CN115463257B - Composite reinforced scleral patch and preparation method thereof - Google Patents
Composite reinforced scleral patch and preparation method thereof Download PDFInfo
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- CN115463257B CN115463257B CN202211114384.0A CN202211114384A CN115463257B CN 115463257 B CN115463257 B CN 115463257B CN 202211114384 A CN202211114384 A CN 202211114384A CN 115463257 B CN115463257 B CN 115463257B
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- silk fibroin
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- scleral
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- AZKVWQKMDGGDSV-UHFFFAOYSA-N genipin Natural products COC(=O)C1=COC(O)C2C(CO)=CCC12 AZKVWQKMDGGDSV-UHFFFAOYSA-N 0.000 claims abstract description 27
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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
- A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
-
- 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
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
-
- 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
A composite reinforced scleral patch is prepared from nano silk fibroin, nano titanium dioxide, polyurethane prepolymer, and electrostatic spinning to obtain nano silk fibroin composite film, shaping by prefabricated concave-convex ceramic mould with 200-500 μm filter holes, cutting, and deep cross-linking and fixing with genipin solution. The patch has composite reinforcing performance of various materials: good biocompatibility, stronger structural mechanics and biomechanical characteristics, no immunogenicity, strong degradation resistance, strong tensile breaking strength and extremely small breaking elongation; is especially suitable for scleral reinforcement and repair.
Description
Technical Field
The invention relates to an ophthalmic medical apparatus, in particular to a compound enhanced scleral patch for treating pathological high myopia and a preparation method thereof, belonging to the technical field of bioengineering materials.
Background
The thickness of the posterior sclera is thinned, the strength is weakened, the continuous expansion occurs, the continuous extension of the eye axis is represented by the continuous increase of the negative refraction degree, the high myopia is represented, and the progressive aggravation occurs; continued expansion of the posterior sclera can also lead to maculolysis, foramina and retinal detachment, with progressive progression of the disease, the patient is often blinded by ocular fundus lesions after adulthood.
A lens, a laser cutting cornea, an anterior chamber with a lens implanted artificial lens and a scleral lens; only vision can be corrected, and progressive exacerbation of high myopia cannot be controlled; laser ablation also risks blindness due to keratoconus.
Currently, the ophthalmology industry widely recognizes that posterior scleral reinforcement is the only method for controlling the progress of the course of high myopia, and the principle is as follows: the patch is transplanted and fixed on the outer surface of the posterior sclera, so that scleral cells migrate to the mesh frame of the scleral patch to grow, the patch and the posterior sclera are fused to form a new sclera with increased thickness, the increase and expansion of the posterior sclera strength are limited, the extension of the ocular axis and the increase of the diopter of myopia are stopped, the choroid and retina are protected, and the occurrence and the aggravation of fundus lesions are prevented.
In recent years, experimental researches show that the posterior scleral reinforcement is performed by pressing and stitching during the fixation of the patch in the operation, so that the posterior sclera is pressed by the semicircular bands in the front-back direction to shorten the eye axis, and the anterior sclera can be used for treating high myopia macular cleavage and macular retinal detachment.
Posterior scleral reinforcement materials are divided into biological and non-biological materials. Allogenic material sources are scarce and regulations prohibit their trade as commodity; the non-biological materials include silica gel, polyester cloth, gel of certain polymer materials and the like, and the materials have wide sources, are not easy to degrade after being implanted into a human body, have reliable tension and toughness, are not easy to stretch and prolong, but have poor tissue compatibility, and can generate chronic aseptic inflammatory immune reaction.
Chinese patent CN 102525729B discloses a technical solution for preparing a scleral patch for posterior scleral reinforcement of human eyes from bovine, equine, porcine or dura mater; the animal has uneven dura mater, uneven thickness and uneven blood vessel distribution like walnut skin, is difficult to find proper surface area for operation, and has extremely low patch yield.
The pericardium of animals (cattle, horses and pigs) is formed by arranging natural collagen fibers and elastic fibers in a single-layer curling way, can be stretched and expanded by external force, and has a stretching and elongation rate of about 30% even after crosslinking, so that the host posterior sclera which is easy to be expanded after operation is stretched and prolonged, and the ocular axis is prolonged continuously and the long-term curative effect of the operation is reduced.
Chinese patent CN 110353856A discloses a method for preparing a biological patch for posterior scleral reinforcement, wherein animal pericardium (bovine, equine, porcine) is subjected to decellularization, carding, crosslinking, and cutting to form a scleral patch; the modified polyurethane has excellent biocompatibility, strong degradation resistance, enhanced breaking strength and better stretch-breaking elongation resistance, can be used for scleral reinforcement, but requires strict screening and control of (mad cow disease) prion factors; at present, the prion killing method is not effectively verified, so that a certain safety risk exists.
Chinese patent CN 106543744A discloses a method for preparing a blended film of silk fibroin and polyurethane, wherein a blended film is prepared by mixing silk fibroin solution and polyurethane prepolymer; although having good biocompatibility and better strength and toughness, the membrane is very elastic and stretchable 1065%, and is easily degraded, and cannot be used as a scleral patch.
