CN100553692C - Nanometer fluorouracil coat artificial crystalloid and preparation method thereof - Google Patents
Nanometer fluorouracil coat artificial crystalloid and preparation method thereof Download PDFInfo
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- CN100553692C CN100553692C CNB2007100391804A CN200710039180A CN100553692C CN 100553692 C CN100553692 C CN 100553692C CN B2007100391804 A CNB2007100391804 A CN B2007100391804A CN 200710039180 A CN200710039180 A CN 200710039180A CN 100553692 C CN100553692 C CN 100553692C
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Abstract
The present invention relates to the intraocular lens.The back regular meeting reaction that causes inflammation in the treatment clinical polymethyl methacrylate commonly used of cataract (PMMA) the intraocular lens implant into body at present; posterior capsule opacification also is the major complications of postcataract; select the antineoplastic agent fluorouracil for use for addressing these problems the present invention; and according to chitosan nano within the eye a little less than the penetration power and the conjunctival epithelial cell characteristics relevant with this nanoparticle size to the amount of engulfing of nanoparticle; as preparing carriers fluorouracil nano particle preparations, mixed coating is on PMMA intraocular lens surface with chitosan-polyacrylic acid.The present invention also provides above-mentioned process for manufacturing intraocular lenses.The present invention not only increased the intraocular lens biocompatibility, suppress posterior capsule opacification behind the implantation of artificial lens, can also prevent cephacoria and after cataract behind the implantation of artificial lens.
Description
Technical field:
The present invention relates to medical technical field, specifically be a kind of coating the intraocular lens (intraocular lenses, IOL) and preparation method thereof.
Background technology:
(Fluorouracil 5-Fu) is the inhibitor of thymidylate synthetase to fluorouracil, can effectively suppress the mitosis of cell, is clinical antitumor drug commonly used.Find after deliberation fluorouracil have the effect that suppresses proliferation of lens epithelial cells and divide a word with a hyphen at the end of a line (referring to Sun Yanxiu, Li Xiaorong, Zhang Xiaohong etc., 5-fluorouracil suppresses rabbit lens epithelial cells (lens epithelial cell, LECs) propagation and the toxic research of ophthalmic, ophthalmology research, 2000; 18 (3): 224-226), can be used for preventing intraocular lens anterior membrane and after cataract behind the implantation of artificial lens, all right glaucoma postoperative cicatrization is (referring to the Bears Xiao Ling, the 5-Fu pharmacokinetic of anti-synulotic Animal Experimental Study of 5-Fu and rabbit aqueous humor behind the glaucoma operation, ophthalmology research, 1993; 11 (3): 157-159).
Cataract is a topmost diseases causing blindness in the world wide.Treating cataractous method has operative therapy and pharmacotherapy, but is used for the treatment of the development that cataractous medicine all can not effectively stop or delay lenticular opacity at present, thereby operative treatment is still the cataractous main means of present treatment.At present using maximum crystalline lens materials clinically is polymethyl methacrylate (polymethylmethacrylate; PMMA); but still there are some problems in the biocompatibility of PMMA; the back regular meeting reaction that causes inflammation in the PMMA implant into body; the formation of the adhesion of intraocular lens's superficial cell, pigmentation, cell proliferation, surface protein film; and the reaction of surrounding tissue, as endothelial cell infringement, uveitis etc.For addressing these problems, often the intraocular lens is carried out finishing to change intraocular lens's surface characteristic, increase its biocompatibility.At present the intraocular lens of existing finishing heparin be applied to clinical (referring to Jin Tao, Li Huiqi, the application of microwave plasma in heparin modified artificial intraocular lenses surface, University Of Science and Technology Of Shandong's journal (natural science edition), 2004; 23 (4): 108-110).
