CN111388755A - Injectable hyaluronic acid/chitosan hydrogel and preparation method thereof - Google Patents
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Abstract
The invention relates to an injectable hyaluronic acid/chitosan hydrogel and a preparation method thereof. The injection type hyaluronic acid/chitosan hydrogel has high biocompatibility and safety, and the preparation method is simple and efficient. The dosage of the hyaluronic acid and the chitosan or the chitosan derivative is less, the preparation method is green and environment-friendly, and the preparation method has wide prospect in the aspect of cartilage repair.
Description
Technical Field
The invention belongs to the field of hydrogel scaffold materials and preparation thereof, and particularly relates to an injectable hyaluronic acid/chitosan hydrogel and a preparation method thereof.
Background
At present, the problem of joint inflammation caused by loss of lubricating fluid in joint cavities due to trauma and aging is more and more common, so that patients suffering from articular cartilage loss and bone tissue damage are more and more, wherein the articular cartilage loss caused by arthritis accounts for a large proportion. Cartilage is a highly differentiated connective tissue, devoid of blood and lymphatic vessels within the tissue, the main nutritional sources being joint synovial fluid and subchondral blood vessels. Chondrocytes are embedded in thick collagen fibers, have no migration ability and limited self-healing ability, so that the repair ability after defect is very limited, and the repair of cartilage defect is still a medical problem. With the development of cartilage tissue engineering, the extracellular environment is simulated by designing biodegradable or absorbable scaffold materials to support the growth of chondrocytes, thereby bringing a new direction for the treatment of cartilage defect.
Hyaluronic Acid (HA) is a large polysaccharide composed of two disaccharide units, D-glucuronic Acid and N-acetylglucosamine. Hyaluronic acid exhibits various important physiological functions in the body due to its unique molecular structure and physicochemical properties, wherein hyaluronic acid is the main component of joint lubricating fluid in the joint cavity. Besides, hyaluronic acid also has the functions of regulating permeability of blood vessel walls, regulating diffusion and movement of proteins and water electrolytes, promoting wound healing and the like. Hyaluronic acid has biochemical medicine with high clinical value, is widely applied to various ophthalmic surgeries, such as crystal implantation, corneal transplantation, anti-glaucoma surgery and the like, and can also be used for treating arthritis and accelerating wound healing. Hyaluronic acid is currently mainly used in cosmetics.
Chitosan (Chitosan, CS), also known as Chitosan, is widely found in the shell of crustaceans and cephalopods in nature and is obtained by deacetylating chitin. The chitosan has the advantages of good adsorption, permeability, moisture absorption, moisture retention, good biocompatibility, antibacterial property, biodegradability and the like. The method has made great progress in the application research in the fields of medicine, food, chemical industry, cosmetics, water treatment, metal extraction and recovery, biochemistry, biomedical engineering and the like. Among them, the application of chitosan in directional repair or local treatment of cartilage loss caused by sports injury and osteoarthritis is a research hotspot of tissue engineering. The derivatives include chitosan lactate, water-soluble chitosan, carboxymethyl chitosan, etc. Common chitosan is only dissolved in partial acid solutions such as inorganic acid and organic acid, and thus the application of the chitosan is limited. The solubility of chitosan derivatives such as water-soluble chitosan with increased deacetylation degree, carboxymethyl chitosan, chitosan lactate and the like in water is improved, and the characteristics of chitosan macromolecules are maintained, so that the chitosan macromolecules are more convenient to apply, and the application range can be wider.
However, HA solution and CS solution generate white flocculate immediately when contacting to prevent cross-linking, and glutaraldehyde HAs cytotoxicity, even trace amount of glutaraldehyde can inhibit cell proliferation and growth.
