-like protein in the MES medium was 15g/mL, to obtain a solution;
(2) Mixing the dissolution solution and the MPC mother solution according to a mass ratio of 4:1 to obtain a mixed solution 1; mixing the mixed solution 1 and DMTMM mother solution according to a mass ratio of 7:1 to obtain a mixed solution 2; wherein, the formula of MPC mother liquor is: 30% 2-methacryloyloxyethyl phosphorylcholine (w/v, g/mL), 10% polyethylene glycol (diol) diacrylate) (v/v), 1% tetramethyl ethylenediamine (v/v), 0.5mol/L solvent MES medium pH 6.5; the formula of the DMTMM mother liquor is as follows: 10%4- (4, 6-dimethoxy-triazin-2-yl) -4-methylmorpholine hydrochloride (w/v, g/mL), 15% ammonium persulfate (w/v, g/mL) and 0.5mol/L MES medium pH 6.5.
(3) Pouring the mixed solution 2 into a cornea mould, and standing for 12 hours at 25 ℃ to obtain a crude cornea product; adding the crude cornea product into PBS (phosphate buffer solution) culture medium with the concentration of 0.1mol/L and the pH of 6.5, and soaking at the temperature of 4 ℃ for 24 hours to obtain the bionic cornea, namely the similar cornea product, which is hereinafter referred to as similar product. The tensile strength and elastic modulus test results of each gel-type artificial cornea are shown in Table 1, wherein the relevant data of the natural cornea are all obtained from literature values.
TABLE 1 tensile Strength and elastic modulus of gel-type artificial corneas
According to the results shown in Table 1, the gel type artificial cornea prepared by the invention has the same order of magnitude as the natural cornea in terms of tensile strength, is relatively similar to the natural cornea, can meet the operation requirements in clinical operations, and has elastic modulus even better than that of the natural cornea, so that the gel type artificial cornea prepared by the invention accords with the use standard, and has mechanical properties equivalent to or even superior to that of the natural cornea. And as can be seen from fig. 1 a and b, the surface appearance of the gel type artificial cornea prepared in example 1 of the present invention is close to the surface of the natural cornea.
It can also be known from the data in table 1: the amounts of collagen, polyethylene glycol derivative and water-soluble metal salt added to the cornea have an effect on the tensile strength and elastic modulus of the gel-type artificial cornea. And, as is clear from the data of comparative examples 1 and 4 and 5, the gel-type artificial cornea prepared by the method of the present invention has poor properties when polyethylene glycol derivatives or water-soluble metal salts are not added during the preparation of the gel-type artificial cornea.
In addition, the preparation process has great influence on the tensile strength and the elastic modulus of the gel type artificial cornea, and particularly has great influence on the final performance of the gel type artificial cornea when the addition sequence of the water-soluble metal salt is changed. Compared with the example 1, when the water-soluble metal salt is added first and then the polyethylene glycol acetate solution is added in the comparative example 7, the tensile strength and the elastic modulus of the prepared gel type artificial cornea are greatly reduced, and the gel type artificial cornea is easy to damage and is unfavorable for later application.
It is worth mentioning that the transmittance of the gel type artificial cornea prepared by the invention can reach more than 90% (the transmittance is measured by LS117 densitometer, the document value of the transmittance of the natural cornea is 91.6+/-2.6%), which indicates that the gel type artificial cornea prepared by the invention can provide better vision recovery effect in the later actual use process.
The gel artificial cornea prepared by the invention has great advantages in terms of tensile strength and elastic modulus, probably because the mutual coordination of substances with specific proportions in the formula and the specific preparation method can lead the product to form a relatively stable network structure, and the network structure is not easy to break under the action of external force due to the mutual traction of molecular structures, thereby being beneficial to improving the tensile strength and the elastic modulus of the gel artificial cornea.
In order to verify the above presumption, the present invention performs electron microscope scanning on a cross section of the gel type artificial cornea prepared in example 1, and the result is shown in fig. 2. As is apparent from fig. 2, the gel-type artificial cornea prepared by the method of the invention has a three-dimensional network structure with complete and stable morphology, and the invention is also proved to have a network structure which is uniformly penetrated by the mutual coordination among cornea collagen, polyethylene glycol derivatives and water-soluble metal salts, so that the tensile strength and elastic modulus of the whole gel-type artificial cornea are improved, and a certain space can be provided for cell proliferation by a three-dimensional porous structure.