The technical scheme for preparing the scleral patch disclosed at present does not exist, and the special requirements of the sclera can not be met: high resistance to degradation and extremely low elongation.
In view of the huge market demand for prevention and control of pathological high myopia and the shortages of the existing scleral patch preparation methods, it is necessary to propose a new preparation method, which overcomes the shortages in the above technical solutions, and provides a scleral patch for posterior scleral reinforcement surgery, which is not weaker than the natural scleral attribute, to meet the needs of many patients for diagnosis and treatment of high myopia.
Genipin is an iridoid heterocyclic compound, has a plurality of active functional groups such as hydroxyl, carboxyl and the like, is an excellent natural crosslinking agent, and can be crosslinked with protein, collagen, gelatin, chitosan and the like to prepare biological materials for clinical medical diagnosis and treatment processes, such as artificial bones, tissue repair, wound dressing materials and the like, and the toxicity of the genipin is far lower than glutaraldehyde (the toxicity of the genipin is one ten thousandth of glutaraldehyde) and other common chemical crosslinking agents. It also has antigen removing effect, and can react with free amino groups of residues such as lysine, hydroxylysine, arginine, etc. in collagen molecule. The cytotoxicity is low because the ring-shaped crosslinks formed by genipin are more stable than other network crosslinks and linear crosslinks. Genipin reacts with amino acid to generate blue pigment, and blue substance is probably generated by genipin and methylamine reaction and consists of 40-44 monomers, which suggests that the blue substance can form molecular cross-links with annular structures in collagen molecules; compared with other crosslinking methods, the genipin crosslinked collagen has the maximum heat shrinkage temperature, elastic modulus and tensile strength; and after being implanted into a human body, calcification is not easy to occur. The toughness, mechanical strength, degradation resistance and other properties of the crosslinked biological film material are related to the crosslinking degree, and the toughness is increased, the mechanical strength is improved, the degradation resistance is improved, but the compliance is reduced as the hardness of the material is increased. The degree of crosslinking is related to the conditions of the crosslinking reaction, such as temperature, pH, concentration of the crosslinking agent, crosslinking time, etc.
The silk fibroin is natural high molecular fibrin extracted from silk, the content of which is about 70% -80% of the silk, and 18 amino acids, wherein glycine, alanine and serine are about more than 80% of the total composition. The silk fibroin itself has good mechanical properties and physicochemical properties, such as good flexibility and tensile strength, air permeability and moisture permeability, slow release property and the like, and can obtain different forms such as fiber, solution, powder, film, gel and the like through different treatments.
The molecular conformations of natural Silk fibroin are divided into two classes, silk I and Silk II structures, the Silk I structure comprising random coils and alpha-helices; the Silk II structure is antiparallel-folded (β -sheet); the silk fibroin is a subunit structure composed of an H chain (mainly composed of glycine, alanine, serine and the like, with a molecular weight of about 30-35 kilodaltons) and an L chain (amino acids with more loose residues and a molecular weight of about 2.5 kilodaltons), and the H chain and the L chain are combined through S-S, so that the silk fibroin can be called a block polymer. Silk fibroin is based on an antiparallel folded chain conformation (beta sheet) to form microfibers with a diameter of about 10nm, innumerable microfibers are closely combined to form a fine fiber with a diameter of about 1 μm, and about 100 fine fibers are arranged along a long axis to form a single fiber with a diameter of about 10-18 μm, namely silk fibroin fiber.
The regenerated silk fibroin has high biocompatibility with human tissues, strong drug permeation, good mechanical property and controllable degradability, and can be applied to biomedicine, medical equipment, tissue engineering and drug delivery systems.
Disclosure of Invention
A composite reinforced scleral patch, characterized by: the scleral patch is formed by mixing three materials, dissolving the three materials into a formic acid solution, performing electrostatic spinning to form a composite membrane, shaping the composite membrane by using a microporous ceramic die, and simultaneously, cross-linking and fixing the composite membrane by using genipin, wherein the mass fraction of nano silk fibroin is 60-80%, the mass fraction of nano titanium dioxide is 0.4-2.0%, and the mass fraction of polyurethane prepolymer dissolved after mixing is 20-40%; the spatial dimension of the composite reinforced scleral patch of the invention is as follows: the radius of the curved surface is 25-28 mm, the maximum width is 12-14 mm, the length is the radius of the curved surface multiplied by pi, the width of the two ends is 4-5 mm, and the thickness is 0.4-0.85 mm.