Posterior capsule opacification is the major complications of postcataract, thinks at present, the propagation of residual lens epithelial cells in the art, divides a word with a hyphen at the end of a line and fibrosis can cause posterior capsule opacification.LECs is the composition that keeps propagation and differentiation capability in the crystalline lens.Cataract operation objectively is a wound, and LECs loses the pressure of cortex to it on the one hand; Some factors act on it and cause traumatic repair mechanism in the aqueous humor on the other hand, show as epithelial cell and divide a word with a hyphen at the end of a line, breed, and lose monolayer during its propagation and transform to fibroblast.The wound healing mechanism inducing fibrosis is given birth to simultaneously, and collagen produces, and makes the back cystic fibrosis, becomes turbid and shrinkage, hinders light and passes through, and causes the crystal off normal, and raising affects one's power of vision.The Drug therapy of posterior capsule opacification is the hot issue of studying at present, and ideal medicine should possess following three conditions: (1) can effectively suppress the lens epithelial cells hypertrophy; (2) to other cell free of toxic effects of ophthalmic; (3) clinical application is convenient feasible.The experimentation of posterior capsule opacification behind the currently reported amycin medicine slow-released system inhibition implantation of artificial lens, tetrandrine suppresses the research of rabbit posterior lens capsule film muddiness, the gemcitabine intra-ocular applications suppresses the experimentation of lagophthalmos postcataract posterior capsule opacification, total alkaloid of harmaline and liposome thereof are to the inhibitory action of rabbit lens epithelial cells, the experimentation of all-trans-retinoic acid slow-released system control posterior capsule opacification, the experimentation of daunorubicin prevention posterior capsule opacification, mitomycin suppresses the experimentation of posterior capsule opacification, tissue plasminogen activator's heparin is to the muddy inhibiting experiment comparative study of posterior lens capsule film.
Summary of the invention:
The intraocular lens who the purpose of this invention is to provide a kind of coating, in order to the biocompatibility that increases the intraocular lens, suppress posterior capsule opacification behind the implantation of artificial lens, and cephacoria and after cataract behind the prevention implantation of artificial lens.Another object of the present invention provides above-mentioned process for manufacturing intraocular lenses.
The intraocular lens of a kind of coating of the present invention, the medicine of posterior capsule opacification after selecting for use the antineoplastic agent fluorouracil as the inhibition implantation of artificial lens, and according to chitosan nano within the eye a little less than the penetration power and the conjunctival epithelial cell characteristics relevant with this nanoparticle size to the amount of engulfing of nanoparticle, as preparing carriers fluorouracil nano particle preparations, mixed coating is on polymethyl methacrylate intraocular lens surface with chitosan-polyacrylic acid.
Fluorouracil nanoparticle mean diameter of the present invention is 100nm～150nm.Behind this nanoparticle suspension eye dripping or the crystalline lens intracapsular injection, because bioadhesive is good, easily by conjunctival epithelial cell or lens epithelial cells absorption is engulfed and penetration power a little less than, at conjunctival sac or phacocyst internal viscosity degree height, the time of staying is long, can improve local drug concentration; Because medicine slowly discharges with the biodegradation of chitosan, can make eye active drug concentration keep the long period, improve curative effect; Because this nanoparticle bioadhesive is good, the dose that is diffused into whole body by nasolacrimal duct or aqueous humor circulation significantly reduces, and can significantly reduce toxic and side effects.
The present invention also provides above-mentioned process for manufacturing intraocular lenses, this method comprises: at first chitosan solution, polyacrylic acid solution and fluorouracil solution mixed by a certain percentage, stir and dialysis with certain speed, make chitosan-polyacrylic acid-fluorouracil nanoparticle suspension, the nanoparticle mean diameter is 100nm～150nm; To be immersed in chitosan-polyacrylic acid-fluorouracil nanoparticle suspension then through the polymethyl methacrylate intraocular lens that surface clean activation and ion processing are crossed 36～72 hours.
(1) material and reagent
PMMA IOL Shanghai deep and clear Lay scientific ﹠ trading Co., Ltd.
