CN112023109B - Self-repairing hemostatic film capable of being adhered and preparation method thereof - Google Patents
Self-repairing hemostatic film capable of being adhered and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an adhesive self-repairing hemostatic film and a preparation method thereof. The hemostatic membrane is prepared by fully reacting dopamine grafted oxidized alginic acid, acrylamide, acrylic acid N-hydroxysuccinimide ester and N, N' -methylene bisacrylamide, adding a blood coagulation cross-linking agent, acrylic acid and a first part of photoinitiator, prepolymerizing, adding a mixed solution of acrylic ester PEG-N hydroxysuccinimide ester, dopamine, acrylamide, acrylic acid N-hydroxysuccinimide ester and a second part of photoinitiator, fully polymerizing, and performing vacuum drying. The hemostatic membrane prepared by the invention can quickly absorb interface moisture, so that the hemostatic membrane interface is fully contacted with a tissue interface, strong adhesion is formed on the tissue through covalent bonds and intermolecular force, mechanical compression is caused on injured blood vessels, and hemostasis is promoted. After the hemostatic membrane absorbs blood or tissue fluid, a dynamic bond can be formed, and the hemostatic membrane has a certain self-repairing function. Therefore, the hemostatic membrane has the effects of fast and efficient hemostasis, adhesion and self-repairing.
Description
Technical Field
The invention belongs to the technical field of biomedical materials, and relates to an adhesive self-repairing hemostatic film and a preparation method thereof. The medical hemostatic membrane has the effects of adhesion, displacement prevention and self repair while rapid hemostasis is achieved.
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 membrane is a material for stopping bleeding of wounds in surgical operations, and when the hemostatic membrane is attached to damaged parts of blood vessels, hydrophilic polymer materials can adhere and aggregate with blood 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.
Sodium alginate is a polysaccharide substance extracted from seaweed plants. The sodium alginate has excellent physical and chemical properties, high water absorption, biodegradability, biocompatibility, low price, strong modifiability and other excellent performances, so that the sodium alginate is widely applied to the aspect of medical hemostatic membranes.
For example, in the patent application No. 201710411687.1, a method for preparing a soluble paper-like alginate composite hemostatic membrane is disclosed, which comprises the following components by mass: 40-79.9% of alginate; 20-60% of polyvinyl alcohol; 0-0.1% of calcium salt cross-linking agent. The preparation method comprises the following steps: (1) dissolving alginate and polyvinyl alcohol in water according to the proportion to prepare a uniform and transparent solution, wherein the concentration of the solution is 7-15%, and then adding a calcium salt cross-linking agent for cross-linking to obtain a spinning solution; (2) and (3) filling the spinning solution into a constant-temperature liquid storage device, and processing and forming at one step by using electrostatic spinning equipment to obtain the soluble paper-shaped alginate composite hemostatic membrane material. The soluble paper-shaped alginate composite hemostatic membrane has a porous net structure and a higher surface area, and can quickly form gel to accelerate the hemostatic process by interacting with blood of a wound; meanwhile, calcium ions in the hemostatic membrane material are released to the wound surface to start coagulation factors, and the effects of gel hemostasis and calcium ion coagulation dual hemostasis are achieved. However, the soluble paper-like alginate composite hemostatic membrane has the defects of difficult degradation and weak adhesion performance to wounds, is easy to fall off when bleeding is large or the blood pressure of the wounds is large, and cannot play a good mechanical hemostatic role.
The invention patent with the application number of 201710918695.5 provides a modified sodium alginate electrospun fiber hemostatic membrane and a preparation method thereof. The modified sodium alginate electrospun fiber hemostatic membrane consists of 10-30 parts by weight of polyvinyl alcohol and 5-15 parts by weight of thiolated alginic acid. The electrospun fiber membrane material has a porous structure, can improve the soft compressibility and water absorption of the material, and provides a space for the adhesion and aggregation of platelets. The flexibility can widen the application range of the hemostatic material and reduce discomfort and pain; the improvement of water absorption can quickly absorb water in blood, increase the viscosity of the blood and slow down and solidify the blood flow; the increase of the adhesion space of the blood platelet is beneficial to the material to gather a large amount of blood platelets in a short time, activate blood coagulation factors and stop bleeding quickly. But the electrospun fiber membrane still has the defects of difficult degradation and poor adhesion performance to wounds.
The common Daqing absorbable hemostatic membrane in the market has the defects of large swelling rate, low mechanical property and poor adhesion property after absorbing blood.
In conclusion, a hemostatic membrane with good biocompatibility, strong adhesion, high strength, self-repairing capability and capability of exciting internal and external dual hemostatic functions is urgently needed clinically.
Disclosure of Invention
The invention aims to provide a hemostatic membrane which has good biocompatibility, strong adhesion and high strength, can self-repair and can stimulate the internal and external dual hemostatic functions.
The invention is realized by the following technical scheme.
