CN112007206A - Hemostatic sponge capable of adhering and promoting repair and preparation method thereof - Google Patents
Hemostatic sponge capable of adhering and promoting repair and preparation method thereof Download PDFInfo
- Publication number
- CN112007206A CN112007206A CN202010804569.9A CN202010804569A CN112007206A CN 112007206 A CN112007206 A CN 112007206A CN 202010804569 A CN202010804569 A CN 202010804569A CN 112007206 A CN112007206 A CN 112007206A
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- Prior art keywords
- sponge
- repair
- hemostatic sponge
- promoting
- hemostatic
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Links
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Images
Classifications
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- 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0036—Porous materials, e.g. foams or sponges
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- A—HUMAN NECESSITIES
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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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
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- C08F2/46—Polymerisation initiated by wave energy or particle radiation
- C08F2/48—Polymerisation initiated by wave energy or particle radiation by ultraviolet or visible light
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- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
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- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/04—Materials for stopping bleeding
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Abstract
The invention discloses an adhesion-promoting repair-promoting hemostatic sponge and a preparation method thereof. The hemostatic sponge is prepared by fully reacting N-maleylation gelatin, exosome, acrylate PEG-N hydroxyl succinimide ester and N, N' -methylene bisacrylamide, adding maleic anhydride, acrylic acid and a first part of photoinitiator, neutralizing with a neutralizer, prepolymerizing, adding a mixed solution of acrylic acid N-hydroxyl succinimide ester and a second part of photoinitiator, fully polymerizing, and lyophilizing. The hemostatic sponge prepared by the invention not only can rapidly absorb blood or tissue fluid to form gel, form mechanical compression on injured blood vessels on the surface of a cavity to promote hemostasis, but also can adhere to the surface of the cavity to further promote hemostasis and prevent displacement. The hemostatic sponge can slowly release gelatin and exosome, and has a long-acting repair promoting function. Therefore, the hemostatic sponge has the effects of quickly and efficiently stopping bleeding, adhering and promoting repair.
Description
Technical Field
The invention belongs to the technical field of biomedical materials, and relates to an adhesion-promoting repair-promoting hemostatic sponge and a preparation method thereof. The medical hemostatic sponge has the effects of being capable of expanding and rapidly stopping bleeding, adhering, preventing displacement and promoting repair.
Background
In emergency, surgery and in war, 50% of deaths are due to massive bleeding. Some conventional hemostatic materials, such as hemostatic gauze, hemostatic bandage, hemostatic cotton yarn, etc., have limited hemostatic ability and unsatisfactory hemostatic effect. Therefore, the development of efficient and fast absorbable hemostatic materials and products, which can effectively and fast stop bleeding within 1-2 minutes or even shorter after bleeding occurs, is one of the main targets of the development of hemostatic materials. The hemostatic sponge is a material for stopping bleeding of wounds during surgical operations, and when the hemostatic sponge is attached to damaged parts of blood vessels, hydrophilic polymer materials can adhere to and aggregate with platelets to form platelet thrombi, and then the platelet thrombi are coagulated into fibrin emboli to block the damaged parts of the blood vessels, so that the hemostatic effect is achieved.
After effective hemostasis, how to accelerate wound repair and thereby reduce scar formation and infection risk has become an important aspect. Gelatin is a natural absorbable material widely applied to the field of biomedicine, has good biocompatibility, no toxicity or stimulation, has a large amount of hydroxyl, amino and carboxyl on the molecular structure, is an amphoteric substance, and has extremely strong hydrophilicity; the hemostatic powder is placed on a bleeding part, quickly absorbs blood, causes platelet rupture, promotes blood coagulation, achieves the aim of hemostasis, and has the function of promoting the formation of new cells and cell adhesion. Gelatin itself has poor mechanical properties, and therefore, gelatin-based biomaterials are generally modified.
For example, in patent application No. 201710574900.0, a method for preparing a gelatin/plant polysaccharide composite hemostatic sponge is disclosed. The composite hemostatic sponge of the gelatin/plant polysaccharide is prepared by the Schiff base reaction of the aldehyde vegetable polysaccharide and the gelatin and freeze drying. The sponge prepared by the invention has excellent hemostatic performance, can quickly absorb liquid when contacting with a wound, accelerates the aggregation of blood platelets and hemoglobin, and quickly stanches bleeding. However, the invention has weak network structure through Schiff base crosslinking, limited improvement on the mechanical strength of the gelatin-based sponge, weak tissue adhesion, and reduced repair promoting function of the gelatin-based sponge due to the addition of the polysaccharide.
In the invention patent with application number 201710662862.4, a medical hemostatic material in the form of a biological sponge is disclosed. The organism spongy medical hemostatic material is prepared by a freeze-drying method through chemical crosslinking reaction of oxidized sodium alginate and gelatin. Compared with other synthetic wound sponges, the synthetic wound sponge has better affinity with biological tissues, less organic solvents and no irritation to skin. The preparation method is simple, and has the characteristics of good flexibility, good biocompatibility and the like. However, the invention still has the problems of weak cross-linked network structure, low mechanical strength of sponge, weak adhesion to tissues and reduced repair promoting function.
In conclusion, a hemostatic sponge with good biocompatibility, difficult displacement, high mechanical strength, high expansion rate, long-acting and efficient repair promoting function is urgently needed clinically.
Disclosure of Invention
The invention aims to provide a hemostatic sponge which has good biocompatibility, difficult displacement, high mechanical strength, high expansion rate and long-acting and efficient repair promoting function.
