CN107007879A - A kind of active artificial cornea and preparation method thereof - Google Patents
A kind of active artificial cornea and preparation method thereof Download PDFInfo
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- CN107007879A CN107007879A CN201710149500.5A CN201710149500A CN107007879A CN 107007879 A CN107007879 A CN 107007879A CN 201710149500 A CN201710149500 A CN 201710149500A CN 107007879 A CN107007879 A CN 107007879A
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- 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
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- 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
- A61L27/28—Materials for coating prostheses
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- 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
- A61L27/28—Materials for coating prostheses
- A61L27/34—Macromolecular materials
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- 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
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- 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
- A61L27/54—Biologically active materials, e.g. therapeutic substances
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- 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
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- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
- A61L2300/414—Growth factors
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- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/606—Coatings
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- 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
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/18—Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment
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- A—HUMAN NECESSITIES
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- A61L2420/00—Materials or methods for coatings medical devices
- A61L2420/02—Methods for coating medical devices
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- 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
- A61L2420/00—Materials or methods for coatings medical devices
- A61L2420/08—Coatings comprising two or more layers
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- 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
Abstract
The present invention discloses a kind of active artificial cornea and preparation method thereof.The artificial cornea is the integral type synthesising macromolecule copolymer hydrogel structure containing gradient composition, includes central optical part and the peripheral part of bioactivity of biologically inert.It is transparent that the present invention prepares central optical, periphery has the artificial cornea base material of gradient hydrogel character, nano coating technology is used again, polyvinylidene fluoride is carried out in artificial cornea base material central part (interior outside), tetrafluoromethane, the coating and corona treatment of heptafluoro-propane, form inactive surfaces, collagen grafting is carried out to base material periphery again, micromolecule polypeptide and growth factor-induced activation, make base material bioactive process with it is engineered, finally obtain central optical excellent, periphery good biocompatibility, it is simple in construction, facilitating operation and the active artificial cornea that can exist steadily in the long term without abjection.Make to have on artificial cornea periphery and run through type pore space structure, be conducive to patient's eye to be brought into close contact with artificial cornea.
Description
Technical field
The present invention relates to ophthalmic medical instrument articles for use, more particularly to a kind of active artificial cornea and preparation method thereof.
Background technology
Disease of cornea is the main blinding illness in eye in the current whole world, accounts for the second of the blinding illness in eye of ophthalmology.There is cornea in China
The people of patient 32,370,000, blinding patient is up to more than 400 ten thousand people, and as the patients such as wound, chemical injury, infection increase, cause
Blind colony is annual with more than 10 ten thousand increases.The best approach for treating disease of cornea is corneal transplantation, among these patients, absolutely mostly
Number people can be seen light again by corneal transplantation.But it is serious in short supply due to donor's cornea material source, angle can be carried out every year
The patient of film transplanting is only 5000 people or so, only accounts for being actually needed the 2% of operation case, can not much meet sufferer needs.
Disease of cornea not only makes patient's disability, reduces quality of life, causes body and spiritual infringement,
Serious loss and financial burden is caused to family, very big adverse effect is also resulted in society.Therefore, cornea substitute --- people
Work cornea, which turns into, treats effective, the feasible Operative approch of such disease, and it is always numerous patients to seek preferable artificial cornea
Dream, is also the striving direction of scientific worker.
Artificial cornea is a kind of special refractive apparatus being made of alloplastic material, suffers from eye by implantation of performing the operation, substitution
The cornea tissue of muddy lesion, so as to reach that holding eyeball is complete, remove infection focus, recover corneal transparency, obtain vision work(
The purposes such as energy.