CN104004232A discloses a biodegradable chitosan-based hydrogel and a preparation method thereof, wherein N-succinylated chitosan is used to obtain N-succinylated chitosan (the N-succinylation degree is 15-30%) with improved water solubility, and the N-succinylated chitosan is mixed with a hyaluronic acid solution to form gel. The acidity of hyaluronic acid can further enhance the solubility of N-succinylchitosan in water. In the method, the concentration of N-succinyl chitosan is 1-1.25 wt%, the concentration of hyaluronic acid is 0.5 wt%, the mixing proportion of N-succinyl chitosan is 65-100% and hyaluronic acid is 0-35%, wherein the molecular weight of N-succinyl chitosan is MW <10000, the molecular weight of hyaluronic acid is 100,000-180,000, the dissolution process is slow, the viscosity of a hyaluronic acid solution is high, and the gel formation time is increased along with the increase of the concentration of N-succinyl chitosan.
CN104208711A discloses a chitosan semifluid sustained-release gel and application thereof, wherein chitosan with molecular weight of 3000-8000 is dissolved in normal saline or distilled water at 4 ℃ to prepare a 0.5020g/m L chitosan solution (component 1), hyaluronic acid chitosan with molecular weight of 500000 and intrinsic viscosity of 3000g/m L is dissolved in a mixed solution of saturated sodium bicarbonate water solution and distilled water at a volume ratio of 1:1 at 4 ℃ to prepare a hyaluronic acid chitosan solution (component 2) of 0.2510g/m L, the component 1 and the component 2 are mixed according to the volume ratio of 1:1, and the formed semifluid is slowly solidified at 26-40 ℃ to form hydrogel which can be used as a sustained-release carrier for embedding fat-soluble drugs and water-soluble protein drugs.
Disclosure of Invention
The invention aims to solve the technical problem of providing an injectable hyaluronic acid/chitosan hydrogel and a preparation method thereof, overcoming the inconvenience that the unusual N-succinyl chitosan is needed in the prior art for preparing hyaluronic acid chitosan gel, and utilizing chitosan with wider sources and easier acquisition or chitosan derivatives such as chitosan lactate, water-soluble chitosan, carboxymethyl chitosan and the like as raw materials to form gel by electrostatic self-adsorption without using a cross-linking agent. According to the invention, a large number of carboxyl groups on a molecular chain of hyaluronic acid in an aqueous solution are dissociated into negative ions to present a polyanion state, and amino groups on the molecular chain of chitosan or a chitosan derivative in the aqueous solution are positively charged to present a polycation state, so that the chitosan or the chitosan derivative is combined to form a hydrogel support under the action of electrostatic force, and an environment which supplies nutrition and is beneficial to the adhesion and growth of seed cells can be provided.
The hyaluronic acid/chitosan hydrogel is prepared by mixing 0.3-1.5 wt% of hyaluronic acid solution and 0.3-4 wt% of chitosan or chitosan derivative solution, and performing electronic self-assembly to obtain the three-dimensional hydrogel.
The molecular weight MW of the chitosan is less than 10000, the deacetylation degree is more than 85%, the water solubility is more than 99%, and the viscosity is less than 100.0 mpa.s; the chitosan derivative is one or more of chitosan lactate, water-soluble chitosan and carboxymethyl chitosan; the molecular weight MW of hyaluronic acid is < 10000.
The degree of deacetylation of the chitosan lactate is more than 85 percent, and the chitosan lactate is 80 meshes; the molecular weight MW of the water-soluble chitosan is less than 10000, the deacetylation degree is more than 98%, the water solubility is more than 99%, and the viscosity is less than 100.0 mpa.s; the degree of substitution of carboxymethyl chitosan is greater than 60%, 80 mesh.
The concentration of the hyaluronic acid solution is 0.5-1.3 wt%; the concentration of the chitosan or chitosan derivative solution is 0.3-2 wt%. The hydrogel is obtained by mixing 0.5 wt% hyaluronic acid aqueous solution and 0.5 wt% chitosan solution or chitosan derivative solution and performing electrostatic force adsorption.
The hydrogel is obtained by mixing 1.2 wt% of hyaluronic acid aqueous solution and 1 wt% of chitosan solution or chitosan derivative solution and obtaining the hydrogel through electrostatic force adsorption.
The hydrogel is obtained by mixing 1.3 wt% of hyaluronic acid aqueous solution and 2 wt% of chitosan solution or chitosan derivative solution and obtaining the hydrogel through electrostatic force adsorption.