An adhesion promoting and repairing hemostatic sponge is prepared by fully mixing N-maleylation gelatin, exosome, acrylic ester PEG-N hydroxyl succinimide ester and N, N' -methylene bisacrylamide, adding maleic anhydride, acrylic acid and a first part of photoinitiator, neutralizing by using a neutralizing agent, prepolymerizing under an ultraviolet lamp, adding a mixed solution of acrylic acid N-hydroxyl succinimide ester and a second part of photoinitiator, performing secondary polymerization under the ultraviolet lamp, and performing freeze-drying and sterilization.
Further, the weight percentage of the N-maleylated gelatin is 15 to 25 percent, and the preferable weight percentage is 17.5 to 22.5 percent; the weight percentage of the maleic anhydride is 0.75-1.25%, preferably 0.875-1.125%; acrylic acid 15-25 wt%, preferably 17.5-22.5 wt%; the weight percentage of the exosome is 0.5-1.0%, preferably 0.7-0.8%; the weight percentage of the acrylic ester PEG-N hydroxysuccinimide ester is 2-4%, preferably 2.5-3.5%; the weight percentage of N, N' -methylene bisacrylamide is 0.01-0.02%; the weight percentage of the first part of the photoinitiator is 0.5 to 0.8 percent; the weight percentage of the acrylic acid N-hydroxysuccinimide ester is 0.5 to 1.0 percent, and the optimized weight percentage is 0.7 to 0.8 percent; the weight percentage of the second part photoinitiator is 0.007 to 0.013 percent.
The molecular weight of the N-maleylated gelatin is 50-100KDa, and the maleylation substitution degree is 85-95%.
The weight ratio of maleic anhydride to acrylic acid was 1: 20.
The neutralizing agent is one or more of sodium hydroxide, disodium hydrogen phosphate, sodium bicarbonate, sodium carbonate, sodium citrate and sodium acetate, and preferably sodium hydroxide.
The first part of photoinitiator and the second part of photoinitiator are 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone.
The power of an ultraviolet lamp used for prepolymerization is 150W, the wavelength is 365nm, and the irradiation time is 20-40min, preferably 25-35 min.
The power of an ultraviolet lamp used for the secondary polymerization is 150W, the wavelength is 365nm, and the irradiation time is 10-20min, preferably 12.5-17.5 min.
The exosome is an exosome secreted by one or more mesenchymal stem cells of adipose mesenchymal stem cells, placenta mesenchymal stem cells and bone marrow mesenchymal stem cells.
The acrylate PEG-N hydroxysuccinimide ester has a molecular weight of 1-10KDa such as 1KDa, 2KDa, 3.4KDa, 5KDa and 10KDa, preferably 2-5 KDa.
The invention also provides a preparation method of the adhesion promoting repair hemostatic sponge, which comprises the following steps:
(1) and (3) crosslinking reaction: adding N-maleylation gelatin, exosome, acrylic ester PEG-N hydroxyl succinimide ester and N, N' -methylene bisacrylamide into purified water, stirring at 100-200rpm until the materials are completely dissolved, and continuing stirring for 20min to obtain a mixed solution after crosslinking reaction.
(2) And (3) neutralization reaction: adding maleic anhydride, acrylic acid and a first part of photoinitiator into the mixed solution obtained in the step (1), stirring at 100-200rpm until the mixture is completely dissolved, neutralizing with a neutralizer, and then continuing stirring for 10 min.
(3) Prepolymerization reaction: and (3) placing the neutralized mixed solution obtained in the step (2) under an ultraviolet lamp for prepolymerization to obtain a gel prepolymer.
(4) And (3) secondary polymerization: and (4) adding a mixed solution of N-hydroxysuccinimide acrylate and a second part of photoinitiator into the gel prepolymer obtained in the step (3), uniformly dispersing the mixed solution on the surface of the gel prepolymer, and carrying out secondary polymerization under an ultraviolet lamp to obtain a gel product.
(5) Freeze-drying: and (4) placing the gel product obtained in the step (4) into a mould, placing the mould into a freeze dryer, and carrying out pre-freezing and programmed sublimation drying to obtain the unsterilized sponge capable of promoting repair and hemostasis by adhesion.
(6) And (3) sterilization: packaging the unsterilized adhesion promotion and repair hemostasis sponge obtained in the step (5), and sterilizing by electron beam irradiation at 15-25K to obtain the finished adhesion promotion and repair hemostasis sponge.
In the preparation method of the adhesion promoting and repairing hemostatic sponge, the neutralization degree after neutralization in the step (2) is 40-60%.
The preparation method of the adhesion promoting and repairing hemostatic sponge comprises the step (4) of uniformly dispersing the mixed solution on the surface of the gel prepolymer by atomization spraying.
The preparation method of the adhesion promoting repair hemostatic sponge comprises the following steps of (5) pre-freezing and freeze-drying: pre-freezing for 4 hours at the temperature of minus 50 ℃, and vacuumizing after the pre-freezing is finished, wherein the vacuum degree is less than 15 pa; after that, the temperature is raised in stages at every 10 ℃, the temperature raising time is 3 hours, the constant temperature time is 2 hours, and the temperature raising is finished until the temperature is raised to 5 ℃.
The components used in the present invention are all commercially available products, the structure and composition of which are also known to those skilled in the art.