Experimental example 2 detection of antigen component
In the experiment, the components of the gel type artificial cornea prepared in the examples 1-4 are detected by a Western blot detection method, and the detection result shows that: the gel type artificial cornea prepared by the invention retains the original collagen component of the natural cornea, and antigen components such as alpha-Gal and the like are not detected in the collagen component in the gel type artificial cornea prepared by the embodiments 1-4, so that the gel type artificial cornea prepared by the invention has lower biological immunogenicity, and is not easy to cause irritation to a receptor in the later use process. Taking the detection result of example 1 as an example, the collagen of the gel type artificial cornea prepared in example 1 comprises type I collagen (79.66%), type VI collagen (18.58%), type V collagen (1.03%), type XII collagen (0.67%) and type XI collagen (0.06%), and antigen components such as α -Gal are not detected, so that it is demonstrated that the gel type artificial cornea retains the original collagen components of biological cornea, has low biological immunogenicity, and can be well adapted to the receptor in subsequent use.
Summarizing: after the polyethylene glycol derivative, the water-soluble metal salt and the cornea collagen are mixed according to a specific proportion and a specific sequence, the interaction of the components is favorable for forming a network structure which is mutually and uniformly penetrated, the tensile strength and the elastic modulus of the gel type artificial cornea are obviously improved, the prepared gel type artificial cornea does not contain antigen components, and immune rejection reaction is not easy to cause after the gel type artificial cornea is transplanted into a receptor. The gel type artificial cornea is prepared by using the preparation method, and the gel type artificial cornea is prepared by using the preparation method.
It is to be understood that this invention is not limited to the particular methodology, protocols, and materials described, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims.
Those skilled in the art will also recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are also encompassed by the appended claims.
Claims (10)
1. The gel type artificial cornea is characterized by comprising, by weight, 0.8-2.5 parts of cornea collagen, 8-15 parts of polyethylene glycol derivatives and 5-15 parts of water-soluble metal salts; preferably, in the preparation process of the gel type artificial cornea, cornea collagen and polyethylene glycol derivatives are mixed first, and then water-soluble metal salt is added.
2. The gel-type artificial cornea according to claim 1, wherein the cornea collagen is 1.2-2 parts by weight, the polyethylene glycol derivative is 10-13 parts by weight, and the water-soluble metal salt is 7-10 parts by weight.
3. The gel-type artificial cornea of claim 1, wherein the polyethylene glycol derivative comprises polyethylene glycol acetate and/or polyethylene glycol dimethylsiloxane.
4. The gel-type artificial cornea of claim 1, wherein the metal ions in the water-soluble metal salt are selected from one or more of cupric ions, ferric ions, and divalent calcium ions.
5. The gel-type artificial cornea according to any one of claims 1 to 4, wherein the preparation step of the cornea collagen comprises:
(1) Acquiring an eyeball without cornea abnormality;
(2) Cutting the eyeball, and only keeping the cornea as an initial cornea;
(3) Mixing the acid solution with the initial cornea to obtain a solution A; preferably, the mass ratio of the acid solution to the initial cornea is 1:10-25;
(4) And dialyzing the solution A in a buffer solution, and freeze-drying to obtain cornea collagen.
6. The gel-type artificial cornea according to claim 5, wherein in the step (3), the acid solution and the initial cornea are mixed for 24 to 72 hours at a temperature of 4 to 30 ℃ to obtain a solution a;
in the step (4), the solution A is transferred to a 3.5-12kDa dialysis bag for dialysis for 10-24 hours, the residual solution B in the dialysis bag is collected, and the residual solution B is freeze-dried for 5-15 hours at the temperature of minus 55-minus 30 ℃.
7. The gel-type artificial cornea of claim 5, wherein the acid solution is selected from one or more of hydrochloric acid solution, acetic acid solution and sulfuric acid solution; the buffer solution is selected from one or more of 2- (N-morpholino) ethane sulfonic acid buffer solution, phosphate buffer salt solution and 4-hydroxyethyl piperazine ethane sulfonic acid buffer solution.
8. The method for preparing the gel type artificial cornea according to any one of claims 1 to 7, which comprises the following steps:
s1, dissolving the cornea collagen in water to obtain a cornea collagen solution;
s2, dissolving a polyethylene glycol derivative in water to obtain a polyethylene glycol derivative solution;
s3, mixing the cornea collagen solution with a polyethylene glycol derivative solution to obtain a solution C;
s4, adding water-soluble metal salt into the solution C, stirring for 0.5-1 h, shaping, washing with water, and sterilizing to obtain the gel type artificial cornea.
9. The method of claim 8, wherein in step S3, the solution C is obtained by mixing the corneal collagen solution with the polyethylene glycol derivative solution at 2 to 15 ℃ for 3 to 6 hours.
10. The method of claim 8, wherein in step S4, the sterilization means comprises ethylene oxide sterilization, electron beam sterilization, or radiation sterilization.
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