The invention discloses a preparation method of hyaluronic acid/chitosan hydrogel, which comprises the following steps:
dissolving hyaluronic acid powder in water to obtain 0.3-1.5 wt% hyaluronic acid solution; preparing 0.3-4 wt% of chitosan or chitosan derivative solution;
mixing hyaluronic acid solution and chitosan or chitosan derivative solution, and obtaining the viscous hyaluronic acid/chitosan hydrogel through electrostatic force action.
The preferred mode of the above preparation method is as follows:
the hyaluronic acid solution specifically comprises: dissolving hyaluronic acid powder in sterilized deionized water, oscillating at room temperature, filtering with a 0.2-0.25 μm filter membrane to obtain 0.3-1.5 wt% hyaluronic acid solution, and refrigerating at 4 deg.C;
the chitosan solution is 0.3-4 wt% of chitosan aqueous solution prepared by dissolving chitosan powder in acetic acid aqueous solution and is refrigerated at 4 ℃; wherein the concentration of the aqueous acetic acid solution is 1 wt%.
The chitosan derivative solution is prepared by dissolving chitosan derivative powder into sterile deionized water and oscillating;
the chitosan derivative aqueous solution is prepared by dissolving chitosan lactate powder into sterile deionized water to prepare 0.3-4 wt% of chitosan lactate solution, and refrigerating at 4 ℃;
the chitosan derivative aqueous solution is prepared by dissolving water-soluble chitosan powder into sterile deionized water to prepare 0.3-4 wt% of water-soluble chitosan solution, and refrigerating at 4 ℃.
The volume ratio of the hyaluronic acid solution to the water-soluble chitosan solution or the chitosan or chitosan derivative solution is 1: 1.
The invention provides application of the hyaluronic acid/chitosan hydrogel in preparation of a cartilage repair material.
Advantageous effects
(1) The hydrogel prepared by the invention can be prepared into injectable hyaluronic acid/chitosan hydrogel by respectively injecting hyaluronic acid solution and chitosan solution into an affected part in vivo and then forming gel through electrostatic self-assembly after contacting, or mixing hyaluronic acid solution and chitosan solution in vitro to form flowable gel and then injecting the flowable gel into the body, and the preparation process is simple. The molecular weight of the hyaluronic acid and the chitosan is low, the solution basically has no viscosity after being dissolved, and the hyaluronic acid solution has low viscosity and good fluidity.
(2) The main raw materials of the invention are hyaluronic acid and chitosan or chitosan derivatives, which are green natural products, the obtaining method is simple, hyaluronic acid can be extracted from animal tissues, chitosan is widely existed in shells of crustaceans and cephalopods in nature, and the hyaluronic acid and the chitosan have good biocompatibility, no sensitization and high safety, and are a research hotspot in the aspect of cartilage repair application;
(3) the preparation method is simple and easy to implement, has low requirements on the dosage of the hyaluronic acid and the chitosan or the chitosan derivative, forms the scaffold gel with the three-dimensional structure by combining the hyaluronic acid and the chitosan or the chitosan derivative through electrostatic force, has no cytotoxicity, can provide an environment beneficial to cell adhesion growth, does not need a cross-linking agent in the reaction process, and is green and safe.
Drawings
FIG. 1 is a gel form of examples 1-9; wherein, A: example 1; b: example 2; c: example 3; d: example 4; e: example 5; f: example 6; g: example 7; h: example 8; i: example 9.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and such equivalents may fall within the scope of the present invention as defined in the appended claims.
Example 1
(1) Dissolving 200mg hyaluronic acid powder (molecular weight MW <10000, available from Ci-an Wan Fang technology Co., Ltd.) in sterilized deionized water 40m L, oscillating at room temperature for 1h, and filtering with 0.2-0.25 μm filter membrane to obtain 0.5 wt% hyaluronic acid water solution;
(2) dissolving 200mg chitosan powder (MW <10000, degree of deacetylation > 85%, viscosity <100.0mpa.s, of national drug group chemical agents Co., Ltd.) in 40m L concentration 1 wt% acetic acid aqueous solution to obtain 0.5 wt% chitosan aqueous solution, and shaking at room temperature for 1 h;
(3) sucking 3m L aqueous solution of hyaluronic acid 0.5 wt% obtained in step (1), and mixing with chitosan aqueous solution 0.5 wt% obtained in step (2) 3m L to obtain gel.