The self-repairing adhesive hemostatic film is prepared with dopamine grafting oxidized alginic acid in 1.5-3.5 wt%, acrylamide in 25-35 wt%, N-hydroxysuccinimide acrylate in 3-7 wt% and N, N' -methylene bisacrylamide in 0.01-0.02 wt%, and through mixing, adding blood coagulation cross-linking agent, acrylic acid in 15-25 wt% and the first partial photoinitiator in 1.2-1.9 wt%, pre-polymerizing, adding the mixture of acrylate PEG-N-hydroxysuccinimide ester in 0.5-1.5 wt%, dopamine in 0.25-1 wt%, acrylamide in 0.2-0.6 wt%, N-hydroxysuccinimide acrylate in 2-4 wt% and the second partial photoinitiator in 0.009-0.028 wt%, polymerizing, vacuum drying and sterilizing.
The viscosity of the dopamine grafting oxidized alginic acid is 200-500 mPa.s, the oxidation degree is 80-90%, and the dopamine grafting rate is 10-20%.
The weight ratio of the dopamine grafted oxidized alginic acid to the blood coagulation cross-linking agent is 9: 1-3.
The coagulation cross-linking agent is one or more of calcium chloride, calcium sulfate and calcium carbonate.
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 20-40 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.
The molecular weight of the acrylate PEG-N-hydroxysuccinimide ester is 1-3.4 KDa.
The invention also provides a preparation method of the adhesive self-repairing hemostatic film, which comprises the following steps:
(1) and (3) crosslinking reaction: adding dopamine grafted oxidized alginic acid, acrylamide, acrylic acid N-hydroxysuccinimide 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 a crosslinking reaction.
(2) Prepolymerization reaction: and (2) adding the mixed solution obtained in the step (1) into a first part of photoinitiator, acrylic acid and a blood coagulation cross-linking agent, stirring at 100-200rpm until the mixture is fully and uniformly mixed, and placing the mixture under an ultraviolet lamp for prepolymerization to obtain a gel prepolymer.
(3) And (3) secondary polymerization: and (3) adding a mixed solution of acrylic ester PEG-N-hydroxysuccinimide ester, dopamine, acrylamide, acrylic acid N-hydroxysuccinimide ester and a second part of photoinitiator into the gel prepolymer obtained in the step (2), 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.
(4) Freeze-drying: and (4) placing the gel product obtained in the step (3) into a mould, placing the mould into a programmed vacuum dryer, and performing programmed vacuum drying to obtain the unsterilized self-repairing hemostatic film capable of adhering.
(5) And (3) sterilization: packaging the unsterilized self-repairing hemostatic film obtained in the step (4) and performing irradiation sterilization by electron beams at 15-25K to obtain a finished product of the self-repairing hemostatic film.
In the preparation method of the self-repairing adhesive hemostatic membrane, the method for uniformly dispersing the mixed solution on the surface of the gel prepolymer in the step (3) is atomization spraying.
The preparation method of the adhesive self-repairing hemostatic film comprises the following steps of (4) and the vacuum drying process: drying at vacuum degree of 100Pa and temperature of 4 deg.C for 1-2h, drying at vacuum degree of 50Pa and temperature of 10 deg.C for 0.5-1h, and drying at vacuum degree of 15Pa and temperature of 15 deg.C for 1.5-2 h.
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 dopamine grafted oxidized alginic acid contains aldehyde group, can react with amino groups in acrylamide and N, N' -methylene bisacrylamide, can generate free radical crosslinking reaction under the catalysis of ultraviolet light, and can generate chelating reaction with calcium ions. The cross-linking mode of multi-dimension, high mixing degree and high cross-linking density ensures the high mechanical strength of the hemostatic membrane.
2. The hemostatic membrane has an outer layer containing amido bonds, an inner layer containing amido bonds and carboxyl groups, and the inner and outer layers can rapidly remove water in the interface between the hemostatic membrane and wound tissues through water absorption kinetics, so that a polyacrylamide chain segment, an N-hydroxysuccinimide ester group and a catechol group in the hemostatic membrane generate strong covalent bonds and intermolecular acting force with tissues, and the hemostatic membrane has high mechanical strength, so that the hemostatic membrane can efficiently stop bleeding through mechanical compression and is not influenced by blood and tissue fluid.
3. The hemostatic membrane contains a dynamic bond combining aldehyde group and amino group, can automatically heal when mechanical injury or rupture occurs, and plays a role in protecting a wound for a long time.
4. The hemostatic membrane contains calcium ions, can activate an endogenous hemostatic way, and accelerates the hemostatic efficiency under the dual actions of exogenous hemostasis and endogenous hemostasis.
Drawings
FIG. 1 is a graph showing the degradation profile of the hemostatic membrane described in example 1 with time.
FIG. 2 is a structural diagram of the hemostatic membrane.
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 hemostatic membrane is detected by adopting 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) Burst strength test
The rupture strength of the self-adhesive self-healing hemostatic film was measured according to the method of ASTM F2392-04, and 5 repetitions were averaged, and 6 measurements were averaged for each sample.
(3) Volume swell ratio test
The volume test method adopts a liquid discharge method and adopts a hemostatic film materialPlacing the material in a measuring cylinder filled with a certain volume of liquid, reading the liquid level rise value, and respectively measuring the volume V of the hemostatic membrane material before water absorption and swelling0And 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 the hemostatic membrane is placed in 2ml of water to be kept stand for 10min, then the hemostatic membrane is centrifuged at the rotating speed of 500rpm for 10min and then taken out, the residual liquid amount is weighed, and each sample is tested for 6 times to obtain an average value.