Chitosan Shanghai Ru Ji biotechnology Development Co., Ltd
Deacetylation is greater than 92%
Polyacrylic acid Beijing Shanghai branch company of the big chemical industry instrument of easypro uncle Co., Ltd
Molecular weight 100kDa, 35% (w/v)
The 0.25g/10ml of fluorouracil Shanghai Xudong Hipu Medicine Co., Ltd
The product analysis of glacial acetic acid Shanghai preparation company of pharmaceuticals is pure
The product analysis of dehydrated alcohol Shanghai preparation company of pharmaceuticals is pure
Surfactant Shanghai preparation company of pharmaceuticals product
Fluorion Shanghai preparation company of pharmaceuticals product
(2) component and proportioning
Chitosan 8～800mg
Polyacrylic acid 40～4000mg
Fluorouracil 100～1000mg
Glacial acetic acid 200～400mg
Distilled water 750～780ml
Fluorion 5 * 10
13～5 * 10
15Ions/cm
2
(3) operating procedure
I prepares fluorouracil-chitosan nano suspension:
(i) preparation A solution: the chitosan powder is fully swollen in the acetum of 0.5%～1% (w/v), be made into the chitosan solution A of 0.02%～2% (w/v);
(ii) prepare B solution: the polyacrylic acid thin up is become 0.02%～2% (w/v) polyacrylic acid solution B;
(iii) prepare C solution: the fluorouracil thin up is become 2.5～25mg/ml, get the fluorouracil solution C;
(iv) prepare the nanoparticle suspension: continue to stir down, by proportioning C solution is dropwise added in the B solution, speed 1～4ml/min is dripped in control, and control pH value 3-7 drips A solution by proportioning again, reacts 30 minutes～2 hours; Or earlier A solution is splashed into B solution by proportioning, and dripping C solution again, reaction condition is identical; Reaction moves to bag filter after finishing, and the two ends folder closes to be placed in the 500ml redistilled water and takes out after dialysis removal in the 5 hours free components, promptly makes chitosan-polyacrylic acid-fluorouracil nanoparticle suspension;
II prepares the nanometer fluorouracil coat intraocular lens:
(i) the PMMA intraocular lens is cleaned 3 times with the ultrasonic cleaning machine under the clean work station environment repeatedly by deionized water, in analytically pure dehydrated alcohol, soaked 24 hours, immersed again after the drying in the surfactant solution 24 hours, and preserved stand-by at the vacuum desiccator inner drying;
(ii) carry out the two-sided injection of fluorion through the activatory intraocular lens of surface clean with the low energy ion implanter, the energy of processing is 70keV, and the dosage of fluorion is 5 * 10
13～5 * 10
15Ions/cm
2
(iii) intraocular lens and the fluorouracil-chitosan nano suspension through fluoride treatment cooperates dipping 48 hours;
(iv) the intraocular lens after above-mentioned processing is modified preserves with oxirane disinfection behind the dry packing with deionized water ultrasonic cleaning repeatedly on superclean bench.
The method that intraocular lens of the present invention proves through zoopery:
1. postoperative is 3 days, and 1,2,4 all row live body examination with slitlamp microscope, observes anterior chamber and back cyst membrane situation, estimates respectively ophthalmic toxicity of group.
(annotate: the muddy grading standard of posterior lens capsule film central optic zone: 0 grade muddy for not having; 1 grade is a small amount of muddy, the visible little gauffer of posterior lens capsule film or monolayer lens epithelial cells (lensepithelial cells, LECs) thin slice; 2 grades is slight muddy, muddy and thicker lens epithelial cells sheet or the fibrous membrane of the visible Nidus Vespae sample of posterior lens capsule film; 3 grades is the moderate muddiness, visible typical Elschnig pearl-like corpusculum or fine and close fibrous membrane; 4 grades is the severe muddiness, visible fine and close Elschnig pearl-like corpusculum.)
2. 4 weeks of postoperative, extract lagophthalmos, get angle Gong Yuan tissue and put into 4% formalin fixedly more than the 48h, the dehydration of gradient alcoholic solution, waxdip, embedding, section, conventional H E dyeing back is observed each several part ocular tissue situation down in light microscopic, estimates ophthalmic toxicity of each group.
Conventional H E colouring method
(1) dimethylbenzene I, dimethylbenzene II dewaxing is 10 minutes,
(2) dehydrated alcohol was washed dimethylbenzene 1 minute, and twice,
(3) 95% ethanol, 90% ethanol, 85% ethanol, 75% ethanol respectively 1 minute,
(4) flowing water was washed 2 minutes,
(5) brazilwood extract dyeing is 3 minutes,
(6) flowing water was washed 2 minutes,
(7) 1% acidic alcohols differentiation 20 seconds,
(8) flowing water was washed 2 minutes,
(9) Yihong dyeing is 1 minute,
(10) 85% ethanol, 90% ethanol, 95% ethanol, dehydrated alcohol respectively 1 minute,
(11) dimethylbenzene I, dimethylbenzene II, dimethylbenzene III are each 2 minutes,
(12) conventional resin mounting.