The technical scheme provided by the invention has the beneficial effects that:
1. the amino groups on the N-maleylation gelatin and the exosome can generate nucleophilic substitution reaction with the acrylate PEG-N-hydroxysuccinimide ester, and the double bond in the acrylate PEG-N-hydroxysuccinimide ester can generate free radical polymerization reaction with the N-maleylation gelatin, the maleic anhydride, the acrylic acid and the N, N' -methylene bisacrylamide under the photoinitiator, so that a chemical crosslinking mode with multiple dimensions and high mixing degree is formed, and the mechanical strength of the hemostatic sponge after swelling is ensured.
2. According to the invention, the acrylate PEG-N hydroxyl succinimide ester with a longer chain segment and the N, N' -methylene bisacrylamide with a shorter chain segment are used as cross-linking agents together, N-maleylation gelatin, maleic anhydride, acrylic acid and exosome are cross-linked, meanwhile, a sufficient swelling space is reserved for a cross-linking network, and the swelling degree of the hemostatic sponge is ensured while the mechanical strength of the hemostatic sponge after swelling is ensured.
3. According to the invention, by utilizing a secondary polymerization method, the acrylic acid N-hydroxysuccinimide ester is crosslinked to the surface of the hemostatic sponge in a free radical polymerization manner, so that the hemostatic sponge can be fully adhered to the surface of a tissue while absorbing tissue fluid and blood, thereby preventing displacement from occurring and influencing the hemostatic effect.
4. The invention crosslinks the gelatin and the exosome into the whole network system of the hemostatic sponge through chemical bonds, and the gelatin and the exosome can be slowly released along with the degradation of the hemostatic sponge at a wound, thereby not only playing a role in promoting the long-acting repair, but also avoiding the problems of single component and poor repair promoting effect of pure gelatin.
5. The invention utilizes the specific processes of freeze-drying, sterilization and preservation, and can ensure the long-acting repair promotion and high-efficiency adhesion functions of the hemostatic sponge while ensuring the aseptic provision of the hemostatic sponge.
Drawings
FIG. 1 is a graph of the degradation of the hemostatic sponge of example 1 over time.
FIG. 2 is a diagram of the hemostatic mechanism of the hemostatic sponge.
Detailed Description
The technical scheme of the present invention will be further described in detail with reference to examples and comparative examples. However, the present invention is not limited to these specific examples. The methods used in the examples are conventional methods unless otherwise specified. The detection method for the hemostatic sponge adopts the following detection method:
(1) surface adhesion test
The back skin of a rat is cut into a wound surface of 1cm multiplied by 1cm, then the test material is attached to the wound surface area, after being pressed for 10min, the test material is peeled from the side surface of the test material, the tensile value is measured, namely the surface adhesive strength of the wound surface, and each sample is tested for 6 times and the average value is taken.
(2) Compression modulus test
The compression modulus adopts a microcomputer electronic universal tester, the running speed is 5mm/min, the diameter of the sponge sample after complete swelling is 10mm, the height is 5mm, and the average value is obtained by repeating the steps for 5 times.
(3) Volume swell ratio test
The volume test method adopts a liquid discharge method, the hemostatic sponge material is placed in a measuring cylinder filled with a certain volume of liquid, the liquid level rise value is read, and the volume V of the hemostatic sponge material before water absorption and swelling is respectively measured0And volume V after sufficient water absorption and swelling1. The volume swelling ratio calculation method comprises the following steps: volume V after saturation swelling1With the initial volume V0The difference of (A) accounts for the initial volume V0In percent, 6 tests were performed per sample and the average was taken.
(4) Test of Water absorption Rate
0.025g of hemostatic sponge is placed in 2ml of water and allowed to stand for 10min, then centrifuged at 500rpm for 10min and then taken out, the residual liquid amount is weighed and calculated, and each sample is tested 6 times to take an average value.
(5) In vitro cytotoxicity assay
Evaluation according to medical device biology part 5: cytotoxicity assays GB/T16886.5-2017 were carried out.
(6) Skin irritation and sensitization test
Part 10 according to the biological evaluation of medical devices: stimulation and delayed type hypersensitivity tests GB/T16886.10-2017 were carried out.
Example 1N-maleylated gelatin (60-90 KDa, degree of substitution 85-95%), exosome (0.75%), acrylate PEG-N hydroxysuccinimide ester (3.4 KDa) 3% and N, N' -methylenebisacrylamide (0.015%) in mass fraction were added to purified water, and after stirring at 100-. Adding 1.0 percent of maleic anhydride, 20 percent of acrylic acid and 0.65 percent of 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone, stirring at 100 plus 200rpm until the mixture is completely dissolved, adding sodium hydroxide solution under stirring at 100 plus 200rpm until the neutralization degree is 50 percent, prepolymerizing for 30 minutes under an ultraviolet lamp with the power of 150W and the wavelength of 365nm, atomizing and spraying a mixed solution of 0.75 percent of N-hydroxysuccinimide acrylate and 0.010 percent of 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone under the power of 150W and the wavelength of 365nm, prefreezing for 4 hours at the temperature of-50 ℃ after polymerizing for 15 minutes under the ultraviolet lamp with the power of 150W and the wavelength of 365nm, vacuumizing after finishing, the vacuum degree should be less than 15 pa; after that, the temperature is raised in stages at every 10 ℃, the temperature raising time is 3 hours, the constant temperature time is 2 hours, and the temperature raising is finished until the temperature is raised to 5 ℃. Packaging the obtained freeze-dried product, and sterilizing by 20K electron beam irradiation to obtain the adhesion promotion and repair hemostasis sponge.