It is all external product clinically to obtain the artificial cornea of application at present, specifically include Boston artificial corneas,
Pintcueei artificial corneas, Osteo-Odonto artificial corneas, Alphacor artificial corneas, and the artificial angles of Strampelli
Film etc..Not yet there is the autonomous artificial cornea product of the China for obtaining extensive clinical practice.The characteristics of these external products, is as follows：
(1) Boston artificial corneas (Dohlman types) need to be arranged on a fresh donor's cornea plant piece, that is, need for donor
Cornea could complete treatment；Patient needs to wear soft corneal contact lens piece after surgery, to prevent eye tear evaporation and reduction people
The depression of work cornea, so as to reduce the necrosis of donor's cornea support and the possibility melted；The formation of artificial cornea fibrin formation film, green grass or young crops
Light eye, continuation epithelial defect, aseptic hyalitis, entophthamia and detachment of retina are that Boston artificial corneas are postoperative most normal
The complication seen, wherein, the incidence of disease of artificial cornea fibrin formation film formation is more up to 24~65%.Moreover, some patientss art
Afterwards it also occur that the complication such as conjunctival flap leak, the thinning dissolving of cornea anterior stroma, even results in artificial cornea discharge.(2) Russia sieve
This production MICOF artificial cornea, which is applied to eye chemical injury, certain curative effect, but there is operation method is more complicated, complication is more etc.
Problem；(3) independent research modified form poly-hydroxyethyl methyl acrylate-poly- first is carried out based on Chirila Pros artificial corneas
Base methyl acrylate integration artificial cornea, is still in the animal experiment stage at present.
From the point of view of the result applied at present, either Boston, Osteo or Alphacor artificial cornea, its artificial material
It is the complexity of biocompatibility, surgical procedure with body, postoperative long-term efficacy, the preventing and treating of postoperative various complication, postoperative
Maintenance of optimal visual function etc. all waits to improve, and these problems are the biggest obstacles that corneal blindness patient recovers lost eyesight, and are also that patient is postoperative
The biggest threat of eyesight, also significantly limit the further development and extensive use of artificial cornea.It is fast with social economy
Speed development, people are to healthy attention rate also more and more higher, and the development of medicine equipment must be combined with modern science and technology, when keeping up with
The paces of generation development, could meet the growing demand to therapeutic effect of people.
At present, in terms of artificial cornea, China Intellectual Property Office authorizes patent of invention 18, open patent of invention 22
, for example：CN1141067C discloses a kind of method of use preparing artificial cornea by filtering out expanded polymer particles, passes through standard screen
Sieve takes pore former, and the dissolving of biocompatible polymer tetrahydrofuran is made into saturated solution, then after being mixed with pore former stirring
Obtained hollow circuit cylinder semi-finished product are poured into ring mould, then by initiator, crosslinking agent, biocompatible polymer monomer
Mixed liquor, which is poured into semi-finished product, to be reacted, and then molded artificial cornea blank cutting, polishing are soaked with ionized water, obtained
To artificial cornea.
CN1128096C discloses a kind of preparation method of biological induction type active artificial cornea, specifically includes chitosan
Acid solution is dissolved in, collagen and hyaluronic acid are dissolved in water；By the aqueous solution of chitosan acid solution and collagen and hyaluronic acid in room
Temperature is lower to be stirred；Carbodiimide cross-linking agent, fibroblast growth factor, epithelical cell growth factor are added in obtained mixed liquor
And transforming growth factor β, then it is sufficiently mixed half an hour；Obtained mixed liquor is injected in prefabricated cornea mould, fill angle
Put it into after film die after drying in oven and take out to obtain cornea product；The cornea product of gained after being dried with clear water soaking and washing
To remove residual impurity, and it is placed in water, biological induction type active artificial cornea has been made.
CN100340309C discloses a kind of biological induction type active artificial cornea, component include chitosan 0.5%~
3%th, collagen 0.5%~3%, hyaluronic acid 0.1%~0.5%, water 93.5%~98.8%, for help stimulate autologous growth because
Sub- enrichment rate, integrates cornea growth factor on material.
CN102920532B discloses a kind of artificial cornea, including support and mirror post, and support extends along a sphere, center
Provided with the poroid carrier base being made up of medical methyl methacrylate, inwall is provided with internal thread；The radial section of mirror post is
It is circular；Including be sequentially connected and coaxial setting introduction segment, thread segment and revealed section；The side face of thread segment is carried and the interior spiral shell
The external screw thread that line coordinates, when support coordinates with the mirror post, the protrusion direction on convex surface is consistent with the protrusion direction of the support.