Example 2
(1) Dissolving 200mg hyaluronic acid powder (molecular weight MW <10000, available from Ci-an Wan Fang technology Co., Ltd.) in sterilized deionized water 40m L, oscillating at room temperature for 1h, and filtering with 0.2-0.25 μm filter membrane to obtain 0.5 wt% hyaluronic acid water solution;
(2) dissolving 200mg of water-soluble chitosan powder (80 mesh, degree of deacetylation > 85% by Shandong Onkang Biotechnology Co., Ltd.) in 40m L deionized water solution to obtain 0.5 wt% water-soluble chitosan water solution, and oscillating at room temperature for 1 h;
(3) sucking 3m L aqueous solution of hyaluronic acid 0.5 wt% obtained in step (1), and mixing with 3m L aqueous solution of water-soluble chitosan 0.5 wt% obtained in step (2), to obtain gel.
Example 3
(1) Dissolving 200mg hyaluronic acid powder (molecular weight MW <10000, available from Ci-an Wan Fang technology Co., Ltd.) in sterilized deionized water 40m L, oscillating at room temperature for 1h, and filtering with 0.2-0.25 μm filter membrane to obtain 0.5 wt% hyaluronic acid water solution;
(2) dissolving 200mg of chitosan lactate powder (Shandong Onkang Biotechnology Co., Ltd., deacetylation degree > 85.0%, viscosity <200mpa.s) in 40m L deionized water solution to obtain 0.5 wt% chitosan lactate aqueous solution, and shaking at room temperature for 1 h;
(3) sucking 3m L aqueous solution of hyaluronic acid 0.5 wt% obtained in step (1), and mixing with chitosan lactate aqueous solution 0.5 wt% obtained in step (2) 3m L to obtain gel.
Example 4
(1) Dissolving 480mg hyaluronic acid powder (molecular weight MW <10000, Ci' an Wan Fang technology Co., Ltd.) in sterilized deionized water 40m L, and shaking at room temperature for 1h to obtain 1.2 wt% hyaluronic acid aqueous solution;
(2) dissolving 400mg chitosan powder (national drug group chemical reagent Co., Ltd., molecular weight MW <10000, degree of deacetylation > 85%, viscosity <100.0mpa.s) in 40m L concentration 1 wt% acetic acid aqueous solution to obtain 1 wt% chitosan aqueous solution, and oscillating for 1 h;
(3) sucking 3m L aqueous solution of hyaluronic acid 1.2 wt% obtained in step (1), and mixing with 3m L aqueous solution of chitosan 1 wt% obtained in step (2) to obtain gel.
Example 5
(1) Dissolving 480mg hyaluronic acid powder (molecular weight MW <10000, Ci' an Wan Fang technology Co., Ltd.) in sterilized deionized water 40m L, and shaking at room temperature for 1h to obtain 0.5 wt% hyaluronic acid aqueous solution;
(2) dissolving 400mg of water-soluble chitosan powder (80 mesh, degree of deacetylation > 85% by Shandong Onkang Biotechnology Co., Ltd.) in 40m L deionized water solution to obtain 1 wt% water-soluble chitosan water solution, and oscillating at room temperature for 1 h;
(3) sucking 3m L aqueous solution of hyaluronic acid 1.2 wt% obtained in step (1), and mixing with 3m L aqueous solution of water-soluble chitosan 1 wt% obtained in step (2), to obtain gel.
Example 6
(1) Dissolving 480mg hyaluronic acid powder (molecular weight MW <10000, Ci' an Wan Fang technology Co., Ltd.) in sterilized deionized water 40m L, and shaking at room temperature for 1h to obtain 1.2 wt% hyaluronic acid aqueous solution;
(2) dissolving 400mg of chitosan lactate powder (Shandong Onkang Biotechnology Co., Ltd., deacetylation degree > 85.0%, viscosity <200mpa.s) in 40m L deionized water solution to obtain 1 wt% chitosan lactate aqueous solution, and shaking at room temperature for 1 h;
(3) sucking 3m L of the 1.2 wt% hyaluronic acid aqueous solution obtained in step (1), and mixing with 3m L of the 1 wt% chitosan lactate aqueous solution obtained in step (2), to obtain gel.