(5) Water absorption Rate test
Dropping 20 μ l of purified water into a hemostatic membrane with a thickness of 1mm and a thickness of 1cm multiplied by 1cm by a liquid-transferring gun, recording the absorption time of the water drops, namely the water absorption rate of the hemostatic membrane, and testing each sample for 5 times to obtain an average value.
(6) Self-repair test
And (3) cutting the swelled hemostatic membrane into two sections, contacting the cut surfaces for 1h, measuring the breaking force of the product after self-repairing and the breaking force of the product which is not cut, wherein the breaking force of the product after self-repairing is greater than that of the product which is not cut, namely the self-repairing rate, and testing each sample for 6 times to obtain an average value.
(7) In vitro cytotoxicity assay
Evaluation according to medical device biology part 5: cytotoxicity assays GB/T16886.5-2017 were carried out.
(8) 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 1A dopamine graft oxidized alginic acid (degree of oxidation 85%, dopamine graft ratio 15%, viscosity 300 mPas) in a mass fraction of 2.5%, 30% acrylamide, 5% N-hydroxysuccinimide acrylate, 0.015% N, N' -methylenebisacrylamide were added to purified water, stirred at 100-200rpm until completely dissolved, further stirred for 20min, added with 1.6% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone, 20% acrylic acid and 0.6% calcium chloride, stirred at 100-200rpm until the solution was homogeneous, prepolymerized at a power of 150W and a wavelength of 365nm for 30min under an ultraviolet lamp, the prepolymer was taken out, and 1.0% PEG-N-hydroxysuccinimide acrylate was sprayed on the surface by atomization, A mixture of 0.6% dopamine, 0.4% acrylamide, 3% N-hydroxysuccinimide acrylate and 0.018% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone was polymerized under UV light at a wavelength of 365nm at a power of 150W for 15 min. And (3) placing the gel product after polymerization into a mold, placing the gel product into a program vacuum drying oven, firstly drying for 1.5 hours at the temperature of 4 ℃ and the vacuum degree of 100Pa, then drying for 0.75 hour at the temperature of 10 ℃ and the vacuum degree of 50Pa, finally drying for 1.75 hours at the temperature of 15 ℃ and the vacuum degree of 15Pa, packaging, and sterilizing by using 20K electron beams to obtain the adhesive hemostatic self-repairing film.
Example 2 dopamine graft oxidation alginic acid (degree of oxidation 80%, dopamine graft ratio 10%, viscosity 200 mPas) with a mass fraction of 3.5%, 25% acrylamide, 3% N-hydroxysuccinimide acrylate, 0.020% N, N' -methylenebisacrylamide were added to purified water, stirred at 100-200rpm until completely dissolved, further stirred for 20min, added with 1.6% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone, 25% acrylic acid and 0.4% calcium chloride, stirred at 100-200rpm until the solution was homogeneous, prepolymerized at a power of 150W and a wavelength of 365nm for 20min under an ultraviolet lamp, the prepolymer was taken out, and 1.5% PEG-N-hydroxysuccinimide acrylate was sprayed on the surface by atomization, A mixture of 1.25% dopamine, 0.6% acrylamide, 4% N-hydroxysuccinimide acrylate and 0.028% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone was polymerized under an ultraviolet lamp at a wavelength of 365nm at a power of 150W for 15 min. And placing the polymerized gel product into a mold, placing the mold into a program vacuum drying oven, firstly drying for 2 hours at the temperature of 4 ℃ and the vacuum degree of 100Pa, then drying for 1 hour at the temperature of 10 ℃ and the vacuum degree of 50Pa, finally drying for 2 hours at the temperature of 15 ℃ and the vacuum degree of 15Pa, packaging and sterilizing by 25K electron beams to obtain the self-repairing adhesive hemostatic film.
Example 3A solution of 1.5% by mass of dopamine graft oxidized alginic acid (degree of oxidation 90%, degree of dopamine graft 20%, viscosity 500 mPas), 35% acrylamide, 7% N-hydroxysuccinimide acrylate, 0.010% N, N' -methylenebisacrylamide, stirred at 100-200rpm for complete dissolution, further stirred for 20min, added with 1.6% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone, 15% acrylic acid and 0.5% calcium chloride, stirred at 100-200rpm for homogenization, prepolymerized at a power of 150W and a wavelength of 365nm under an ultraviolet lamp for 40min, taken out of the prepolymer, and sprayed with 0.5% PEG-N-hydroxysuccinimide acrylate by atomization on the surface, A mixture of 0.25% dopamine, 0.2% acrylamide, 2% N-hydroxysuccinimide acrylate and 0.009% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone was polymerized for 25min under an ultraviolet lamp at a power of 150W and a wavelength of 365 nm. And placing the polymerized gel product into a mold, placing the mold into a program vacuum drying oven, firstly drying for 1 hour at the temperature of 4 ℃ and the vacuum degree of 100Pa, then drying for 0.5 hour at the temperature of 10 ℃ and the vacuum degree of 50Pa, finally drying for 1.5 hours at the temperature of 15 ℃ and the vacuum degree of 15Pa, and packaging and sterilizing by 15K electron beams to obtain the self-repairing hemostatic film capable of adhering.