CN104368046B discloses a kind of fiber reinforcement type and carries liquid medicine gel artificial cornea skirt hanger and its preparation side
Method, skirt hanger is made up of hydrophilic hydrogel, fiber and biodegradable drug bearing microsphere, and the content of fiber is 6~10%, can
The content of biodegradable drug bearing microsphere is that the content of 8~15%, hydrophilic hydrogel is 75~86%, and fiber is disorderly distributed in
In hydrophilic hydrogel.
CN 1314461C disclose a kind of artificial comea having biological activital activity, including optical centre and peripheral bracket, peripheral bracket
It is to be prepared by bioactivity calcium salt, high-molecular polyivnyl alcohol, solvent, polyvinyl alcohol is first dissolved in solvent, biological active calcium is added
Salt is so well mixed that to add pore-foaming agent after mixed solution and obtain mixture, and mixture is placed in into mould molding for hollow circular cylinder periphery
Support, it is removed in deionized water behind shaped optical center in peripheral bracket inner chamber the solvent of residual, pore-foaming agent and its
Its impurity.
CN100484497C discloses a kind of preparation method of the artificial cornea with bioactivity, with animal corneal matrix
For material, grown using enzymic digestion, multigelation, washing, Co-60 irradiation, compound promotion keratocyte or/and prevent local disease
The step of function ingredients for becoming development, prepares artificial cornea.
CN101380486B provides a kind of active regeneration artificial cornea graft and preparation method thereof, and constituent includes
Chitosan, collagen, chondroitin sulfate, polyethylene glycol, polyvinyl alcohol and, tri-distilled water, in addition to appropriate keratocyte growth factor,
Fibronectin and laminin.Chitosan, collagen and chondroitin sulfate are dissolved in hydrochloric acid, acetic acid and water respectively, then pressed
Each component is stirred at room temperature after mixing in injection mould and dried by ratio, then obtains artificial cornea after the cleaning, drying that is soaked in water
Product.
CN101843923B discloses a kind of utilization fresh amnion and prepares carrier bracket of tissue engineering artificial corneal endothelium
Method, first carries out soaking disinfection to fresh amnion using tobramycin sulfate liquid, is inverted and digests through trypsase-EDTA digestive juices
Afterwards, amnioic epithelium face is gently scraped with cell scraper all to remove residual epithelium cell, acquisition removes epithelial layer amnion, is laid in culture
In plate hole after firm dry doubling, spend the special coating buffer of epithelial layer amnion and carry out coating processing, suctioning out after coating buffer is dried to make
Used for the carrier bracket of tissue engineering artificial corneal endothelium.
CN102580147B discloses a kind of artificial cornea with antibacterial activity, including porous peripheral bracket portion and optics
Central part, cradle portion includes chitosan derivatives, polyvinyl alcohol, nano phosphate with antibiotic property, and optical centre portion includes
Polyvinyl alcohol hydrogel, poly hydroxy ethyl acrylate hydrogel.
CN102755204B discloses a kind of novel assembled artificial cornea, including central optical part and fixed support portion
Point, opticator includes spherical cap body and the cylindricality transparent body, and the upper surface of spherical cap body is the upper surface of sphere, lower surface and the transparent body
Connection, the middle part of holder part is provided with through hole, and through-hole side wall is provided with retainer ring；The transparent body runs through fixed support portion by through hole
Point.
CN103830021B discloses a kind of artificial cornea and preparation method thereof, includes the cornea bulk optics function of spherical crown shape
Area and the Support of spherical zone shape, optical function area be combined with each other with Support, and its junction surface is the integral type of fusion of being interweaved
Transition structure；Wherein, cornea bulk optics functional areas are by the poly-hydroxyethyl acrylic acid first with good biocompatibility and translucency
Ester hydrogel is made, and Support is naturally integrated between the two by being made through the uniform enhanced PHEMA porous supports of fibroin fiber
Connection.
CN104436302B discloses artificial cornea and the making of a kind of Nano ultrathin biomembrane difference modification front and rear surfaces
Method, deposition has polycation layer and epidermal growth factor sublayer repeatedly successively on the preceding surface of optical section；The rear surface of optical section by
It is interior and it is outer successively deposition has polycation layer and HA layer repeatedly, outermost layer is HA layers, and its preparation method is including making artificial cornea
Surface lotus is with negative electrical charge；Make polycation and EGF alternating sorbent on the preceding surface of artificial cornea；Make polycation and
HA alternating sorbents surface after artificial cornea, last re-dry, is packed.