Example 7
(1) Dissolving 520mg hyaluronic acid powder (molecular weight MW <10000, Ci' an Wan Fang technology Co., Ltd.) in sterilized deionized water 40m L, and shaking at room temperature for 1h to obtain 1.3 wt% hyaluronic acid aqueous solution;
(2) dissolving 800mg chitosan powder (national drug group chemical reagent Co., Ltd., molecular weight MW <10000, degree of deacetylation > 85%, viscosity <100.0mpa.s) in 40m L concentration 1 wt% acetic acid aqueous solution to obtain 2 wt% chitosan aqueous solution, and oscillating for 1 h;
(3) sucking 3m L aqueous solution of hyaluronic acid 1.3 wt% obtained in step (1), and mixing with chitosan aqueous solution 2 wt% obtained in step (2) 3m L to obtain gel.
Example 8
(1) Dissolving 520mg hyaluronic acid powder (molecular weight MW <10000, Ci' an Wan Fang technology Co., Ltd.) in sterilized deionized water 40m L, and shaking at room temperature for 1h to obtain 1.3 wt% hyaluronic acid aqueous solution;
(2) dissolving 800mg of water-soluble chitosan powder (80 mesh, deacetylation degree > 85% by Shandong Onkang Biotechnology Co., Ltd.) in 40m L deionized water solution to obtain 2 wt% water-soluble chitosan water solution, and oscillating at room temperature for 1 h;
(3) sucking 3m L aqueous solution of hyaluronic acid 1.3 wt% obtained in step (1), and mixing with aqueous solution of water-soluble chitosan 2 wt% obtained in step (2) 3m L to obtain gel.
Example 9
(1) Dissolving 520mg hyaluronic acid powder (molecular weight MW <10000, Ci' an Wan Fang technology Co., Ltd.) in sterilized deionized water 40m L, and shaking at room temperature for 1h to obtain 1.3 wt% hyaluronic acid aqueous solution;
(2) dissolving 800mg of chitosan lactate powder (Shandong Onkang Biotechnology Co., Ltd., deacetylation degree > 85.0%, viscosity <200mpa.s) in 40m L deionized water solution to obtain 2 wt% chitosan lactate aqueous solution, and shaking at room temperature for 1 h;
(3) sucking 3m L of the 1.3 wt% hyaluronic acid aqueous solution obtained in step (1), and mixing with 3m L of the 2 wt% chitosan lactate aqueous solution obtained in step (2), to obtain gel.
Example 10
(1) 480mg of hyaluronic acid powder is dissolved in 40m L sterilized deionized water, and the solution is shaken for 1 hour at room temperature to obtain 1.2 wt% hyaluronic acid aqueous solution;
(2) dissolving 400mg carboxymethyl chitosan powder (degree of substitution > 60%, 80 mesh, Shandong Okang Biotech Co., Ltd.) in 40m L deionized water solution to obtain 1 wt% water-soluble chitosan water solution, and oscillating for 1h at room temperature for use;
(3) a1.2 wt% hyaluronic acid aqueous solution obtained in the step (1) of 3m L was sucked and mixed with a 1 wt% carboxymethyl chitosan aqueous solution obtained in the step (2) of 3m L, no reaction occurred, and no gel was obtained.
As shown in fig. 1-a, the gel form formed after the hyaluronic acid aqueous solution with the concentration of 0.5 wt% and the chitosan solution are contacted is formed, and the hyaluronic acid and the chitosan are combined into white floccule with dispersibility by electrostatic force after being contacted, and the floccule has no viscosity.
As shown in FIG. 1-B, the gel form is formed after the 0.5 wt% hyaluronic acid solution and the 0.5 wt% water-soluble chitosan solution are contacted, the hyaluronic acid and the water-soluble chitosan are combined into white aggregates through electrostatic force after being contacted, most of the internal water is released, and the gel form has viscosity.