Example 4A dopamine graft oxidized alginic acid (degree of oxidation 85%, dopamine graft ratio 15%, viscosity 300 mPas) in a mass fraction of 2.5%, acrylamide 35%, N-hydroxysuccinimide acrylate 7%, N' -methylenebisacrylamide 0.020% were added to purified water, stirred at 100-200rpm until completely dissolved, further stirred for 20min, added 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone 1.9%, acrylic acid 25% and calcium chloride 0.6%, stirred at 100-200rpm until the solution was homogeneous, prepolymerized at a power of 150W and a wavelength of 365nm for 30min under an ultraviolet lamp, the prepolymer was taken out, and sprayed by atomization on the surface with 1.0% of PEG-N-hydroxysuccinimide acrylate, A mixture of 0.6% dopamine, 0.4% acrylamide, 3% N-hydroxysuccinimide acrylate and 0.018% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone was polymerized under UV light at a wavelength of 365nm at a power of 150W for 15 min. And (3) placing the gel product after polymerization into a mold, placing the gel product into a program vacuum drying oven, firstly drying for 1.5 hours at the temperature of 4 ℃ and the vacuum degree of 100Pa, then drying for 0.75 hour at the temperature of 10 ℃ and the vacuum degree of 50Pa, finally drying for 1.75 hours at the temperature of 15 ℃ and the vacuum degree of 15Pa, packaging, and sterilizing by using 20K electron beams to obtain the adhesive hemostatic self-repairing film.
Example 5 dopamine graft oxidation alginic acid (degree of oxidation 85%, dopamine graft ratio 15%, viscosity 300 mPas) with mass fraction of 2.5%, 25% acrylamide, 3% N-hydroxysuccinimide acrylate, 0.010% N, N' -methylenebisacrylamide were added to purified water, stirred at 100-200rpm until completely dissolved, further stirred for 20min, added 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone 1.2%, acrylic acid 15% and calcium chloride 0.6%, stirred at 100-200rpm until the solution was homogeneous, prepolymerized under an ultraviolet lamp at a power of 150W and a wavelength of 365nm for 30min, the prepolymer was taken out, and sprayed by atomization on the surface with 1.0% PEG-N-hydroxysuccinimide acrylate, A mixture of 0.6% dopamine, 0.4% acrylamide, 3% N-hydroxysuccinimide acrylate and 0.018% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone was polymerized under UV light at a wavelength of 365nm at a power of 150W for 15 min. And (3) placing the gel product after polymerization into a mold, placing the gel product into a program vacuum drying oven, firstly drying for 1.5 hours at the temperature of 4 ℃ and the vacuum degree of 100Pa, then drying for 0.75 hour at the temperature of 10 ℃ and the vacuum degree of 50Pa, finally drying for 1.75 hours at the temperature of 15 ℃ and the vacuum degree of 15Pa, packaging, and sterilizing by using 20K electron beams to obtain the adhesive hemostatic self-repairing film.
Example 6A dopamine graft oxidized alginic acid (degree of oxidation 85%, dopamine graft ratio 15%, viscosity 300 mPas) in a mass fraction of 2.5%, 30% acrylamide, 5% N-hydroxysuccinimide acrylate, 0.015% N, N' -methylenebisacrylamide were added to purified water, stirred at 100-200rpm until completely dissolved, further stirred for 20min, added with 1.6% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone, 20% acrylic acid and 0.3% calcium chloride, stirred at 100-200rpm until the solution was homogeneous, prepolymerized at a power of 150W and a wavelength of 365nm for 20min under an ultraviolet lamp, the prepolymer was taken out, and sprayed with 0.5% PEG-N-hydroxysuccinimide acrylate by atomization on the surface, A mixture of 0.25% dopamine, 0.2% acrylamide, 2% N-hydroxysuccinimide acrylate and 0.009% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone was polymerized under UV lamp at a power of 150W and a wavelength of 365nm for 10 min. And (3) placing the gel product after polymerization into a mold, placing the gel product into a program vacuum drying oven, firstly drying for 1.5 hours at the temperature of 4 ℃ and the vacuum degree of 100Pa, then drying for 0.75 hour at the temperature of 10 ℃ and the vacuum degree of 50Pa, finally drying for 1.75 hours at the temperature of 15 ℃ and the vacuum degree of 15Pa, packaging, and sterilizing by using 20K electron beams to obtain the adhesive hemostatic self-repairing film.