Example 2N-maleylated gelatin (50-80 KDa, degree of substitution 85-95%), exosome (0.5%), acrylate PEG-N hydroxysuccinimide ester (2 KDa) 2% and N, N' -methylenebisacrylamide (0.02%) in mass fraction of 15% were added to purified water, and after stirring at 100-. Adding 1.25% maleic anhydride, 25% acrylic acid and 0.8% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone, stirring at 100-200rpm to completely dissolve, adding sodium hydroxide solution and disodium hydrogen phosphate solution under stirring at 100-200rpm to neutralize to 60% neutralization degree, prepolymerizing under an ultraviolet lamp at a power of 150W and a wavelength of 365nm for 40min, spray-atomizing a mixture of 0.5% N-hydroxysuccinimide acrylate and 0.007% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone, polymerizing under an ultraviolet lamp at a power of 150W and a wavelength of 365nm for 10min, pre-freezing at-50 ℃ for 4 hours, vacuumizing after the vacuum is finished, wherein the vacuum degree is less than 15 pa; after that, the temperature is raised in stages at every 10 ℃, the temperature raising time is 3 hours, the constant temperature time is 2 hours, and the temperature raising is finished until the temperature is raised to 5 ℃. Packaging the obtained freeze-dried product, and sterilizing by 15K electron beam irradiation to obtain the adhesion promotion and repair hemostasis sponge.
Example 3N-maleylated gelatin (70-100 KDa, degree of substitution 85-95%), exosome (1.0%), acrylate PEG-N hydroxysuccinimide ester (4 KDa) and N, N' -methylenebisacrylamide (0.01%) were added to purified water in a mass fraction of 25%, stirred at 100-. Adding 0.75% of maleic anhydride, 15% of acrylic acid and 0.5% of 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone, stirring at 200rpm of 100-, vacuumizing after the vacuum is finished, wherein the vacuum degree is less than 15 pa; after that, the temperature is raised in stages at every 10 ℃, the temperature raising time is 3 hours, the constant temperature time is 2 hours, and the temperature raising is finished until the temperature is raised to 5 ℃. Packaging the obtained freeze-dried product, and sterilizing by 25K electron beam irradiation to obtain the adhesion promotion and repair hemostasis sponge.
Example 4 mass fractions of 20% N-maleylated gelatin (60-90 kDa, degree of substitution 85-95%), 1.0% exosome, 4% acrylate PEG-N hydroxysuccinimide ester (3.4 kDa) and 0.015% N, N' -methylenebisacrylamide were added to purified water, stirred at 100-. Adding 1.0 percent of maleic anhydride, 20 percent of acrylic acid and 0.65 percent of 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone, stirring at 200rpm of 100 plus until the mixture is completely dissolved, adding sodium hydroxide solution and sodium acetate solution under stirring at 200rpm of 100 plus until the neutralization degree is 50 percent, prepolymerizing for 30 minutes under an ultraviolet lamp at the power of 150W and the wavelength of 365nm, atomizing and spraying a mixed solution of 0.75 percent of N-hydroxysuccinimide acrylate and 0.01 percent of 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone at the power of 150W and the wavelength of 365nm, and prefreezing for 4 hours at the temperature of 50 ℃ after polymerizing for 15 minutes under the ultraviolet lamp, vacuumizing after the vacuum is finished, wherein the vacuum degree is less than 15 pa; after that, the temperature is raised in stages at every 10 ℃, the temperature raising time is 3 hours, the constant temperature time is 2 hours, and the temperature raising is finished until the temperature is raised to 5 ℃. Packaging the obtained freeze-dried product, and sterilizing by 20K electron beam irradiation to obtain the adhesion promotion and repair hemostasis sponge.
Example 5 mass fractions of 20% N-maleylated gelatin (60-90 kDa, degree of substitution 85-95%), 0.5% exosome, 2% acrylate PEG-N hydroxysuccinimide ester (3.4 kDa) and 0.015% N, N' -methylenebisacrylamide were added to purified water, stirred at 100-. Adding 1% maleic anhydride, 20% acrylic acid and 0.65% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone, stirring at 100-200rpm to completely dissolve, adding sodium hydroxide solution under 100-200rpm to neutralize to 50%, prepolymerizing under an ultraviolet lamp at a power of 150W and a wavelength of 365nm for 30min, atomizing and spraying a mixed solution of 0.75% N-hydroxysuccinimide acrylate and 0.01% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone under a power of 150W and a wavelength of 365nm, after polymerizing for 15min under an ultraviolet lamp, prefreezing at-50 ℃ for 4 hours, and vacuumizing after finishing, the vacuum degree should be less than 15 pa; after that, the temperature is raised in stages at every 10 ℃, the temperature raising time is 3 hours, the constant temperature time is 2 hours, and the temperature raising is finished until the temperature is raised to 5 ℃. Packaging the obtained freeze-dried product, and sterilizing by 20K electron beam irradiation to obtain the adhesion promotion and repair hemostasis sponge.
Example 6 mass fractions of 20% N-maleylated gelatin (60-90 kDa, degree of substitution 85-95%), 0.75% exosome, 3% acrylate PEG-N hydroxysuccinimide ester (3.4 kDa) and 0.015% N, N' -methylenebisacrylamide were added to purified water, stirred at 100-. Adding 1% maleic anhydride, 20% acrylic acid and 0.65% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone, stirring at 100-200rpm to completely dissolve, adding sodium hydroxide solution under 100-200rpm to neutralize to 50%, prepolymerizing under an ultraviolet lamp at a power of 150W and a wavelength of 365nm for 30min, atomizing and spraying a mixture of 1.0% N-hydroxysuccinimide acrylate and 0.013% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone at a power of 150W and a wavelength of 365nm, after polymerizing under an ultraviolet lamp for 15min, pre-freezing at-50 ℃ for 4 hours, and vacuumizing after finishing, the vacuum degree should be less than 15 pa; after that, the temperature is raised in stages at every 10 ℃, the temperature raising time is 3 hours, the constant temperature time is 2 hours, and the temperature raising is finished until the temperature is raised to 5 ℃. Packaging the obtained freeze-dried product, and sterilizing by 20K electron beam irradiation to obtain the adhesion promotion and repair hemostasis sponge.