3. 4 weeks of postoperative, extract lagophthalmos, separate the posterior lens capsule film, get posterior lens capsule film central part tissue, 2.5% glutaraldehyde solution of putting into 4 ℃ immediately is fixedly more than the 24h, the dyeing of 1% osmic acid, 618 embedding liquid embeddings, the ultramicrotome section, uranium-plumbous electron staining, the row transmission electron microscope is seen the posterior capsule opacification situation of looking into.
Concrete sample for use in transmitted electron microscope preparation process
Preceding fixing: 2% glutaraldehyde PBS fixative is fixed 2 hours under 4 ℃ of conditions.
Rinsing: the PBS buffer is washed twice under 4 ℃ of conditions, each 10 minutes.
The back is fixing: 1% osmic acid PBS fixative is fixed 2 hours under 4 ℃ of conditions.
Rinsing: the PBS buffer is washed twice under 4 ℃ of conditions, each 10 minutes.
Dehydration: 30%-50%-70% ethanol is by reaching dehydration (70% ethanol contains 3% uranium acetate), and each 10 minutes, 4 ℃ of pieces dyed, and 80%-95%-100% ethanol pursues and dehydration, each 10 minutes.
Displacement: expoxy propane displacement secondary, each 10 minutes.
Soak into: 618 embedding liquid and expoxy propane (ratio 1: 1), soaked into 2 hours.618 embedding liquid and expoxy propane (ratio 2: 1) are crossed liquid, and pure 618 embedding liquid soaked into 6 hours under 37% condition.
Embedding: in 60 ℃ of baking ovens 48 hours.
Section: LKB V-type ultramicrotome section.
Dyeing: uranium-plumbous electron staining.
The present invention can suppress posterior capsule opacification behind the implantation of artificial lens, the prevention after cataract, and ophthalmic toxicity is less.
The specific embodiment:
Below in conjunction with embodiment the present invention is further described:
Embodiment 1: preparation coating intraocular lens
One, component and proportioning
Chitosan 8mg
Polyacrylic acid 40mg
Fluorouracil 100mg
Glacial acetic acid 400mg
Distilled water 752ml
Fluorion 5 * 10
13Ions/cm
2
Two, preparation method
(1) preparation fluorouracil-chitosan nano suspension:
1, preparation A solution: get glacial acetic acid 400mg and be dissolved in the 40ml distilled water, add abundant swelling under the 8mg chitosan powder room temperature, be made into 0.02% chitosan-acetic acid solution A;
2, preparation B solution: get the 40mg polyacrylic acid and be dissolved in the 200ml distilled water and be made into 0.02% polyacrylic acid solution B;
3, preparation C solution: get the 100mg fluorouracil and be dissolved in the 12ml distilled water, get the fluorouracil solution C;
4, preparation nanoparticle suspension: continue 500rpm and stir down, dropwise drip solution C in B solution, fast 2ml/min is dripped in control, and control pH value 3-7 drips A solution again, drips fast 2ml/min, reacts 2 hours; Reaction moves to bag filter after finishing, and the two ends folder closes to be placed in the 500ml redistilled water and takes out after dialysis removal in the 5 hours free components.
(2) preparation nanometer fluorouracil coat intraocular lens:
1, the PMMA intraocular lens is cleaned 3 times with the ultrasonic cleaning machine under the clean work station environment repeatedly by deionized water.In analytically pure dehydrated alcohol, soak 24h, immerse 24h in the surfactant solution after the drying again, preserve stand-by at the vacuum desiccator inner drying.
2, carry out the two-sided injection of fluorion through the activatory intraocular lens of surface clean with the low energy ion implanter.The energy of handling is 70keV, and the dosage of fluorion is 5 * 10
13Ions/cm
2
3, intraocular lens and the fluorouracil-chitosan nano suspension through fluoride treatment cooperates dipping 48h.
4, the intraocular lens after above-mentioned processing is modified preserves with oxirane disinfection behind the dry packing with deionized water ultrasonic cleaning repeatedly on superclean bench.
Embodiment 2: the application of coating intraocular lens on lagophthalmos of embodiment 1 preparation
The coating intraocular lens of embodiment 1 preparation is implanted lagophthalmos:
1. experimental design grouping is labeled as A1-5, B1-5, C1-5, D1-5 respectively with 20 rabbits.