Example 7 dopamine graft oxidation alginic acid (degree of oxidation 85%, dopamine graft ratio 15%, viscosity 300 mPas) in mass fraction of 2.5%, acrylamide 30%, N-hydroxysuccinimide acrylate 5%, N' -methylenebisacrylamide 0.015% were added to purified water, stirred at 100-200rpm until completely dissolved, further stirred for 20min, added 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone 1.6%, acrylic acid 20% and calcium chloride 0.8%, stirred at 100-200rpm until the solution was homogeneous, prepolymerized under an ultraviolet lamp at a power of 150W and a wavelength of 365nm for 40min, the prepolymer was taken out, and sprayed by atomization on the surface with 1.5% of PEG-N-hydroxysuccinimide acrylate, A mixture of 1.25% dopamine, 0.6% acrylamide, 4% N-hydroxysuccinimide acrylate and 0.028% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone was polymerized for 20min under an ultraviolet lamp at a wavelength of 365nm and a power of 150W. And (3) placing the gel product after polymerization into a mold, placing the gel product into a program vacuum drying oven, firstly drying for 1.5 hours at the temperature of 4 ℃ and the vacuum degree of 100Pa, then drying for 0.75 hour at the temperature of 10 ℃ and the vacuum degree of 50Pa, finally drying for 1.75 hours at the temperature of 15 ℃ and the vacuum degree of 15Pa, packaging, and sterilizing by using 20K electron beams to obtain the adhesive hemostatic self-repairing film.
Example 8A dopamine graft oxidized alginic acid (degree of oxidation 85%, dopamine graft ratio 15%, viscosity 300 mPas) in a mass fraction of 2.5%, 30% acrylamide, 5% N-hydroxysuccinimide acrylate, 0.015% N, N' -methylenebisacrylamide were added to purified water, stirred at 100-200rpm until completely dissolved, further stirred for 20min, added with 1.6% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone, 20% acrylic acid and 0.6% calcium chloride, stirred at 100-200rpm until the solution was homogeneous, prepolymerized at a power of 150W and a wavelength of 365nm for 30min under an ultraviolet lamp, the prepolymer was taken out, and 1.0% PEG-N-hydroxysuccinimide acrylate was sprayed on the surface by atomization, A mixture of 0.6% dopamine, 0.4% acrylamide, 3% N-hydroxysuccinimide acrylate and 0.018% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone was polymerized under UV light at a wavelength of 365nm at a power of 150W for 15 min. And placing the polymerized gel product into a mold, placing the mold into a program vacuum drying oven, firstly drying for 2 hours at the temperature of 4 ℃ and the vacuum degree of 100Pa, then drying for 0.75 hour at the temperature of 10 ℃ and the vacuum degree of 50Pa, finally drying for 1.5 hours at the temperature of 15 ℃ and the vacuum degree of 15Pa, packaging, and sterilizing by using 20K electron beams to obtain the self-repairing hemostatic film capable of adhering.
Comparative example 1A dopamine graft oxidized alginic acid (degree of oxidation 85%, dopamine graft ratio 15%, viscosity 300 mPas) in mass fraction of 2.5%, acrylamide 30% and N, N' -methylenebisacrylamide 0.015% were added to purified water, stirred at 200rpm 100-, 3% of N-hydroxysuccinimide acrylate and 0.018% of 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone, and polymerizing for 15min under an ultraviolet lamp at a power of 150W and a wavelength of 365 nm. And (3) placing the gel product after polymerization into a mold, placing the gel product into a program vacuum drying oven, firstly drying for 1.5 hours at the temperature of 4 ℃ and the vacuum degree of 100Pa, then drying for 0.75 hour at the temperature of 10 ℃ and the vacuum degree of 50Pa, finally drying for 1.75 hours at the temperature of 15 ℃ and the vacuum degree of 15Pa, packaging, and sterilizing by using 20K electron beams to obtain the adhesive hemostatic self-repairing film.
Comparative example 2A solution of 2.5% by mass of dopamine graft oxidized alginic acid (degree of oxidation 85%, dopamine graft ratio 15%, viscosity 300 mPas), 30% acrylamide, 5% N-hydroxysuccinimide acrylate, 0.015% N, N' -methylenebisacrylamide was added to purified water, stirred at 100-200rpm until completely dissolved, further stirred for 20min, added with 1.6% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone and 0.6% calcium chloride, stirred at 100-200rpm until the solution was homogeneous, prepolymerized under an ultraviolet lamp at a power of 150W and a wavelength of 365nm for 30min, taken out of the prepolymer, sprayed with 1.0% acrylate PEG-N-hydroxysuccinimide ester by atomization on the surface, A mixture of 0.6% dopamine, 0.4% acrylamide, 3% N-hydroxysuccinimide acrylate and 0.018% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone was polymerized under UV light at a wavelength of 365nm at a power of 150W for 15 min. And (3) placing the gel product after polymerization into a mold, placing the gel product into a program vacuum drying oven, firstly drying for 1.5 hours at the temperature of 4 ℃ and the vacuum degree of 100Pa, then drying for 0.75 hour at the temperature of 10 ℃ and the vacuum degree of 50Pa, finally drying for 1.75 hours at the temperature of 15 ℃ and the vacuum degree of 15Pa, packaging, and sterilizing by using 20K electron beams to obtain the adhesive hemostatic self-repairing film.