Example 7 mass fractions of 20% N-maleylated gelatin (60-90 kDa, degree of substitution 85-95%), 0.75% exosome, 3% acrylate PEG-N hydroxysuccinimide ester (3.4 kDa) and 0.015% N, N' -methylenebisacrylamide were added to purified water, stirred at 100-. Adding 1% maleic anhydride, 20% acrylic acid and 0.65% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone, stirring at 200rpm of 100-, the vacuum degree should be less than 15 pa; after that, the temperature is raised in stages at every 10 ℃, the temperature raising time is 3 hours, the constant temperature time is 2 hours, and the temperature raising is finished until the temperature is raised to 5 ℃. Packaging the obtained freeze-dried product, and sterilizing by 20K electron beam irradiation to obtain the adhesion promotion and repair hemostasis sponge.
Comparative example 1N-maleylated gelatin (60-90 kDa, degree of substitution 85-95%), 3% acrylate PEG-N hydroxysuccinimide ester (3.4 kDa) and 0.015% N, N' -methylenebisacrylamide were added to purified water in mass percentages, and after stirring at 100-200rpm until completely dissolved, stirring was continued for 20 min. Adding 1% maleic anhydride, 20% acrylic acid and 0.65% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone, stirring at 100-200rpm to completely dissolve, adding sodium hydroxide solution under 100-200rpm to neutralize to 50%, prepolymerizing under an ultraviolet lamp at a power of 150W and a wavelength of 365nm for 30min, atomizing and spraying a mixed solution of 0.75% N-hydroxysuccinimide acrylate and 0.007% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone at a power of 150W and a wavelength of 365nm, pre-freezing at-50 ℃ for 4 hours after polymerizing for 15min under the ultraviolet lamp, and vacuumizing after finishing, the vacuum degree should be less than 15 pa; after that, the temperature is raised in stages at every 10 ℃, the temperature raising time is 3 hours, the constant temperature time is 2 hours, and the temperature raising is finished until the temperature is raised to 5 ℃. Packaging the obtained freeze-dried product, and sterilizing by 20K electron beam irradiation to obtain the adhesion promotion and repair hemostasis sponge.
Comparative example 2N-maleylated gelatin (60-90 KDa, degree of substitution 85-95%), exosome (2.0%), acrylate PEG-N hydroxysuccinimide ester (3.4 KDa) 3% and N, N' -methylenebisacrylamide (0.015%) were added to purified water in mass fraction of 30%, stirred at 100-. Adding 2 percent of maleic anhydride, 20 percent of acrylic acid and 0.68 percent of 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone, stirring at 200rpm of 100 plus for complete dissolution, adding a sodium hydroxide solution under stirring at 200rpm of 100 plus for neutralization to 50 percent, pre-polymerizing for 30 minutes under an ultraviolet lamp at the power of 150W and the wavelength of 365nm, atomizing and spraying a mixed solution of 0.75 percent of N-hydroxysuccinimide acrylate and 0.007 percent of 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone under the power of 150W and the wavelength of 365nm, pre-freezing for 4 hours at the temperature of-50 ℃ after polymerizing for 15 minutes under the ultraviolet lamp, and vacuumizing after finishing the pre-freezing, the vacuum degree should be less than 15 pa; after that, the temperature is raised in stages at every 10 ℃, the temperature raising time is 3 hours, the constant temperature time is 2 hours, and the temperature raising is finished until the temperature is raised to 5 ℃. Packaging the obtained freeze-dried product, and sterilizing by 20K electron beam irradiation to obtain the adhesion promotion and repair hemostasis sponge.
Comparative example 3A mixture of 0.75% by mass of exosome, 3% by mass of acrylate PEG-N hydroxysuccinimide ester (3.4 KDa) and 0.015% by mass of N, N' -methylenebisacrylamide was added to purified water, and after stirring at 100-. Adding 1% maleic anhydride, 20% acrylic acid and 0.65% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone, stirring at 100-200rpm to completely dissolve, adding sodium hydroxide solution under 100-200rpm to neutralize to 50%, prepolymerizing under an ultraviolet lamp at a power of 150W and a wavelength of 365nm for 30min, atomizing and spraying a mixed solution of 0.75% N-hydroxysuccinimide acrylate and 0.007% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone at a power of 150W and a wavelength of 365nm, pre-freezing at-50 ℃ for 4 hours after polymerizing for 15min under the ultraviolet lamp, and vacuumizing after finishing, the vacuum degree should be less than 15 pa; after that, the temperature is raised in stages at every 10 ℃, the temperature raising time is 3 hours, the constant temperature time is 2 hours, and the temperature raising is finished until the temperature is raised to 5 ℃. Packaging the obtained freeze-dried product, and sterilizing by 20K electron beam irradiation to obtain the adhesion promotion and repair hemostasis sponge.