2. anesthesia before the art: 3% pentobarbital sodium, quantitatively anaesthetize from auricular vein by every kg body weight 1ml, an amount of lignocaine local anaesthesia of sub-conjunctival injection, the eye table drips the topical anesthesia of Ai Er caine eye liquid.
3. after the anesthesia rabbit is lain on one's side on the rabbit platform, the operation eye is left eye.Routine disinfection, shop list, last eye speculum.The 11-1 point is made the conjunctival flap that above arched roof is substrate, and 1mm does anti-eyebrow scleral flap behind the 11-1 point limbus of corneae, the high 2.5mm of lobe, locate to pierce through cornea at 2, cut tunnel incision, inject hyaluronate sodium 0.2ml in the anterior chamber to 3.2mm, the Tweezers for eye surgery curvilinear capsulorhexis, diameter 6mm, separated form water.
4.Geu about 7 seconds of der ultrasonic emulsification instrument ultrasonic emulsification (55% energy), sucking-off cortex is injected hyaluronate sodium 0.2ml.
A1-5: implant non-folding common intraocular lens, in the capsule bag, it is placed in the middle to adjust the position, remaining medicinal liquid and viscoelastic agent in the sucking-off anterior chamber.
B1-5: implant non-folding nanometer fluorouracil coat intraocular lens, in the capsule bag, it is placed in the middle to adjust the position, remaining medicinal liquid and viscoelastic agent in the sucking-off anterior chamber.
C1-5: implant non-folding common intraocular lens, and inject 0.2ml fluorouracil-chitosan nano particle suspension, effect 5min, sucking-off suspension and other remaining medicinal liquid and viscoelastic agent.
D1-5: implant non-folding common intraocular lens, and inject the fluorouracil solution of the 80ug/ml of 0.2ml, effect 5min, sucking-off fluorouracil solution and other remaining medicinal liquid and viscoelastic agent.
5. postoperative is not wrapped up, and conventional allusion quotation is eye drop eye very.
6. postoperative is 3 days, and 1,2,4 week row live body examination with slitlamp microscope anterior chamber and posterior lens capsule films.Get cornea, iris and the capable light microscopy checking of part sclera in 12 weeks of postoperative, get the capable electron microscopic examination of back cyst membrane.
The light microscopic result:
The A group: the cornea tissue structural integrity, show no obvious abnormalities, each is well arranged, and endotheliocyte has disappearance.The room corner structure is loose.The iris stroma form is normal, does not have obvious inflammation.Ciliary processes epithelial cell major part is transparent cavity shape, does not have obvious edema.
B group: cornea, iris tissue clear in structure.Cornea tissue is well arranged, Non Apparent Abnormality.The room corner structure is torn, is lacked because of drawing materials.Iris and corpus ciliare, ciliary processes tissue are normal, and epithelial cell is arranged complete, and substrate does not have edema and unusual, does not see obvious inflammatory cell infiltration.
The C group: the cornea level is owed clearly, and inflammatory cell infiltration and new vessels are arranged, and corneal endothelium has monocytoid cell to adhere to.The room corner structure is unclear, disappearance.Iris vasodilation, full.Disperse, focal inflammation cellular infiltration are arranged in the shallow-layer sclera, and see monokaryon sample lymphocyte in the vitreous body of ciliary processes adhesion.Inflammatory cell infiltration is arranged in the ciliary processes, monocytoid cell and lymphoid cell are arranged.
The D group: the cornea tissue level is arranged normal, a little inflammatory cell infiltration.Angle, room internal hemorrhage has inflammatory cell, the vacuolation of part ciliary processes epithelial cell, and ciliary processes vasodilation, full, seeing has the minority monocytoid cell to adhere to.
Electronic Speculum result:
The A group: lens epithelial cells is multiple layer, flat, fusiformis, and cell space is big, and a large amount of mitochondrions and rough endoplasmic reticulum are arranged in the cell, and number of filaments is a lot, and there are a large amount of euchromatins in the nucleus short texture, and the prompting cell proliferation is active.
The B group: lens epithelial cells is closely arranged, cell appearance is irregular, and iuntercellular connects apart from the phase embedding, is full of the filament spline structure in the cell, mitochondrion quantity is few, volume is less, and ridge is intensive, all the other organelle negligible amounts, nucleus ovum circle or irregular shape, chromatin is even, and obvious kernel is arranged, the necrolysis of part cell.The prompting cell proliferation is inactive.