A method for preparing a composite reinforced scleral patch, which is characterized by comprising the following steps: the method comprises the following steps of
Step S1: preparation of a solution of Nano silk fibroin comprising
1) The silkworm cocoons with pupa removed are put into 0.05 to 0.5 percent sodium bicarbonate (Na) 2 CO 3 ) In the solution, the solid-liquid ratio is 1 (10-20); boiling for 30-60 min, repeating for 3 times, repeatedly cleaning with deionized water, and drying in a vacuum drying oven for 24h to obtain solid silk fibroin;
2) Solid silk fibroin was placed into 50% CaCL 2 In the solution, the solid-to-liquid ratio W/V is 1:20, boiling is carried out until the silk fibroin solid is completely dissolved, the solid impurities are removed by suction filtration, then the solution is dialyzed for 2 to 3 days by deionized water by a dialysis bag, the pure silk fibroin solution is obtained, and then the solution is ultrafiltered by a polyethersulfone membrane with the interception relative molecular weight of 30 kDa;
3) Adding tween-20 with the v/v of 0.25-0.5% into the silk fibroin solution with the concentration of 0.05% after ultrafiltration, and performing ultrasonic crushing treatment, wherein the parameters are as follows: the frequency is 300KHz, the action time is 5S, the interval is 5S, and the operation is repeated 15 times; filtering with 0.22 μm pore size polyethersulfone membrane, concentrating with glycerol in dialysis bag for 8 hr, collecting concentrated solution, and performing ultrasonic crushing under the same conditions as above; can obtain ideal silk fibroin solution containing nanometer scale.
Step S2: the preparation of the composite reinforced composite film comprises the following steps:
1) Adding 0.4-2.0% (weight percentage) of nano titanium dioxide into the nano silk fibroin solution, adjusting the PH value to 5-6, and magnetically stirring for 30-120 min;
2) Mixing 5 parts of polypropylene glycol and 4 parts of dimethylolpropionic acid, heating to 120 ℃, preserving heat for 30min, cooling to 85 ℃, adding 3 parts of benzene diisocyanate for reaction, cooling to room temperature, adding 0.5 part of acrylic acid, 2 parts of acetone and 1 part of trihexylamine, stirring, placing in ice water, and standing for 40min in cold bath; filtering to obtain polyurethane prepolymer;
3) In the presence of titanium dioxide (TiO 2 ) Adding 3 parts of lithium bromide solution into 4 parts of nano silk fibroin solution mixed solution, stirring, mixing, introducing into a ceramic ultrafiltration membrane with the aperture of 200-500 mu m, and filtering to obtain concentrated solution; adding polyurethane prepolymer into the concentrated solution according to the proportion of 20-40 wt%, dispersing (the rotation speed of a centrifugal machine is 800rpm/15 min), and standing for 40min; drying for 1h at 50-60 ℃ to obtain a mixture;
4) Dissolving the mixture into formic acid solution with the concentration of 1-10% according to the W/V ratio of 6%, and adding the mixture into a high-pressure drug feeder of double-nozzle electrostatic spinning equipment after complete dissolution; spinning conditions: static voltage is 30-35 KV, distance is 15-20 cm, and speed is 0.5-1.5 ml/h; the two spray heads are opposite and are distributed in a front-back crossing way, the rotating speed of the roller is 500-3000 rpm, the humidity in the electrospinning box is 30-50%, and the temperature is 18-40 ℃; preparing a nano composite film with the thickness of 0.6-3.0 mm, and step S3: shaping, cross-linking, fixing, packaging and sterilizing the composite film, including:
1) Thoroughly cleaning the composite membrane with deionized water for 3-5 min each time, repeating for 3 times, placing the composite membrane into a concave-convex ceramic mould for shaping and cutting, locking the mould and immersing the composite membrane (without the mould) into 0.25-1.0% genipin solution according to the proportion of 15:100 for crosslinking for 24-96 h, wherein the crosslinking degree reaches 80-95%, and forming the composite reinforced sclera patch; the crosslinking device parameters were: the temperature is 35-37 ℃ and the shaking table frequency is 1-5 Hz/min; amplitude is 1-3 degrees;
the ceramic mould is a concave-convex symmetrical mould which is sintered and made and distributed with 200-500 mu m micropores; the height of the fusiform bulge of the male die is equal to the depth of the fusiform pit of the female die, the male die and the female die can be embedded up and down, the fusiform edge of the male die and the female die can cut the composite film, and the residual clearance after the die is buckled and locked is equal to the thickness of the patch; cavity/feature structure dimensions of the male and female mold: the radius of the curved surface is 25-28 mm, the maximum arc width is 12-14 mm, the maximum arc length is the radius of the curved surface multiplied by pi, and the width of the two ends of the arc is 4-5 mm.
2) Taking out the compound enhanced scleral patch, putting the compound enhanced scleral patch into 5-30% glycine solution for neutralization reaction for 40min, and rinsing with distilled water for 3-5 times, each time for 3-5 min;
3) Packaging with bubble cap containing liquid, and sterilizing with one of gamma ray, linear accelerator or ethylene oxide; sterilizing to obtain scleral patch; the space structure size is as follows: the radius of the curved surface is 25-28 mm, the maximum width is 12-14 mm, the length is the radius of the curved surface multiplied by pi, and the width of two ends is 4-5 mm; the thickness is 0.40-0.85 mm.