Comparative example 4N-maleylated gelatin (60-90 kDa, degree of substitution 85-95%), exosome (0.75%), acrylate PEG-N hydroxysuccinimide ester (3.4 kDa) (3%), and N, N' -methylenebisacrylamide (0.015%) were added to purified water in mass fractions of 20%, stirred at 100 and 200rpm until completely dissolved, and then stirred for 20 min. 1% of maleic anhydride and 0.03% of 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone are added, stirring at 100-200rpm until complete dissolution, adding sodium hydroxide solution under stirring at 100-200rpm until the neutralization degree is 50%, prepolymerizing under an ultraviolet lamp at 365nm and 150W for 30min, atomizing and spraying a mixture of 0.75% of N-hydroxysuccinimide acrylate and 0.007% of 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone, polymerizing under an ultraviolet lamp with the power of 150W and the wavelength of 365nm for 15min, pre-freezing for 4 hours at the temperature of 50 ℃ below zero, and vacuumizing after finishing, wherein the vacuum degree is less than 15 pa; after that, the temperature is raised in stages at every 10 ℃, the temperature raising time is 3 hours, the constant temperature time is 2 hours, and the temperature raising is finished until the temperature is raised to 5 ℃. Packaging the obtained freeze-dried product, and sterilizing by 20K electron beam irradiation to obtain the adhesion promotion and repair hemostasis sponge.
Comparative example 5N-maleylated gelatin (60-90 kDa, degree of substitution 85-95%), exosome (0.75%), acrylate PEG-N-hydroxysuccinimide ester (3.4 kDa) (3%), and N, N' -methylenebisacrylamide (0.015%) were added to purified water in mass fractions of 20%, stirred at 100-. Adding 20% of acrylic acid and 0.62% of 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone, stirring at 100-200rpm until complete dissolution, adding sodium hydroxide solution under stirring at 100-200rpm until the neutralization degree is 50%, prepolymerizing under an ultraviolet lamp at 365nm and 150W for 30min, atomizing and spraying a mixture of 0.75% of N-hydroxysuccinimide acrylate and 0.007% of 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone, polymerizing under an ultraviolet lamp with the power of 150W and the wavelength of 365nm for 15min, pre-freezing for 4 hours at the temperature of 50 ℃ below zero, and vacuumizing after finishing, wherein the vacuum degree is less than 15 pa; after that, the temperature is raised in stages at every 10 ℃, the temperature raising time is 3 hours, the constant temperature time is 2 hours, and the temperature raising is finished until the temperature is raised to 5 ℃. Packaging the obtained freeze-dried product, and sterilizing by 20K electron beam irradiation to obtain the adhesion promotion and repair hemostasis sponge.
Comparative example 6N-maleylated gelatin (60-90 KDa, degree of substitution 85-95%), exosome 0.75% and N, N' -methylenebisacrylamide 0.015% by mass were added to purified water, and after stirring at 100-. Adding 1% maleic anhydride, 20% acrylic acid and 0.65% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone, stirring at 100-200rpm to completely dissolve, adding sodium hydroxide solution under 100-200rpm to neutralize to 50%, prepolymerizing under an ultraviolet lamp at a power of 150W and a wavelength of 365nm for 30min, atomizing and spraying a mixed solution of 0.75% N-hydroxysuccinimide acrylate and 0.007% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone at a power of 150W and a wavelength of 365nm, pre-freezing at-50 ℃ for 4 hours after polymerizing for 15min under the ultraviolet lamp, and vacuumizing after finishing, the vacuum degree should be less than 15 pa; after that, the temperature is raised in stages at every 10 ℃, the temperature raising time is 3 hours, the constant temperature time is 2 hours, and the temperature raising is finished until the temperature is raised to 5 ℃. Packaging the obtained freeze-dried product, and sterilizing by 20K electron beam irradiation to obtain the adhesion promotion and repair hemostasis sponge.
Comparative example 7N-maleylated gelatin (60-90 kDa, degree of substitution 85-95%), exosome (0.75%), acrylate PEG-N hydroxysuccinimide ester (3.4 kDa) (3%), and N, N' -methylenebisacrylamide (0.015%) were added to purified water in mass fractions of 20%, stirred at 100-. Adding 1% maleic anhydride, 20% acrylic acid and 0.65% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone, stirring at 200rpm of 100-, the vacuum degree should be less than 15 pa; after that, the temperature is raised in stages at every 10 ℃, the temperature raising time is 3 hours, the constant temperature time is 2 hours, and the temperature raising is finished until the temperature is raised to 5 ℃. Packaging the obtained freeze-dried product, and sterilizing by 20K electron beam irradiation to obtain the adhesion promotion and repair hemostasis sponge.
Comparative example 8N-maleylated gelatin (60-90 kDa, degree of substitution 85-95%), exosome (0.75%), acrylate PEG-N hydroxysuccinimide ester (3.4 kDa) (3%), and N, N' -methylenebisacrylamide (0.015%) were added to purified water in mass fractions of 20%, stirred at 100 and 200rpm until completely dissolved, and then stirred for 20 min. Adding 1% maleic anhydride, 20% acrylic acid and 0.65% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone, stirring at 100-200rpm to completely dissolve, adding sodium hydroxide solution under 100-200rpm to neutralize to 50%, prepolymerizing under an ultraviolet lamp at a power of 150W and a wavelength of 365nm for 30min, atomizing and spraying a mixed solution of 0.75% N-hydroxysuccinimide acrylate and 0.007% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone at a power of 150W and a wavelength of 365nm, pre-freezing at-50 ℃ for 4 hours after polymerizing for 15min under the ultraviolet lamp, and vacuumizing after finishing, the vacuum degree should be less than 15 pa; after that, the temperature is raised in stages at every 10 ℃, the temperature raising time is 3 hours, the constant temperature time is 2 hours, and the temperature raising is finished until the temperature is raised to 30 ℃. Packaging the obtained freeze-dried product, and sterilizing by 20K electron beam irradiation to obtain the adhesion promotion and repair hemostasis sponge.