The C group: lens epithelial cells is flat, and the endoplasmic reticulum of a lot of expansions is arranged in the cell, and a small amount of mitochondrion is arranged, and nucleus is flat, and the prompting cell proliferation is inactive.
D group: lens epithelial cells quantity seldom is dispersed in and is distributed in the fibrous membrane, the intracellular plastochondria seldom, karyopyknosis, the prompting cell proliferation is inactive.
Embodiment 3: preparation coating intraocular lens
One, component and proportioning
Chitosan 80mg
Polyacrylic acid 400mg
Fluorouracil 500mg
Glacial acetic acid 200mg
Distilled water 760ml
Fluorion 5 * 10
15Ions/cm
2
Two, preparation method is:
(1) preparation fluorouracil-chitosan nano suspension:
1, preparation A solution: get glacial acetic acid 200mg and be dissolved in the 40ml distilled water, add abundant swelling under the 80mg chitosan powder room temperature, be made into 0.2% chitosan-acetic acid solution A;
2, preparation B solution: get the 400mg polyacrylic acid and be dissolved in the 200ml distilled water and be made into 0.2% polyacrylic acid solution B;
3, preparation C solution: get the 500mg fluorouracil and be dissolved in the 20ml distilled water, get the fluorouracil solution C;
4, preparation nanoparticle suspension: continue 600rpm and stir down, dropwise drip solution C in B solution, fast 2ml/min is dripped in control, and control pH value 3-7 drips A solution again, drips fast 2ml/min, reacts 2 hours; Reaction moves to bag filter after finishing, and the two ends folder closes to be placed in the 500ml redistilled water and takes out after dialysis removal in the 5 hours free components.
(2) preparation nanometer fluorouracil coat intraocular lens:
1, the PMMA intraocular lens is cleaned 3 times with the ultrasonic cleaning machine under the clean work station environment repeatedly by deionized water.In analytically pure dehydrated alcohol, soak 24h, immerse 24h in the surfactant solution after the drying again, preserve stand-by at the vacuum desiccator inner drying.
2, the activatory intraocular lens of surface clean carries out the two-sided injection of fluorion with the low energy ion implanter.The energy of handling is 70keV, and the dosage of fluorion is 5 * 10
15Ions/cm
2
3, intraocular lens and the fluorouracil-chitosan nano suspension through fluoride treatment cooperates dipping 48h.
4, the intraocular lens after above-mentioned processing is modified preserves with oxirane disinfection behind the dry packing with deionized water ultrasonic cleaning repeatedly on superclean bench.
Embodiment 4: the application of coating intraocular lens on lagophthalmos of embodiment 3 preparations
The coating intraocular lens of embodiment 3 preparations is implanted lagophthalmos:
1. experimental design grouping is labeled as A6-10, B6-10, C6-10, D6-10 respectively with 20 rabbits.
2. anesthesia before the art: 3% pentobarbital sodium, quantitatively anaesthetize from auricular vein by every kg body weight 1ml, an amount of lignocaine local anaesthesia of sub-conjunctival injection, the eye table drips the topical anesthesia of Ai Er caine eye liquid.
3. after the anesthesia rabbit is lain on one's side on the rabbit platform, the operation eye is left eye.Routine disinfection, shop list, last eye speculum.The 11-1 point is made the conjunctival flap that above arched roof is substrate, and 1mm does anti-eyebrow scleral flap behind the 11-1 point limbus of corneae, the high 2.5mm of lobe, locate to pierce through cornea at 2, cut tunnel incision, inject hyaluronate sodium 0.2ml in the anterior chamber to 3.2mm, the Tweezers for eye surgery curvilinear capsulorhexis, diameter 6mm, separated form water.
4.Geu about 7 seconds of der ultrasonic emulsification instrument ultrasonic emulsification (55% energy), sucking-off cortex is injected hyaluronate sodium 0.2ml.
A6-10: implant non-folding common intraocular lens, in the capsule bag, it is placed in the middle to adjust the position, remaining medicinal liquid and viscoelastic agent in the sucking-off anterior chamber.
B6-10: implant non-folding nanometer fluorouracil coat intraocular lens, in the capsule bag, it is placed in the middle to adjust the position, remaining medicinal liquid and viscoelastic agent in the sucking-off anterior chamber.