CN106139249A discloses a kind of preparation method of multipolymer artificial cornea, including polynary common by synthesizing
Poly- material, prepare cornea three-dimensional rack, using 3D biometric prints machine print cornea shape 3 D stereo support, utilize ECM pairs
Three-dimensional rack carries out the steps such as functionalized modification, the structure of remaining cornea micro-assembly robot method, is prepared for artificial cornea.
CN105688282A discloses a kind of new bio artificial cornea in body inducing cellization and fast transparent, uses
Preparation method include by cornea raw material obtain, corneal stent prepare, corneal stent depth modify, cornea depth inactivation go
The steps such as pyrogen, cornea irradiation sterilization, the culture of endothelial cell and plantation construct the biological people of different-thickness depth, shallow flaggy
Work cornea and holostrome bio-artificial cornea.
Because, inherently from the point of view of, to obtain can clinical practice and stable artificial cornea, it is necessary to solve two disasters
Topic：
(1) the superior bio compatibility of artificial cornea periphery and human eye：
The corneal material of many manual manufactures, due to using high polymer material, metal or inorganic material, causing bio-compatible
Property it is not enough, produce immune response etc., cause inflammation, occur corneal solution, artificial cornea abjection, its basic reason is artificial material
Preferable biotic elictor can not be produced with host cornea.
(2) optical transparence and any biological inert at artificial cornea center (laminating pupil) position are kept：Some materials gram
The deficiency of biocompatibility has been taken, and can be brought into close contact with human eye, still, because cell is grown into, new vessels is grown into, or eye
The adhesion of the material of other in eyeball and deposition, cause the formation of front and rear film, make corneal material over time, and centre can be by
Gradually lose optical clear, it is impossible to maintain optimal visual function, cause artificial cornea material failure.
But, for current existing patent and product, generally existing is not enough as follows：
(1) the problems such as existing patent less biocompatibility in view of artificial cornea periphery, use can promote periphery
The active component of keratocyte growth is less, while also not considering the hydrogel for using gradient as the weight of cornea periphery material
The property wanted；
(2) most artificial corneas use integrated design, and central optical position is also compounded with hydrogel component, thus very
Some cells are easily caused to grow into new vessels, or the material of other in eyes adhesion and deposition, cause the formation of front and rear film,
Gradually devitrification；
(3) in existing artificial cornea patent, the central part of designed cornea is not all used at biologically inert
Reason.
The content of the invention
In order to overcome the shortcoming and deficiency of prior art, primary and foremost purpose of the invention is to provide a kind of activity artificial angle
Film.There is middle body optical clear the invention provides one kind, the novel artificial cornea of periphery bioactivity is purple by gradient
Outer smooth irradiation polymerization technology prepares that central optical is transparent, and periphery has the artificial cornea base material of gradient hydrogel character, then uses
Nano coating technology, polyvinylidene fluoride, tetrafluoromethane, heptafluoro-propane are carried out in artificial cornea base material central part (interior outside)
Coating and corona treatment, form inactive surfaces, further base material periphery is carried out collagen grafting, micromolecule polypeptide and
BFGF induced activations, make base material bioactive process with it is engineered, finally obtain central optical excellent, periphery biofacies
Capacitive is good, simple in construction, facilitating operation and can steadily in the long term exist without abjection active artificial cornea.
Another object of the present invention is to provide a kind of preparation method of above-mentioned active artificial cornea.
The purpose of the present invention is achieved through the following technical solutions：
A kind of active artificial cornea, the artificial cornea is the integral type synthesising macromolecule copolymer hydrogel containing gradient composition
Structure, includes central optical part and the peripheral part of bioactivity of biologically inert.
Described high molecular polymer is the polymer of acrylic acid derivative, specifically includes the polymerization of methyl methacrylate
Thing, the copolymer of hydroxyethyl methacrylate-acrylic acid.