The physical and chemical properties and biology of the hemostatic sponge were tested according to the surface adhesion test method, the compression modulus test method, the volume swelling ratio test method, the water absorption rate test method, the in vitro cytotoxicity test method, and the skin irritation and sensitization test method, respectively, and the results are shown in tables 1 and 2.
As can be seen from examples 1 to 3 in table 1 and comparative example 8 in table 2, the surface adhesion of the hemostatic sponge is related to the content of N hydroxysuccinimide on the surface of the sponge, and the adhesion of the hemostatic sponge gradually increases with the increase of the content of N hydroxysuccinimide, and when the adhesion of the hemostatic sponge increases to a certain strength, the content of N hydroxysuccinimide increases again, and the adhesion of the hemostatic sponge does not increase greatly.
As can be seen from examples 1 to 8 in Table 1 and comparative examples 1 to 6 and comparative example 8 in Table 2, the compression modulus, the volume swelling ratio and the water absorption ratio of the hemostatic sponge are related to the cross-linking density and the length of the cross-linking agent in the sponge, and when the cross-linking density in the sponge is higher and the length of the cross-linking agent is lower, the compression modulus of the sponge is higher and the volume swelling ratio and the water absorption ratio are lower.
As is clear from example 1 in Table 1 and comparative example 7 in Table 2, the ultraviolet irradiation time in the reaction system affects the progress of the reaction, and too short irradiation time causes incomplete crosslinking, which causes cytotoxicity, stimulation of sensitization reaction, and the like.
As can be seen from the examples 1 to 9 in Table 1, the biocompatibility of the hemostatic sponge is good, and the cytotoxicity test, the skin irritation test and the sensitization test of the hemostatic sponge all meet the biocompatibility requirement of the medical hemostatic sponge.
The samples described in example 1 were subjected to in vitro degradation tests according to the following protocol, and the results are shown in FIG. 1, where the hemostatic sponge was completely degraded within 68 days.
Detection of in vitro degradation time:
1. preparation of a sample to be tested: the samples were cut into 1cm by 1cm cubes of sponge for use.
2. PBS buffer solution with pH value of 7.4 is prepared.
3. Detection of in vitro degradation time: putting the prepared sample 1 into a closed container filled with PBS buffer solution, transferring the sample into an incubator at 37 +/-1 ℃, weighing the sample once every 72 hours, and observing the change condition of the sample in the buffer solution until the sample cannot be seen by naked eyes, namely the in-vitro degradation time of the sample.
And (3) hemostasis test:
the samples described in example 1 (test group) and comparative example 1 (control group) were subjected to the following test protocol, and the results are shown in Table 2.
(1) Femoral artery hemostasis test
The femoral artery injury bleeding of SD rats is used as a model, leg hairs are shaved off after anesthesia, the groin and the hind limb are exposed, thigh skin and muscle are transversely cut, the artery is exposed, and a surgical needle punctures the artery to produce the major bleeding. The wound was immediately covered with a 0.5g sample and pressed with gauze and observed by lifting the gauze every 5 seconds until hemostasis was complete. And (5) counting the hemostasis time and the bleeding amount.
(2) Hemostasis test for liver trauma
The SD rat was subjected to bleeding due to liver injury as a model, anesthetized by intraperitoneal injection of a chloral hydrate aqueous solution and shaved by abdominal hair, and opened in the abdomen to expose the liver. A wound with a length of 1cm and a depth of 1cm was incised with a scalpel. The top of the bleeding liver was sprinkled directly with 0.1g of material, covered with gauze pad and subjected to a conventional pressing operation. Lifting the gauze every 5s, observing the bleeding until hemostasis, and counting the bleeding time and the bleeding amount.
(3) Establishing a mouse skin wound model:
the mice were anesthetized with ether, the back was clipped, the back side was shaved with a razor, and the skin was cleaned with 70% ethanol for disinfection. A circular mark slightly larger than 1cm in diameter was made at the same position on each of the left and right sides of the spine, and a full-thickness skin wound was made in the circular mark using a 1cm diameter skin biopsy punch under sterile conditions. After the model is made, the wound is exposed, and the animal is raised in a single cage. The day of injury was recorded as day 0.
Grouping of test animals
36 male Kunming mice of SPF grade 18-22g, after 1 week of acclimatized feeding, were randomly divided into 2 groups of 18 mice each, including control and test groups. The test group adopts the formula in the example 1 to treat the skin wound of the mouse; the control group was treated with the sample described in comparative example 1 for skin wounds in mice. Wound healing was observed within 22 days.
Determination of wound healing Rate in mouse skin
The wounds of the mice were photographed every two days after the injury, and the wound area of the mice was calculated using Image-Pro Plus Version 6.0 Image analysis software until the wounds healed.
Healing rate = (original wound area-non-healed wound area)/original wound area × 100%
Standard of wound healing (complete epithelialization of the wound surface): complete healing occurs when the area of healing is greater than 95% of the original wound area or the wound area is less than 5% of the original wound area.
As can be seen from Table 3, the liver hemostasis and femoral artery hemostasis tests performed by the self-adhesive self-repairing hemostatic sponge have better effects than those of the control group, and the liver hemostasis time is reduced by 45% compared with that of the control group, the liver hemorrhage amount is reduced by 45%, the femoral artery hemostasis time is reduced by 32% compared with that of the control group, and the femoral artery hemorrhage amount is reduced by 57%. Therefore, the exosome can not only improve the repair promoting efficiency of the hemostatic sponge, but also optimize the network structure of the hemostatic sponge, so that the hemostatic effect of the hemostatic sponge is greatly improved.