C6-10: implant non-folding common intraocular lens, and inject the fluorouracil-chitosan nano particle suspension of 50 times of 0.2ml dilutions, effect 5min, sucking-off suspension and other remaining medicinal liquid and viscoelastic agent.
D6-10: implant non-folding common intraocular lens, and inject the fluorouracil solution of the 80ug/ml of 0.2ml, effect 5min, sucking-off fluorouracil solution and other remaining medicinal liquid and viscoelastic agent.
5. postoperative is not wrapped up, and conventional allusion quotation is eye drop eye very.
6. postoperative is 3 days, and 1,2,4 all row examination with slitlamp microscope.Get cornea, iris and the capable light microscopy checking of part sclera in 4 weeks of postoperative, get the capable electron microscopic examination of back cyst membrane.
The light microscopic result:
The A group: the cornea tissue structural integrity, show no obvious abnormalities, each is well arranged, and endotheliocyte has disappearance.The room corner structure because of the people that draws materials for tearing.The iris stroma form is normal, does not have obvious inflammation, contains a little monocytic vitreous body adhesion outside rarely seen iris pupil district.Ciliary processes is because of getting artificial intraocular lenses's fragmentation of rupturing, and epithelial cell is arranged normal substantially, does not have obvious edema, abnormal change.
B group: cornea, iris tissue clear in structure.Cornea tissue is well arranged, Non Apparent Abnormality.The room corner structure is torn, is lacked.Iris and corpus ciliare, ciliary processes tissue are normal, and epithelial cell is arranged complete, and substrate does not have edema and unusual, and karyon, endochylema ratio are normal, do not see obvious inflammatory cell infiltration.
The C group: the cornea level is owed clearly, and inflammatory cell infiltration and new vessels are arranged, and corneal endothelium has monocytoid cell to adhere to, and seeing behind the posterior elastic membrane has outgrowth fibrous tissue.The room corner structure is unclear, disappearance.Iris vasodilation, full.Around ciliary processes, see have a small amount of monocytoid cell to adhere to, inflammatory cell infiltration is arranged in the ciliary processes, monocytoid cell and lymphoid cell are arranged.
The D group: the cornea tissue level is arranged normal, a little inflammatory cell infiltration.Angle, room internal hemorrhage has inflammatory cell, and seeing has that to have a liking for blue dyed particles residual, the vacuolation of part ciliary processes epithelial cell, and ciliary processes vasodilation, full, seeing has the minority monocytoid cell to adhere to.
Electronic Speculum result:
The A group: lens epithelial cells is multiple layer, flat, fusiformis, and cell space is big, and a large amount of mitochondrions and rough endoplasmic reticulum are arranged in the cell, and number of filaments is a lot, and there are a large amount of euchromatins in the nucleus short texture, and the prompting cell proliferation is active.
The B group: the part lens epithelial cells comes off, loses, surplus structural integrity.Cell is arranged closely, is cube, has the phase embedding to connect each other, a small amount of mitochondrion in the cell, and filament structure is abundant, and nuclear is irregular shape.The prompting cell proliferation is inactive.。
The C group: lens epithelial cells is flat, and the endoplasmic reticulum of a lot of expansions is arranged in the cell, and a small amount of mitochondrion is arranged, and nucleus is flat.The prompting cell proliferation is inactive.
D group: lens epithelial cells quantity seldom is dispersed in and is distributed in the fibrous membrane, the intracellular plastochondria seldom, karyopyknosis.The prompting cell proliferation is inactive.
Claims (3)
1, a kind of polymethyl methacrylate process for manufacturing intraocular lenses of coating, it is characterized in that this method comprises: at first 0.02%～2% (w/v) chitosan solution, 0.02%～2% (w/v) polyacrylic acid solution and 2.5～25mg/ml fluorouracil solution are mixed, preparing the used chitosan of above-mentioned solution is 8～800mg, polyacrylic acid is 40～4000mg, and fluorouracil is 100～1000mg; 500rpm or 600rpm stir and dialysis, make chitosan-polyacrylic acid-fluorouracil nanoparticle suspension, and the nanoparticle mean diameter is 100nm～150nm; To be immersed in chitosan-polyacrylic acid-fluorouracil nanoparticle suspension then through the polymethyl methacrylate intraocular lens that surface clean activation and the two-sided injection of fluorion were handled 36～72 hours.