The inventor invents in the research, the concentration and the crosslinking time of genipin determine the crosslinking degree of the material, the crosslinking effect can strengthen the strength of the material, mask the exposed groups in the molecular chain of the fiber structure, improve and provide the degradation resistance, reduce the immunogenicity and improve the biocompatibility;
by test comparison, the amount of titanium dioxide is added, so that the tensile elongation of the composite material is determined, the huge specific surface area and dispersibility of the nano titanium dioxide are determined, the physical filling and wrapping and molecular bonding linking of the nano titanium dioxide to polyurethane fibers are determined, the elastic space of the polyurethane fibers is reduced, and the elastic extension of the polyurethane and silk fibroin composite film material is reduced; the combination proportion of the nano silk fibroin and polyurethane is determined to have good biocompatibility characteristics and meet certain material mechanical requirements of the scleral patch; genipin has strengthening effect on the above mentioned items (degradation resistance, strength, biocompatibility, pore diameter).
A composite reinforced scleral patch of the present invention compares to scleral patch substitutes (surgical patches, human dura mater, human sclera, pericardial patches) of the prior art and with the actual application of the present invention: has the following advantages:
1. the material has strong material mechanical characteristics while ensuring the material compliance: the breaking strength of the material is more than 60MPa; far better than 12MPa of breaking strength of human sclera;
2. has excellent biocompatibility characteristics: the nanometer silk fibroin molecules fully wrap polyurethane fibers, and the proper cross-linking of genipin is used for covering fiber residual groups, so that the composite scleral patch has enhanced biocompatibility and extremely low immunogenicity;
3. the filling and wrapping of the polyurethane fiber are assisted by the cross-linking action of genipin due to the nano-size dispersibility of the titanium dioxide, so that the extending elastic space of the polyurethane polymer fiber is eliminated, and the composite scleral patch has very low breaking elongation less than or equal to 2% while ensuring stronger breaking strength;
4. the genipin fully cross-links the composite membrane material (the cross-linking degree is 80-95 percent), so that the scleral patch further improves the degradation resistance; the degradation degree is less than 3%;
these advantages are the necessary conditions for fusion and symbiosis with the host sclera after scleral patch implantation.
Description of the drawings
1: a concave die; 11-hemispherical dimples; 12-curved fusiform depressions; 13-width of two ends of the curved fusiform recess; 14-maximum width of curved fusiform recess; 15-concave die locking holes;
2. a male die; 21-hemispherical protrusions; 22-curved fusiform ridges; 23-width of both ends of the curved fusiform bulge; 24-maximum width of the curved fusiform bulge; 25-male mold locking holes;
3. a composite reinforced scleral patch; 31-radius of curvature of the scleral patch; 32-maximum width of scleral patch; 33-width of both ends of scleral patch.
Drawings
FIG. 1 is a schematic view of a ceramic concave mold of a scleral patch for posterior scleral reinforcement according to the present invention:
fig. 2 is a schematic structural view of a ceramic convex mold of a scleral patch for posterior scleral reinforcement according to the present invention:
FIG. 3 is a schematic view of the spatial configuration of a posterior scleral patch according to the present invention;
Detailed Description
The technical scheme of the present invention will be further specifically described by the following specific examples, and it should be understood that the implementation of the present invention is not limited to the following examples, and any form of modification and/or variation of the present invention will fall within the scope of protection of the present invention.
In the present invention, unless otherwise specified, all parts and percentages are by weight, and the equipment, materials, etc. used are commercially available or are conventional in the art. The methods in the following examples are conventional in the art unless otherwise specified.
The reagents used in the following examples, unless otherwise specified, were purchased from conventional biochemical reagent stores.
In a first mode, referring to the drawings, an embodiment of the present invention includes the following steps:
step S1: the preparation of the nano silk fibroin solution comprises the following steps:
1) The silkworm cocoons with pupa removed are put into 0.05 to 0.5 percent sodium bicarbonate (Na) 2 CO 3 ) In the solution, the solid-liquid ratio is 1:10-20; boiling for 30-60 min, repeating for 3 times, repeatedly cleaning with deionized water, and drying in a vacuum drying oven for 24h to obtain solid silk fibroin;
2) Solid silk fibroin was placed into 50% CaCL 2 In the solution, the solid-liquid ratio W/V is 1:20, boiling for 10-15 minn to completely dissolve, filtering to remove solid impurities, dialyzing with deionized water for 2-3 days by using a dialysis bag to obtain a pure silk fibroin solution, and then ultrafiltering with a polyether sulfone membrane with the interception relative molecular weight of 30 kDa; the molecular weight distribution range of the silk fibroin can be separated from 43K-331 kDa into a continuum in the range of 52K-331 kDa; the purpose is to filter the L chain of silk fibroin, which has a molecular weight of about 25kDa.
3) Adding tween-20 with v/v of 0.25-0.5% into the silk fibroin solution with the adjusted concentration of 0.05% after ultrafiltration, and performing ultrasonic crushing treatment, wherein the parameters are as follows: the frequency is 300KHz, the action time is 5S, the interval is 5S, and the operation is repeated 15 times; filtering with 0.22 μm pore size polyethersulfone membrane, concentrating with glycerol in dialysis bag for 8 hr, and collecting concentrated solution; the method and the conditions are the same, and ultrasonic crushing is carried out again; can obtain ideal silk fibroin solution containing nanometer scale.