Described gradient components refer to content distribution gradient of the high polymer in different parts for constituting whole artificial cornea,
Specially central optical position, that is, press close to the artificial cornea of pupil position, its composition be pure PMMA (methyl methacrylate it is poly-
Compound, i.e.,：Polymethyl methacrylate), a diameter of 5 millimeters；Central part is left, its PMMA content is gradually reduced, P (HEMA-
AAS) content of (copolymer of hydroxyethyl methacrylate-acrylic acid) gradually increases, during to periphery, and PMMA contents are 0, all
For P (HEMA-AAS), the change of gradient turns to radius and often increases 0.5 millimeter, and PMMA contents decline containing for 15%, P (HEMA-AAS)
Amount increase by 15%.
The composition of the central optical part of described biologically inert is polymer P MMA, and transparent fluorine-containing chemical combination is coated with above
Thing, obtains both keeping optical transparence, the opticator for also possessing biologically inert.
The transparent fluorochemical of described coating, first, coats 50~200 nanometers of poly- inclined difluoro on polymer P MMA
Vinyl coating, forms nanometer plastic coating of fluoride, then using plasma technology, on the coating layer further 30~80 nanometers of coating
Tetrafluoromethane, heptafluoro-propane coating, pass through double-deck coating and produce biologically inert layer.
The peripheral part of described bioactivity, its main body is made up of P (HEMA-AAS) hydrogel, wherein containing through
Pore space structure, its part is combined by grafting with molecule, is loaded with bioactive ingredients.
Described pore space structure is to process to obtain by excimer laser process technology, and the hole aperture is received for 160~200
Rice, pore size distribution is big in outer footpath position density, few by middle body hole.
Described is combined by grafting with molecule, is loaded with bioactive ingredients：First collagen egg is grafted in hydrogel main body
In vain, the self assembly of micromolecule polypeptide, then the growth factor on polypeptide surface is compound are then carried out.
Described micromolecule polypeptide is V6D2(small-molecular peptides containing valine and aspartic acid) and ALPs are (containing alanine, bright
The small-molecular peptides of propylhomoserin, proline and serine) two kinds of peptides compound.
Described growth factor is at least one of bFGF and EGF etc..Wherein, bFGF refers to that basic fibroblast is given birth to
The long factor, EGF refers to epithelical cell growth factor.
A kind of preparation method of active artificial cornea, comprises the following steps：
The first step：Intend with acrylic acid derivative etc. as raw material, free radical is triggered by light trigger, it is purple using laminated gradient
Outer smooth irradiation polymerization technology, prepares the artificial cornea base material with gradient hydrogel character, and the center of base material (is pasted with human eye pupil
Close, a diameter of 5 millimeters) position be pure PMMA, periphery is then with increasing radius, and PMMA component content is gradually successively decreased, P (HEMA-
AAS) content gradually be incremented by, P (HEMA-AAS) hydrogel structure can keep cornea to moisten, and the growth of beneficial keratocyte and
With merging for eye cornea.Then, using excimer laser process technology, eleven punch 11 processing is successively entered, obtaining has reasonable hole
Hole structure, porous support has the characteristic of similar cell epimatrix, it would be preferable to support the outer base of cell growth, propagation and secretory cell
Matter, is allowed to integral with host cornea healing, can stablize and support base material central (optical section) to reach longer-term persistence.Such as Fig. 1 institutes
Show.
Described acrylic acid derivative is acrylic acid (sodium) (AAS), methyl methacrylate (MMA), hydroxyethyl methacrylate
Ethyl ester (HEMA).
Second step：For the biological activity in reduction artificial cornea centre, we use nano coating technology, artificial
Cornea base material central part (interior outside), carries out polyvinylidene fluoride coating treatment, forms nanometer plastic coating of fluoride, then exists again
The enterprising step of coating carries out tetrafluoromethane, heptafluoro-propane corona treatment, and center portion position forms inactive surfaces in the substrate, makes light
Department of the Chinese Academy of Sciences's position not adherent cell, it is to avoid cell is grown into, new vessels is grown into, or the material of other in eyes adhesion and deposition, it is to avoid
The common front and rear film of other materials is formed, to ensure the visual performance steady in a long-term at the position.