Comparative example 3A solution of 2.5% by mass of dopamine graft oxidized alginic acid (85% degree of oxidation, 15% dopamine graft ratio, 300 mPas viscosity), 5% N-hydroxysuccinimide acrylate, 0.015% N, N' -methylenebisacrylamide, stirred at 200rpm for 100-, A mixture of 0.6% dopamine, 0.4% acrylamide, 3% N-hydroxysuccinimide acrylate and 0.018% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone was polymerized under UV light at a wavelength of 365nm at a power of 150W for 15 min. And (3) placing the gel product after polymerization into a mold, placing the gel product into a program vacuum drying oven, firstly drying for 1.5 hours at the temperature of 4 ℃ and the vacuum degree of 100Pa, then drying for 0.75 hour at the temperature of 10 ℃ and the vacuum degree of 50Pa, finally drying for 1.75 hours at the temperature of 15 ℃ and the vacuum degree of 15Pa, packaging, and sterilizing by using 20K electron beams to obtain the adhesive hemostatic self-repairing film.
Comparative example 4A solution of 2.5% by mass of dopamine graft oxidized alginic acid (degree of oxidation 85%, dopamine graft ratio 15%, viscosity 300 mPas), 30% acrylamide, 5% N-hydroxysuccinimide acrylate, and 0.015% N, N' -methylenebisacrylamide was added to purified water, stirred at 100-200rpm until completely dissolved, further stirred for 20min, added with 1.6% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone and 20% acrylic acid, stirred at 100-200rpm until the solution was homogeneous, prepolymerized under an ultraviolet lamp at a power of 150W and a wavelength of 365nm for 30min, taken out of the prepolymer, and sprayed with 1.0% acrylate PEG-N hydroxysuccinimide ester by atomization on the surface, A mixture of 0.6% dopamine, 0.4% acrylamide, 3% N-hydroxysuccinimide acrylate and 0.018% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone was polymerized under UV light at a wavelength of 365nm at a power of 150W for 15 min. And (3) placing the gel product after polymerization into a mold, placing the gel product into a program vacuum drying oven, firstly drying for 1.5 hours at the temperature of 4 ℃ and the vacuum degree of 100Pa, then drying for 0.75 hour at the temperature of 10 ℃ and the vacuum degree of 50Pa, finally drying for 1.75 hours at the temperature of 15 ℃ and the vacuum degree of 15Pa, packaging, and sterilizing by using 20K electron beams to obtain the adhesive hemostatic self-repairing film.
Comparative example 5 dopamine graft oxidation alginic acid (degree of oxidation 85%, dopamine graft ratio 15%, viscosity 300 mPas) with mass fraction of 2.5%, 30% acrylamide, 5% N-hydroxysuccinimide acrylate, 0.015% N, N' -methylenebisacrylamide were added to purified water, stirred at 100-200rpm until completely dissolved, stirred for 20min, added with 1.6% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone, 20% acrylic acid and 0.6% calcium chloride, stirred at 100-200rpm until the solution was homogeneous, prepolymerized at a power of 150W and a wavelength of 365nm for 30min under an ultraviolet lamp, the prepolymer was taken out, and sprayed with 0.4% acrylamide, 3% N-hydroxysuccinimide acrylate and 0.018% 2-hydroxy-2-methyl-imide by atomization on the surface Polymerizing the mixed solution of 1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone for 15min under an ultraviolet lamp with the power of 150W and the wavelength of 365 nm. And (3) placing the gel product after polymerization into a mold, placing the gel product into a program vacuum drying oven, firstly drying for 1.5 hours at the temperature of 4 ℃ and the vacuum degree of 100Pa, then drying for 0.75 hour at the temperature of 10 ℃ and the vacuum degree of 50Pa, finally drying for 1.75 hours at the temperature of 15 ℃ and the vacuum degree of 15Pa, packaging, and sterilizing by using 20K electron beams to obtain the adhesive hemostatic self-repairing film.
Comparative example 6A solution of 2.5% by mass of dopamine graft oxidized alginic acid (degree of oxidation 85%, dopamine graft ratio 15%, viscosity 300 mPas), 30% acrylamide, 5% N-hydroxysuccinimide acrylate, 0.015% N, N' -methylenebisacrylamide, stirred at 100-200rpm until completely dissolved, further stirred for 20min, added with 1.6% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone, 20% acrylic acid and 0.6% calcium chloride, stirred at 100-200rpm until homogeneous, prepolymerized at a power of 150W and a wavelength of 365nm for 30min under an ultraviolet lamp, taken out of the prepolymer, sprayed with 1.0% PEG-N-hydroxysuccinimide acrylate by atomization on the surface, 0.6 percent of dopamine and 0.018 percent of 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-acetone, and polymerizing for 15min under an ultraviolet lamp with the power of 150W and the wavelength of 365 nm. And (3) placing the gel product after polymerization into a mold, placing the gel product into a program vacuum drying oven, firstly drying for 1.5 hours at the temperature of 4 ℃ and the vacuum degree of 100Pa, then drying for 0.75 hour at the temperature of 10 ℃ and the vacuum degree of 50Pa, finally drying for 1.75 hours at the temperature of 15 ℃ and the vacuum degree of 15Pa, packaging, and sterilizing by using 20K electron beams to obtain the adhesive hemostatic self-repairing film.