As can be seen from Table 4, the effect of the test of healing the skin wound of the mouse by using the adhesion-promoting and healing-promoting hemostatic sponge is obviously better than that of the control group, the test group can promote the healing of the wound in 10 days, and the time for promoting the healing of the wound of the control group is 22 days. As can be seen, the adhesible healing promoting hemostatic sponge which is covalently combined with exosome in the hemostatic sponge and is subjected to a specific freeze-drying process has a good healing promoting function.
The above disclosure is only for a few specific embodiments of the present invention, but the present invention is not limited thereto, and any variations that can be made by those skilled in the art are intended to fall within the scope of the present invention.
Claims (10)
1. An adhesion promoting and repairing hemostatic sponge is characterized in that the adhesion promoting and repairing hemostatic sponge is prepared by fully reacting 15-25% of N-maleylated gelatin, 0.5-1.0% of exosome, 2-4% of acrylate PEG-N hydroxysuccinimide ester and 0.01-0.02% of N, N' -methylene bisacrylamide, adding 0.75-1.25% of maleic anhydride, 15-25% of acrylic acid and 0.5-0.8% of a first part photoinitiator, neutralizing by using a neutralizing agent, prepolymerizing under an ultraviolet lamp, adding a mixed solution of 0.5-1.0% of N-hydroxysuccinimide acrylate and 0.007-0.013% of a second part photoinitiator, performing secondary polymerization under the ultraviolet lamp, lyophilizing and sterilizing.
2. The sponge according to claim 1, wherein the molecular weight of the N-maleylated gelatin is 50-100KDa, and the degree of maleylation substitution is 85-95%.
3. The sponge according to claim 1, wherein the weight ratio of maleic anhydride to acrylic acid is 1: 20; the neutralizer is one or more of sodium hydroxide, disodium hydrogen phosphate, sodium bicarbonate, sodium carbonate, sodium citrate and sodium acetate.
4. An adhesion promoting repair hemostatic sponge according to claim 1, wherein the first portion of photoinitiator and the second portion of photoinitiator are 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone.
5. The sponge for promoting adhesion and repair of hemostasis as claimed in claim 1, wherein the pre-polymerization is carried out with an ultraviolet lamp power of 150W, a wavelength of 365nm, and an irradiation time of 20-40 min; the power of an ultraviolet lamp used for the secondary polymerization is 150W, the wavelength is 365nm, and the irradiation time is 10-20 min.
6. The sponge for promoting adhesion and repair of hemostasis as claimed in claim 1, wherein the exosome is secreted by one or more mesenchymal stem cells selected from adipose mesenchymal stem cells, placenta mesenchymal stem cells and bone marrow mesenchymal stem cells; the molecular weight of the acrylate PEG-N hydroxysuccinimide ester is 1-10 KDa.
7. An adherable repair promoting hemostatic sponge according to claim 1, comprising the steps of:
(1) and (3) crosslinking reaction: adding N-maleylation gelatin, exosome, acrylic ester PEG-N hydroxyl succinimide ester and N, N' -methylene bisacrylamide into purified water, stirring at 100-200rpm until the materials are completely dissolved, and continuing stirring for 20min to obtain a mixed solution after crosslinking reaction;
(2) and (3) neutralization reaction: adding maleic anhydride, acrylic acid and a first part of photoinitiator into the mixed solution obtained in the step (1), stirring at 100-200rpm until the mixture is completely dissolved, neutralizing with a neutralizer, and continuing stirring for 10 min;
(3) prepolymerization reaction: placing the neutralized mixed solution obtained in the step (2) under an ultraviolet lamp for prepolymerization to obtain a gel prepolymer;
(4) and (3) secondary polymerization: adding a mixed solution of N-hydroxysuccinimide acrylate and a second part of photoinitiator into the gel prepolymer obtained in the step (3), uniformly dispersing the mixed solution on the surface of the gel prepolymer, and carrying out secondary polymerization under an ultraviolet lamp to obtain a gel product;
(5) freeze-drying: placing the gel product obtained in the step (4) in a mould, placing the mould in a freeze dryer, and obtaining the unsterilized sponge capable of adhering and promoting repair of the hemostatic sponge after pre-freezing and programmed sublimation drying;
(6) and (3) sterilization: packaging the unsterilized adhesion promotion and repair hemostasis sponge obtained in the step (5), and sterilizing by electron beam irradiation at 15-25K to obtain the finished adhesion promotion and repair hemostasis sponge.
8. The method for preparing the adhesible self-repairing hemostatic sponge as claimed in claim 7, wherein the neutralization degree in step (2) is 40% -60%.
9. The method for preparing an adhesion promoting and repairing hemostatic sponge according to claim 7, wherein the step (4) of uniformly dispersing the mixed solution on the surface of the gel prepolymer is spraying.
10. The method for preparing an adhesion promoting repair hemostatic sponge according to claim 7, wherein the pre-freezing and lyophilization process in step (5) comprises: pre-freezing for 4 hours at the temperature of minus 50 ℃, and vacuumizing after the pre-freezing is finished, wherein the vacuum degree is less than 15 pa; after that, the temperature is raised in stages at every 10 ℃, the temperature raising time is 3 hours, the constant temperature time is 2 hours, and the temperature raising is finished until the temperature is raised to 5 ℃.
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