2, the polymethyl methacrylate process for manufacturing intraocular lenses of a kind of coating according to claim 1 is characterized in that this method is made up of following steps:
I prepares chitosan-polyacrylic acid-fluorouracil nanoparticle suspension:
(i) preparation A solution: the chitosan powder is fully swollen in the acetum of 0.5%～1% (w/v), be made into the chitosan solution A of 0.02%～2% (w/v);
(ii) prepare B solution: the polyacrylic acid thin up is become 0.02%～2% (w/v) polyacrylic acid solution B;
(iii) prepare C solution: the fluorouracil thin up is become 2.5～25mg/ml, get the fluorouracil solution C;
(iv) prepare the nanoparticle suspension: continue to stir down, the C solution that (iii) prepares is dropwise added in the B solution of (ii) preparation, speed 1～4ml/min is dripped in control, controls pH value 3-7, drips the A solution of (i) preparation again, reacts 30 minutes～2 hours; Or A solution that earlier will (i) preparation splashes into the (ii) B solution of preparation, drips the C solution that (iii) prepares again, and reaction condition is identical; Reaction moves to bag filter after finishing, and the two ends folder closes to be placed in the 500ml redistilled water and takes out after dialysis removal in the 5 hours free components, promptly makes chitosan-polyacrylic acid-fluorouracil nanoparticle suspension; II prepares the nanometer fluorouracil coat intraocular lens:
(i) the PMMA intraocular lens is cleaned 3 times with the ultrasonic cleaning machine under the clean work station environment repeatedly by deionized water, in analytically pure dehydrated alcohol, soaked 24 hours, immersed again after the drying in the surfactant solution 24 hours, and preserved stand-by at the vacuum desiccator inner drying;
(ii) carry out the two-sided injection of fluorion through the activatory intraocular lens of surface clean with the low energy ion implanter, the energy of processing is 70keV, and the dosage of fluorion is 5 * 10
13～5 * 10
15Ions/cm
2
(iii) intraocular lens and the chitosan-polyacrylic acid-fluorouracil nanoparticle suspension through fluoride treatment cooperates dipping 48 hours;
(iv) the intraocular lens after above-mentioned processing is modified preserves with oxirane disinfection behind the dry packing with deionized water ultrasonic cleaning repeatedly on superclean bench.
3, the polymethyl methacrylate intraocular lens of a kind of coating that makes according to claim 1 or 2 described preparation methoies.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100391804A CN100553692C (en) | 2007-04-06 | 2007-04-06 | Nanometer fluorouracil coat artificial crystalloid and preparation method thereof |
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| CN103099706B (en) * | 2013-02-08 | 2016-01-27 | 首都医科大学附属北京同仁医院 | A kind of for intraocular lens preventing and treating after cataract and preparation method thereof |
| CN104352289A (en) * | 2014-10-27 | 2015-02-18 | 浙江大学 | Intraocular lens loaded with drug slow-releasing thin layers on loop surfaces |
| CN106215236B (en) * | 2016-07-20 | 2019-09-17 | 国家纳米科学中心 | A kind of gold nanorods region modification intraocular lens and its preparation method and application |
| CN106492287B (en) * | 2016-10-27 | 2019-06-14 | 国家纳米科学中心 | Intraocular lens and its preparation method and application are modified in a kind of iron-base magnetic nano particle region |
| CN112402098B (en) * | 2020-11-19 | 2022-03-08 | 浙江大学 | Drug-eluting intraocular lens with slow release function and preparation method thereof |
| CN113018508A (en) * | 2021-03-15 | 2021-06-25 | 西安交通大学医学院第一附属医院 | Surface-modified artificial lens and preparation method thereof |
| CN114870002A (en) * | 2022-05-26 | 2022-08-09 | 天津医科大学眼科医院 | Functions of plasmin in preventing after cataract |
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| Title |
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| 微波等离子体在肝素修饰人工晶体表面中的应用. 靳涛，李惠琪.山东科技大学学报（自然科学版），第23卷第4期. 2004 |
| 微波等离子体在肝素修饰人工晶体表面中的应用. 靳涛，李惠琪.山东科技大学学报（自然科学版），第23卷第4期. 2004 * |
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