Comparative example 7A solution of 2.5% by mass of dopamine graft oxidized alginic acid (degree of oxidation 85%, dopamine graft ratio 15%, viscosity 300 mPas), 30% acrylamide, 5% N-hydroxysuccinimide acrylate, 0.015% N, N' -methylenebisacrylamide, stirred at 100-200rpm until completely dissolved, further stirred for 20min, added with 1.6% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone, 20% acrylic acid and 0.6% calcium chloride, stirred at 100-200rpm until homogeneous, prepolymerized at a power of 150W and a wavelength of 365nm for 30min under an ultraviolet lamp, taken out of the prepolymer, sprayed with 1.0% PEG-N-hydroxysuccinimide acrylate by atomization on the surface, A mixture of 0.6% dopamine, 0.4% acrylamide, 3% N-hydroxysuccinimide acrylate and 0.018% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone was polymerized under UV light at a wavelength of 365nm at a power of 150W for 15 min. And placing the polymerized gel product into a mold, placing the mold into a program vacuum drying oven, drying for 3 hours at the temperature of 4 ℃ and the vacuum degree of 100Pa, drying for 2 hours at the temperature of 10 ℃ and the vacuum degree of 50Pa, drying for 4 hours at the temperature of 15 ℃ and the vacuum degree of 15Pa, packaging, and sterilizing by using 20K electron beams to obtain the self-repairing adhesive hemostatic film.
Comparative example 8A solution of 2.5% by mass of dopamine graft oxidized alginic acid (degree of oxidation 85%, dopamine graft ratio 15%, viscosity 300 mPas), 30% acrylamide, 5% N-hydroxysuccinimide acrylate, 0.015% N, N' -methylenebisacrylamide, stirred at 100-200rpm until completely dissolved, further stirred for 20min, added with 1.6% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone, 20% acrylic acid and 0.6% calcium chloride, stirred at 100-200rpm until the solution is homogeneous, prepolymerized at a power of 150W and a wavelength of 365nm for 30min under an ultraviolet lamp, taken out of the prepolymer, sprayed with 1.0% PEG-N-hydroxysuccinimide acrylate by atomization on the surface, A mixture of 0.6% dopamine, 0.4% acrylamide, 3% N-hydroxysuccinimide acrylate and 0.018% 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone was polymerized under UV light at a wavelength of 365nm at a power of 150W for 15 min. And (3) placing the polymerized gel product into a mold, placing the mold into a program vacuum drying oven, drying for 0.5h at the temperature of 4 ℃ and the vacuum degree of 100Pa, drying for 0.5h at the temperature of 10 ℃ and the vacuum degree of 50Pa, drying for 1h at the temperature of 15 ℃ and the vacuum degree of 15Pa, packaging, and sterilizing by using 20K electron beams to obtain the self-repairing hemostatic film capable of adhering.
The physicochemical properties and biology of the hemostatic membrane were examined according to a surface adhesion test method, a rupture strength test method, a volume swelling ratio test method, a water absorption rate test method, a self-repair test method, a water absorption rate test method, an in vitro cytotoxicity test method, and a 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, comparative example 1 and comparative examples 5 to 6 in Table 2, the surface adhesion of the hemostatic membrane is related to the grafting ratio of the acrylate PEG-N-hydroxysuccinimide ester, dopamine, polyacrylamide and N-hydroxysuccinimide ester on the surface of the membrane, the water absorption rate of the membrane and the volume swelling ratio of the membrane. The lower the volume swelling ratio of the film is, the faster the water absorption rate is, the higher the grafting rate of the acrylate PEG-N-hydroxysuccinimide ester, dopamine, polyacrylamide and acrylic acid N-hydroxysuccinimide ester on the surface of the film is, and the stronger the adhesion of the hemostatic film is.
As is clear from examples 1 to 8 in Table 1 and comparative examples 1 to 8 in Table 2, the rupture strength of the hemostatic membrane is related to the membrane surface adhesion and the intra-membrane crosslink density. The stronger the surface adhesion of the hemostatic membrane is, the higher the crosslink density in the membrane is, and the higher the rupture strength of the hemostatic membrane is.
As can be seen from examples 1 to 8 in Table 1 and comparative examples 1 to 8 in Table 2, the volume swelling ratio and water absorption rate of the hemostatic membrane are related to the crosslink density in the membrane, and the higher the amino group content, aldehyde group content, initiator content and crosslinking agent content in the membrane, the higher the crosslink density of the membrane, and the lower the volume swelling ratio and water absorption rate of the membrane. In addition, as is clear from example 1 in table 1 and comparative examples 2 to 3 in table 2, the volume swell ratio and the water absorption capacity are related to the carboxyl group and amide group contents in the film, and the higher the carboxyl group and amide group contents are, the higher the volume swell ratio and the water absorption capacity of the film are.
As can be seen from examples 1 to 8 in Table 1 and comparative examples 1 to 6 in Table 2, the self-repairing test results of the hemostatic membrane are related to the dopamine grafting rate, the aldehyde group content, the amino group content and the calcium ion concentration in the membrane, and the self-repairing rate of the hemostatic membrane is higher as the dopamine grafting rate, the aldehyde group content, the amino group content and the calcium ion concentration are higher.