3rd step：Centre is avoided, collagen grafting is carried out to base material periphery, then carry out micromolecule polypeptide (V6D2With
The compound of two kinds of peptides of ALPs) self assembly, and carry out the compound adhesion of bFGF, EGF molecule, make base material bioactive process and tissue
Engineering, the artificial cornea that acquisition can be with patient's highly compatible.
As preferred scheme, bFGF, EGF growth factor for being used by the present invention, micromolecule polypeptide active component by and
Southern university's genetically engineered drug national project center production, or produced by Lang Tai pharmaceutical Co. Ltds of Guangdong Nanhai.
As preferred scheme, the polyvinylidene fluoride used by the present invention is by du pont company or MIT
The polyvinylidene fluoride product of production.
As preferred scheme, tetrafluoromethane, the heptafluoro-propane used by the present invention is had by the gas chemical industry of section of Foshan City
Limit company produces.
The present invention has the following advantages and effect relative to prior art：
(1) function-graded material technology of preparing is used, in slice gradient casting uv photopolymerization method, preparing has gradient
The integrated artificial cornea matrix material of MMA-HEMA-AAS component contents, substrate center (center) presses close to pupil portion and is
PMMA, as radius extends, PMMA ratios are gradually reduced, and P (HEMA-AAS) ratio gradually increases, to base material periphery, then whole
For P (HEMA-AAS), the matching problem of artificial cornea intensity and hydrogel biocompatibility is solved with this, makes the artificial angle of making
Film, which implants, to be existed steadily in the long term.
(2) excimer laser process technology is used, makes to have on artificial cornea periphery and runs through type pore space structure, reasonably
Pore structure and the growth offer support for being distributed as host cornea cell, are conducive to patient's eye to be brought into close contact with artificial cornea.
(3) using nano coating technology, tetrafluoromethane and the heptafluoro-propane plasma pair of Kynoar transparent material
The centre (interior outside) of artificial cornea carries out deactivation processing, the artificial cornea central optic portion of making is kept lazy
Property, cell can not be grown into blood vessel, and protein and other secretion can not be adhered in opticator, to maintain optimal visual function.
(4) using " grafting-compound " technical method, by I- Collagen Type VIs, micromolecule polypeptide and Basic Fibroblast Growth Factor
(bFGF) artificial cornea periphery surface is fixed on, the active coating with biological inducing action is obtained, can be actively after implanting
Body favorable factor is transferred, host cell biology behavior is adjusted.
Brief description of the drawings
Fig. 1 is the overall diagram of the artificial cornea of the present invention；Wherein, (1)-central optical part, (2)-periphery with hole
Hydrogel active part.
Embodiment
With reference to embodiment and accompanying drawing, the present invention is described in further detail, but embodiments of the present invention are not limited
In this.
Using acrylic acid, methyl methacrylate, hydroxyethyl methacrylate as raw material, light trigger is added, passes through layering
Gradient ultraviolet light irradiation polymerization technique, prepares the artificial cornea base material with gradient hydrogel character, the center of base material is (with human eye
Pupil is fitted, a diameter of 5 millimeters) position is pure PMMA, periphery often increases by 0.5 millimeter, PMMA component contains then with increasing radius
Amount reduces 15%, P (HEMA-AAS) content increase by 15%, until the PMMA component content at outside position is zero, P (HEMA-AAS)
Content is 100%.Then, in artificial cornea base material central part (interior outside), polyvinylidene fluoride coating treatment is carried out, is formed
Nanometer plastic coating of fluoride, then carries out tetrafluoromethane, heptafluoro-propane corona treatment, in the substrate in the enterprising step of coating again
Center portion position forms inactive surfaces, finally, using excimer laser process technology, eleven punch 11 processing is entered to periphery, then carry out collagen
Albumen is grafted and micromolecule polypeptide (V6D2With the compound of two kinds of peptides of ALPs) self assembly, and carry out bFGF molecules be combined, obtain
Can be with the highly biocompatible artificial cornea of patient.