Step S2: the preparation of the mixed synergistic enhanced composite membrane comprises the following steps:
1) Adding 0.4-2.0% (weight percentage) nanometer into nanometer silk fibroin solutionTitanium dioxide (TiO) 2 ) Adjusting the PH value to 5-6, and magnetically stirring for 30-120 min;
2) Mixing 5 parts of polypropylene glycol and 4 parts of dimethylolpropionic acid, heating to 120 ℃, preserving heat for 30min, cooling to 85 ℃, adding 3 parts of benzene diisocyanate for reaction, cooling to room temperature, adding 0.5 part of acrylic acid, 2 parts of acetone and 1 part of trihexylamine, stirring, placing in ice water, and standing for 40min in cold bath; filtering to obtain polyurethane prepolymer;
3) In the presence of titanium dioxide (TiO 2 ) Adding 3 parts of lithium bromide solution into 4 parts of nano silk fibroin solution mixed solution, stirring, mixing, introducing into a ceramic filter membrane with the aperture of 200-500 mu m, and ultrafiltering to obtain concentrated solution; adding polyurethane prepolymer into the concentrated solution according to the proportion of 20-40 wt%, dispersing (the rotation speed of a centrifugal machine is 800rpm/15 min), and standing for 40min; drying for 1h at 50-60 ℃ to obtain a mixture;
4) Dissolving the mixture into 10% formic acid solution for 20-30 min according to the W/V ratio of 6%, and adding into a high-pressure drug feeder of double-nozzle electrostatic spinning equipment; the spinning conditions are: static voltage is 30-35 KV, distance is 15-20 cm, and speed is 0.5-1.5 ml/h; the two spray heads are opposite and are distributed in a front-back crossing way, the rotating speed of the roller is 500-3000 rpm, the humidity in the electrospinning box is 30-50%, and the temperature is 18-40 ℃; preparing a nano composite film with the thickness of 0.6-3.0 mm;
step S3: shaping, cross-linking, fixing, packaging and sterilizing the composite film, including:
1) Thoroughly cleaning the composite membrane by using deionized water for 3-5 minutes each time, and repeating for 3 times; placing the composite membrane in a concave-convex ceramic mould for shaping and cutting, referring to figures 1 and 2, immersing the composite membrane and the mould (according to 15g of the mass of the composite membrane) into 0.25-1.0% genipin solution for crosslinking and fixing for 24-96 hours, wherein the crosslinking degree is 80-95%, and forming a composite reinforced scleral patch (referring to figure 3); the crosslinking device parameters were: the temperature is 35 ℃, and the shaking table frequency is 1-3 Hz/min; amplitude is 1-3 degrees;
if the weight of the liquid contained in the composite film is 1 part, the weight part of the medicinal genipin with the purity of 98 percent is 1/(15-60);
2) Taking out the enhanced scleral patch, putting the enhanced scleral patch into 10-30% glycine solution for neutralization reaction for 30-60 min, and rinsing with distilled water for 3-5 times, each time for 3-5 min;
3) Packaging with blister containing liquid, and sterilizing with one of gamma ray, linear accelerator or ethylene oxide.
The ceramic mould is a concave-convex symmetrical mould which is sintered and made and distributed with 200-500 mu m micropores; the buckled edge can cut the composite film, the depth of the fusiform concave of the concave mould is equal to the height of the bulge of the convex mould, and the locking degree (residual gap) of the mould after buckling determines the thickness of the patch; cavity/feature structure dimensions of the male and female mold: the radius of the curved surface is 25-28 mm, the maximum arc width is 12-14 mm, the maximum arc length is the radius of the curved surface multiplied by pi, and the width of the two ends of the arc is 4-5 mm; the concave-convex mould is tightly embedded.
The cross-linking agent is medicinal genipin, and is white crystal powder with purity more than or equal to 98%.
The compound enhanced scleral patch prepared by the method has a curved surface fusiform space structure, has good applicability to the curvature of the sclera at the posterior pole of the eyeball, is comprehensively clung to the posterior pole of the eyeball, and is beneficial to postoperative rehabilitation and fusion symbiosis.
Mode two: preferred in step S2
Adding tween-20 with v/v of 0.5% into the silk fibroin solution with the adjusted concentration of 0.05% after ultrafiltration, and performing ultrasonic crushing treatment, wherein the parameters are as follows: the frequency is 300KHz, the action time is 5S, the interval is 5S, and the operation is repeated 15 times; filtering with 0.22 μm pore size polyethersulfone membrane, concentrating with glycerol in dialysis bag for 8 hr, and collecting concentrated solution; the method and the conditions are the same, and ultrasonic crushing is carried out again; the silk fibroin solution containing nanometer scale is ideal, the particle size of the silk fibroin molecules after treatment is reduced to below 3.2 mu m, and the silk fibroin molecules with the particle size less than or equal to 1 mu m account for more than 75 percent;
the rest steps and methods remain consistent with the mode;
through comparative test research, the addition ratio of the dispersing agent Tween-20 is preferably 0.5%, and the solution without the nano-scale silk fibroin molecules can be crushed and separated into nano-scale molecules to the greatest extent through an ultrasonic crushing device. The polyurethane coating and shielding after the material is compounded and intermolecular and intramolecular crosslinking is formed between the polyurethane coating and shielding and the genipin, and the biocompatibility and the degradation resistance are improved.