As can be seen from example 1 in Table 1 and comparative examples 7-8 in Table 2, the procedural vacuum drying process of the hemostatic membrane directly affects various performance parameters of the hemostatic membrane.
As is clear from example 1 in Table 1 and comparative example 3 in Table 2, the aldehyde group reaction in the reaction system is incomplete, and cytotoxicity, irritative sensitization, and the like are caused.
Through the examples 1-9 in table 1, the biocompatibility of the hemostatic membrane is better, and the cytotoxicity test, the skin irritation test and the sensitization test of the hemostatic membrane all meet the biocompatibility requirement of the medical hemostatic membrane.
The sample of example 1 was subjected to in vitro degradation test according to the following test protocol, and the result is shown in FIG. 1, and the hemostatic membrane can be completely degraded within 124 days.
Detection of in vitro degradation time:
1. preparation of a sample to be tested: the samples were cut into 1cm by 1cm square membranes 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 96 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.
The samples 1 (test group) described in example and 1 (control group) were used for 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.
As can be seen from Table 3, the liver hemostasis and femoral artery hemostasis tests performed by the self-adhesive self-repairing hemostatic membrane have better effects than those of the control group, the liver hemostasis time is reduced by 36% compared with that of the control group, the liver hemorrhage amount is reduced by 38%, the femoral artery hemostasis time is reduced by 57% compared with that of the control group, and the femoral artery hemorrhage amount is reduced by 57%. Therefore, the hemostatic effect of the hemostatic membrane is greatly improved by adding the N-hydroxysuccinimide acrylate.
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 (6)
1. The self-repairing self-adhesive hemostatic film is characterized in that 1.5-3.5 wt% of dopamine grafted oxidized alginic acid, 25-35 wt% of acrylamide, 3-7 wt% of N-hydroxysuccinimide acrylate and 0.01-0.02 wt% of N, N' -methylene bisacrylamide are fully mixed, a blood coagulation cross-linking agent, 15-25 wt% of acrylic acid and 1.2-1.9 wt% of a first part of photoinitiator are added, the prepolymer is taken out after prepolymerization, a mixed solution of 0.5-1.5 wt% of acrylate PEG-N-hydroxysuccinimide ester, 0.25-1 wt% of dopamine, 0.2-0.6 wt% of acrylamide, 2-4 wt% of N-hydroxysuccinimide acrylate and 0.009-0.028% of a second part of photoinitiator is sprayed on the surface in an atomizing mode, and after secondary polymerization, program vacuum drying is carried out, and, Sterilizing to obtain the product;
the viscosity of the dopamine grafting oxidized alginic acid is 200-500 mPa.s, the oxidation degree is 80-90%, and the dopamine grafting rate is 10-20%;
the method for the programmed vacuum drying comprises the following steps: drying at vacuum degree of 100Pa and temperature of 4 deg.C for 1-2h, drying at vacuum degree of 50Pa and temperature of 10 deg.C for 0.5-1h, and drying at vacuum degree of 15Pa and temperature of 15 deg.C for 1.5-2 h.
2. The self-healing hemostatic membrane according to claim 1, wherein the weight ratio of the dopamine grafted oxidized alginic acid to the blood coagulation cross-linking agent is 9: 1-3; the coagulation cross-linking agent is calcium chloride.
3. The self-adhesive self-healing hemostatic film according to claim 1, wherein the first portion of the photoinitiator and the second portion of the photoinitiator are 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone.
4. The self-healing adhesive hemostatic film according to claim 1, wherein the pre-polymerization is performed 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.
5. The self-healing hemostatic membrane according to claim 1, wherein the acrylate PEG-N hydroxysuccinimide ester has a molecular weight of 1-3.4 KDa.
6. The self-healing self-adherable hemostatic film according to claim 1, comprising the steps of:
(1) and (3) crosslinking reaction: adding dopamine grafted oxidized alginic acid, acrylamide, acrylic acid N-hydroxysuccinimide 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 a crosslinking reaction;
(2) prepolymerization reaction: adding a first part of photoinitiator, acrylic acid and a blood coagulation cross-linking agent into the mixed solution obtained in the step (1), stirring at 100-200rpm until the mixture is fully and uniformly mixed, and placing the mixture under an ultraviolet lamp for prepolymerization to obtain a gel prepolymer;
(3) and (3) secondary polymerization: adding a mixed solution of acrylic ester PEG-N-hydroxysuccinimide ester, dopamine, acrylamide, acrylic acid N-hydroxysuccinimide ester and a second part of photoinitiator into the gel prepolymer obtained in the step (2), 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;
(4) freeze-drying: placing the gel-like product obtained in the step (3) into a mould, placing the mould into a programmed vacuum dryer, and performing programmed vacuum drying to obtain an unsterilized self-repairing hemostatic film capable of adhering;
(5) and (3) sterilization: packaging the unsterilized self-repairing hemostatic film obtained in the step (4) and capable of being adhered, and performing irradiation sterilization by using an electron beam at 15-25K to obtain a finished product of the self-repairing hemostatic film capable of being adhered;
the method for uniformly dispersing the mixed solution on the surface of the gel prepolymer in the step (3) is atomization spraying.
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