The Japan large ear rabbit 10 of selection 3 months, is modeled by alkali burn mode, is then implanted into the people of the present invention
Work cornea, observes cornea recovery situation within a period under microscope, setting observation index is as follows：1. artificial cornea is in bit rate
And the time in place；2. there is secondary glaucoma situation；3. there is situation in the front/rear propagation film of artificial cornea；4. entophthamia occurs
Situation；5. corneal solution situation, results of animal shows, the artificial cornea of the invention time in place and is conformed in bit rate
Ask；Secondary glaucoma incidence is small, and proportion meets statistical requirements；Pass through the processing of fluorochemical, people of the invention
Work cornea occurs without propagation film substantially；In implantation 1 week, it may appear that slight entophthamia, then fade away；There is not angle
Film dissolves situation, shows that artificial cornea prepared by the present invention has preferable applicability.
Above-described embodiment is preferably embodiment, but embodiments of the present invention are not by above-described embodiment of the invention
Limitation, other any Spirit Essences without departing from the present invention and the change made under principle, modification, replacement, combine, simplification,
Equivalent substitute mode is should be, is included within protection scope of the present invention.
Claims (10)
1. a kind of active artificial cornea, it is characterised in that：The artificial cornea is the integral type synthesis polyphosphazene polymer containing gradient composition
Compound hydrogel structure, includes central optical part and the peripheral part of bioactivity of biologically inert.
2. active artificial cornea according to claim 1, it is characterised in that：
Described high molecular polymer is the polymer of acrylic acid derivative, specifically includes the polymer of methyl methacrylate,
The copolymer of hydroxyethyl methacrylate-acrylic acid.
3. active artificial cornea according to claim 1, it is characterised in that：
Described gradient components refer to content distribution gradient of the high polymer in different parts for constituting whole artificial cornea, specifically
For central optical position, that is, press close to the artificial cornea of pupil position, its composition is pure PMMA, a diameter of 5 millimeters；Leave central portion
Position, its PMMA content is gradually reduced, and P (HEMA-AAS) content gradually increases, during to periphery, and PMMA contents are 0, all P
(HEMA-AAS), the change of gradient turns to radius and often increases 0.5 millimeter, and the content that PMMA contents decline 15%, P (HEMA-AAS) increases
Plus 15%.
4. active artificial cornea according to claim 1, it is characterised in that：
The composition of the central optical part of described biologically inert is polymer P MMA, and transparent fluorochemical is coated with above,
Both optical transparence is kept, the opticator for also possessing biologically inert.
5. active artificial cornea according to claim 4, it is characterised in that：
The transparent fluorochemical of described coating, first, coats 50~200 nanometers of polyvinylidene fluoride on polymer P MMA
Coating, forms nanometer plastic coating of fluoride, then using plasma technology, on the coating layer the four of further 30~80 nanometers of coating
Fluoromethane, heptafluoro-propane coating, biologically inert layer is produced by bilayer coating.
6. active artificial cornea according to claim 1, it is characterised in that：
The peripheral part of described bioactivity, its main body is made up of P (HEMA-AAS) hydrogel, wherein containing through hole
Structure, its part is combined by grafting with molecule, is loaded with bioactive ingredients.
7. active artificial cornea according to claim 6, it is characterised in that：
The aperture of described pore space structure is 160~200 nanometers, and pore size distribution is big in outer footpath position density, by middle body hole
Hole is few.
8. active artificial cornea according to claim 6, it is characterised in that：
Described is combined by grafting with molecule, is loaded with bioactive ingredients：Collagen first is grafted in hydrogel main body, so
The self assembly of micromolecule polypeptide, then the growth factor on polypeptide surface is compound are carried out afterwards.
9. active artificial cornea according to claim 8, it is characterised in that：
Described micromolecule polypeptide is V6D2With the compound of two kinds of peptides of ALPs.
10. active artificial cornea according to claim 8, it is characterised in that：
Described growth factor is at least one of bFGF and EGF.
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| CN109820621A (en) * | 2019-03-01 | 2019-05-31 | 广州锐澄医疗技术有限公司 | A kind of composite artificial cornea and preparation method thereof |
| JP2020065849A (en) * | 2018-10-26 | 2020-04-30 | 国立研究開発法人農業・食品産業技術総合研究機構 | Hydrogel membrane and application thereof |
| CN116322812A (en) * | 2022-08-25 | 2023-06-23 | 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) | Large-diameter artificial cornea endothelial sheet and application thereof |
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