Mode three: preferred in step S2
Adding 1.8 to percent (weight percent) of nano titanium dioxide (TiO) into the nano silk fibroin solution 2 ) Adjusting the PH value to 5-6, and magnetically stirring for 30-120 min;
the rest steps and methods remain consistent with the mode; the test of the prepared composite reinforced scleral patch shows that the elongation at break is smaller than or equal to 2%;
through a contrast test study, the dispersibility of the nano titanium dioxide and the huge specific surface area thereof are fully contacted and filled with the polyurethane fiber, and after the polyurethane fiber is fully crosslinked by genipin, the polyurethane fiber keeps the original tensile breaking strength and simultaneously eliminates the space for being pulled and extended; the test result of the invention is that when the titanium dioxide addition is 0.8%, the composite material shows smaller elongation at break which is less than or equal to 2%; this will be more advantageous for using the composite reinforced scleral patch of the present invention for post-operative maintenance of the permanent reinforcement of the scleral patch without a decrease in efficacy due to continued expansion of the ocular axis as a result of the material being degraded or elastically expanded post-operative.
Mode four: application example A preparation method of a compound enhanced scleral patch is preferred, and comprises the following steps
Step S1: the preparation of the nano silk fibroin solution comprises the following steps:
1) The silkworm cocoons from which pupa were removed were put into 0.5% sodium bicarbonate (Na 2 CO 3 ) In the solution, the solid-liquid ratio is 1:10; boiling for 30min, repeating for 3 times, repeatedly cleaning with deionized water, and drying in a vacuum drying oven for 24 hr to obtain solid silk fibroin.
2) Solid silk fibroin was placed into 50% CaCL 2 In the solution, the solid-liquid ratio W/V is 1:10, boiling for 15minn to completely dissolve, filtering to remove solid impurities, dialyzing with deionized water for 3 days by using a dialysis bag to obtain pure silk fibroin solution, and then ultrafiltering with a polyethersulfone membrane with the interception relative molecular weight of 30 kDa; silk fibroin filtering eggThe L chain of white is used for obtaining a silk fibroin solution of a continuum with the molecular weight distribution range of 52K-331 kDa.
3) Adding tween-20 with v/v of 0.5% into silk fibroin solution with concentration of 0.05% after ultrafiltration for ultrasonic disruption, and processing parameters: the frequency is 300KHz, the action time is 5S, the interval is 5S, and the operation is repeated 15 times; filtering with 0.22 μm pore size polyethersulfone membrane, concentrating with glycerol in dialysis bag for 8 hr, and collecting concentrated solution; the conditions and the method are the same, and ultrasonic crushing is carried out again; obtaining the nano silk fibroin solution with the particle diameter of less than 3.2 mu m and more than 75 percent of silk fibroin molecules smaller than 1 mu m.
Step S2: the preparation of the mixed synergistic enhanced composite membrane comprises the following steps:
2) Adding 1.8% (weight percent) nano titanium dioxide (TiO) into nano silk fibroin solution 2 ) Adjusting the PH value to 5-6, and magnetically stirring for 30-120 min;
2) Mixing 5 parts of polypropylene glycol and 4 parts of dimethylolpropionic acid, heating to 120 ℃, preserving heat for 30min, cooling to 85 ℃, adding 3 parts of benzene diisocyanate for reaction, cooling to room temperature, adding 0.5 part of acrylic acid, 2 parts of acetone and 1 part of trihexylamine, stirring, placing in ice water, and standing for 40min in cold bath; filtering to obtain polyurethane prepolymer;
3) In the presence of titanium dioxide (TiO 2 ) Adding 3 parts of lithium bromide solution into 4 parts of nano silk fibroin solution mixed solution, stirring, mixing, introducing into a ceramic filter membrane with the aperture of 200-500 mu m, and ultrafiltering to obtain concentrated solution; adding polyurethane prepolymer into the concentrated solution according to the proportion of 20-40 wt%, dispersing (the rotation speed of a centrifugal machine is 800rpm/15 min), and standing for 40min; drying for 1h at 50-60 ℃ to obtain a mixture;
4) Dissolving the mixture into 10% formic acid solution according to the W/V ratio of 6% until the mixture is completely dissolved, and adding the mixture into a high-pressure drug feeder of double-nozzle electrostatic spinning equipment; spinning conditions: static voltage is 35KV, distance is 18cm, and speed is 1.0ml/h; the two spray heads are opposite and are distributed in a front-back crossing way, the rotating speed of the roller is 1000rpm, the humidity in the electrospinning box is 45%, and the temperature is 25 ℃; the nano composite film with the thickness of 0.6-3.0 mm is prepared.
Step S3: shaping, cross-linking, fixing, packaging and sterilizing the composite film, including:
1) Thoroughly cleaning the composite membrane by using deionized water for 3-5 minutes each time, repeating for 3 times, placing the composite membrane in a concave-convex ceramic mould for shaping and cutting, and then immersing the composite membrane and the mould in 0.5% genipin solution for cross-linking and fixing for 96 hours to form a curved-surface fusiform sclera patch; the crosslinking device parameters were: the temperature is 35 ℃, and the shaking table frequency is 1-3 Hz/min; amplitude is 1-3 degrees; if the weight of the liquid contained in the composite film is 1 part, the weight part of the used 98% purity pharmaceutical grade genipin is 1/30;
2) Taking out the curved surface fusiform sclera patch, putting the curved surface fusiform sclera patch into 10-20% glycine solution for neutralization reaction for 40min, and rinsing with distilled water for 3-5 times for 3-5 min each time;
3) Packaging with bubble cap, and sterilizing with one of gamma ray, linear accelerator or ethylene oxide; the sterilized compound enhanced scleral patch can be used for posterior scleral reinforcement.
The ceramic mould is a concave-convex symmetrical mould which is sintered and made and distributed with 200-500 mu m micropores; the height of the fusiform bulge of the male die is equal to the depth of the fusiform pit of the female die, the male die and the female die can be embedded up and down, the fusiform edge of the male die and the female die can cut the composite film, and the residual clearance after the die is buckled and locked is equal to the thickness of the patch; cavity/feature structure dimensions of the male and female mold: the radius of the curved surface is 25-28 mm, the maximum arc width is 12-14 mm, the maximum arc length is the radius of the curved surface multiplied by pi, and the width of the two ends of the arc is 4-5 mm.
The cross-linking agent is: the genipin of medical grade is white crystal powder, and the purity is more than or equal to 98 percent.
The compound enhanced scleral patch prepared by the method has a curved surface fusiform space structure, has good applicability to curvature of the sclera at the posterior pole of the eyeball, is comprehensively clung to the posterior pole of the eyeball, and is beneficial to postoperative rehabilitation and fusion symbiosis of the patch and the host sclera;
the nano silk fibroin molecules fully wrap polyurethane, so that the scleral patch has good biocompatibility under the crosslinking and shielding effects of genipin; filling gaps among molecular chains of polyurethane by the nano dispersibility of titanium dioxide and combining various materials between molecules and in molecules under the cross-linking of genipin, so that the scleral patch eliminates the elastic extensibility of the polyurethane material and has good structural mechanical property and anti-extension property; through moderate crosslinking of genipin, the crosslinking degree is more than or equal to 80 percent, so that the composite scleral patch has very good degradation resistance, thereby meeting scleral requirements; the breaking elongation is less than or equal to 3 percent, the breaking strength is more than or equal to 70MPa, the thermal shrinkage temperature is more than or equal to 65 ℃, and the degradation rate is less than or equal to 2 percent/180 d.
Claims (2)
1. A method for preparing a composite reinforced scleral patch, which is characterized by comprising the following steps: the method comprises the following steps:
step S1: the preparation of the nano silk fibroin solution comprises the following steps:
1) Placing the silkworm cocoons subjected to pupation removal into 0.05-0.5% sodium bicarbonate solution, wherein the solid-liquid ratio is 1:10-20; boiling for 30-60 min, repeating for 3 times, repeatedly cleaning with deionized water, and drying in a vacuum drying oven for 24h to obtain solid silk fibroin;
2) Solid silk fibroin was placed into 50% CaCL 2 In the solution, the solid-to-liquid ratio w/v is 1:20, boiling is carried out until the silk fibroin solid is completely dissolved, the solid impurities are removed by suction filtration, then the solution is dialyzed for 2 to 3 days by deionized water by a dialysis bag, the pure silk fibroin solution is obtained, and then the solution is ultrafiltered by a polyethersulfone membrane with the interception relative molecular weight of 30 kDa;
3) Adding tween-20 with the v/v of 0.25-0.5% into the silk fibroin solution with the concentration of 0.05% after ultrafiltration, and performing ultrasonic crushing treatment, wherein the parameters are as follows: the frequency is 300kHz, the action time is 5s, the interval is 5s, and the operation is repeated 15 times; filtering with 0.22 μm pore size polyethersulfone membrane, concentrating with glycerol in dialysis bag for 8 hr, collecting concentrated solution, and performing ultrasonic crushing under the same conditions as above; the ideal silk fibroin solution containing nanometer scale can be obtained;
step S2: preparing a composite reinforced composite film, comprising:
adding 0.4-2.0 wt% of nano titanium dioxide into the nano silk fibroin solution, adjusting the pH value to 5-6, and magnetically stirring for 30-120 min;
2) The weight is as follows: mixing 5 parts of polypropylene glycol and 4 parts of dimethylolpropionic acid, heating to 120 ℃, preserving heat for 30min, cooling to 85 ℃, adding 3 parts of benzene diisocyanate for reaction, cooling to room temperature, adding 0.5 part of acrylic acid, 2 parts of acetone and 1 part of trihexylamine, stirring, placing in ice water, and standing for 40min in cold bath; filtering to obtain polyurethane prepolymer;
3) Adding 3 parts of lithium bromide solution into 4 parts of the mixed solution of the nano silk fibroin solution containing titanium dioxide, stirring, mixing, introducing into a ceramic ultrafiltration membrane with the aperture of 200-500 mu m, and filtering to obtain a concentrated solution; adding the polyurethane prepolymer into the concentrated solution according to the proportion of 20-40 wt% for dispersion; the rotation speed of the centrifugal machine is 800rpm, and the time is 15min; standing for 40min; drying for 1h at 50-60 ℃ to obtain a mixture;
4) Dissolving the mixture into a formic acid solution with the concentration of 1-10% according to the w/v ratio of 6%, and adding the mixture into a high-pressure drug feeder of double-nozzle electrostatic spinning equipment after complete dissolution; the spinning conditions are: the static voltage is 30-35 kV, the distance is 15-20 cm, and the speed is 0.5-1.5 mL/h; the two spray heads are opposite and are distributed in a front-back crossing way, the rotating speed of the roller is 500-3000 rpm, the humidity in the electrospinning box is 30-50%, and the temperature is 18-40 ℃; preparing a nano composite film with the thickness of 0.6-3.0 mm;
step S3: shaping, cross-linking and fixing, packaging and sterilizing the composite film, wherein the method comprises the following steps of:
1) Thoroughly cleaning the composite membrane by using deionized water for 3-5 min each time, repeating for 3 times, placing the composite membrane into a concave-convex ceramic mould for shaping and cutting, locking the mould and the composite membrane in the mould according to the proportion of 15:100, immersing the composite membrane without the mould into 0.25-1.0% genipin solution for crosslinking for 24-96 h to form a composite reinforced scleral patch; the crosslinking device parameters were: the temperature is 35-37 ℃, and the shaking table frequency is 1-5 Hz/min; the amplitude is 1-3 degrees;
2) Placing the compound enhanced scleral patch into 5-30% glycine solution for neutralization reaction for 40min, and rinsing with distilled water for 3-5 times, each time for 3-5 min;
3) The package is sealed with bubble cap containing liquid, and can be sterilized by one of gamma ray, linear accelerator or ethylene oxide.
2. The method of preparing a composite enhanced scleral patch according to claim 1, wherein: the ceramic mould is a concave-convex symmetrical mould which is sintered and made and distributed with 200-500 mu m micropores; the height of the fusiform bulge of the male die is equal to the depth of the fusiform pit of the female die, the male die and the female die can be embedded up and down, the fusiform edge of the male die and the female die can cut the composite film, and the residual clearance after the die is buckled and locked is equal to the thickness of the patch; cavity/feature structure dimensions of the male and female mold: the radius of the curved surface is 25-28 mm, the maximum arc width is 12-14 mm, the maximum arc length is the radius of the curved surface multiplied by pi, and the width of the two ends of the arc is 4-5 mm.
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| CN102525729A (en) * | 2012-02-02 | 2012-07-04 | 温州医学院附属眼视光医院 | Biomembrane material strip belt for high-myopia posterior scleral reinforcement surgery and manufacture method thereof |
| CN110353856A (en) * | 2019-01-30 | 2019-10-22 | 张亚平 | A kind of Posterior scleral reinforcement biological sticking patch and preparation method thereof |
| CN112533626A (en) * | 2018-06-04 | 2021-03-19 | 柯坤生物科技公司 | Silk-based product formulations and methods of use |
| CN114306752A (en) * | 2022-01-10 | 2022-04-12 | 诺一迈尔（苏州）医学科技有限公司 | Sclera repairing support and preparation method thereof |
| CN114699556A (en) * | 2022-04-08 | 2022-07-05 | 深圳高性能医疗器械国家研究院有限公司 | Preparation method of silk fibroin repair patch and silk fibroin repair patch |
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| CN102525729A (en) * | 2012-02-02 | 2012-07-04 | 温州医学院附属眼视光医院 | Biomembrane material strip belt for high-myopia posterior scleral reinforcement surgery and manufacture method thereof |
| CN112533626A (en) * | 2018-06-04 | 2021-03-19 | 柯坤生物科技公司 | Silk-based product formulations and methods of use |
| CN110353856A (en) * | 2019-01-30 | 2019-10-22 | 张亚平 | A kind of Posterior scleral reinforcement biological sticking patch and preparation method thereof |
| CN114306752A (en) * | 2022-01-10 | 2022-04-12 | 诺一迈尔（苏州）医学科技有限公司 | Sclera repairing support and preparation method thereof |
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