As shown in FIG. 1-C, the gel form is formed after the contact of 0.5 wt% hyaluronic acid aqueous solution and 0.5 wt% chitosan lactate solution, the hyaluronic acid and the chitosan lactate are combined into white aggregates through electrostatic force after the contact, most of the internal water is released, and the gel form has viscosity.
As shown in FIG. 1-D, the gel form is formed after 1.2 wt% hyaluronic acid solution and 1 wt% chitosan solution contact, when hyaluronic acid and chitosan contact, a layer of film is formed, after oscillation, hyaluronic acid is wrapped by the film to form vesicles, and the vesicle film has high strength and is not easy to break and has no viscosity.
As shown in FIG. 1-E, the gel form formed by contacting 1.2 wt% hyaluronic acid aqueous solution and 1 wt% water-soluble chitosan solution is mostly white agglomerates, and the small part is vesicles wrapping hyaluronic acid, and the vesicle membrane is fragile and sticky.
As shown in FIG. 1-F, the gel form formed after the contact between the 1.2 wt% hyaluronic acid aqueous solution and the 1 wt% chitosan lactate solution is mainly vesicles wrapping hyaluronic acid, the vesicle membrane has small strength and is easy to break, and the internal hyaluronic acid escapes and then is combined with the chitosan lactate to form floccules without viscosity.
As shown in FIG. 1-G, the gel form formed by contacting 1.3 wt% hyaluronic acid solution and 2 wt% chitosan solution is mainly vesicles wrapping hyaluronic acid, and the vesicle membrane has high strength, is not easy to break, and has no viscosity.
As shown in FIG. 1-H, the gel form formed by contacting 1.3 wt% hyaluronic acid aqueous solution and 2 wt% water-soluble chitosan solution is mainly white agglomerates, and the small part is vesicles wrapping hyaluronic acid, wherein the vesicle membrane is fragile, the hyaluronic acid in the vesicle is released and then combined with water-soluble chitosan to form floccules with viscosity.
As shown in figure 1-I, the gel form formed after the contact of 1.3 wt% hyaluronic acid aqueous solution and 2 wt% chitosan lactate solution is mainly vesicles wrapping hyaluronic acid, the vesicle membrane has small strength and is easy to break, and the internal hyaluronic acid escapes and then is combined with the chitosan lactate to form floccules without viscosity.
Claims (10)
1. The hyaluronic acid/chitosan hydrogel is characterized in that a hyaluronic acid solution in an amount of 0.3-1.5 wt% and a chitosan or chitosan derivative solution in an amount of 0.3-4 wt% are mixed, and electronic self-assembly is performed to obtain a three-dimensional hydrogel; the chitosan derivative is one or more of chitosan lactate, water-soluble chitosan and carboxymethyl chitosan.
2. The hydrogel of claim 1, wherein the chitosan has a molecular weight MW <10000, a degree of deacetylation > 85%, and a viscosity <100.0 mpa.s; the molecular weight MW of hyaluronic acid is < 10000.
3. The hydrogel of claim 2, wherein the chitosan lactate has a degree of deacetylation > 85%, 80 mesh; the molecular weight MW of the water-soluble chitosan is less than 10000, the deacetylation degree is more than 98%, the water solubility is more than 99%, and the viscosity is less than 100.0 mpa.s; the degree of substitution of carboxymethyl chitosan is greater than 60%, 80 mesh.
4. The hydrogel according to claim 1, wherein the hyaluronic acid solution has a concentration of 0.5 to 1.3 wt%; the concentration of the chitosan or chitosan derivative solution is 0.3-2 wt%.
5. The hydrogel according to claim 1, which is obtained by mixing 0.5 wt% hyaluronic acid aqueous solution and 0.5 wt% chitosan solution or chitosan derivative solution, and is obtained by electrostatic force adsorption.
6. The hydrogel according to claim 1, which is obtained by mixing a 1.2 wt% aqueous solution of hyaluronic acid and a 1 wt% chitosan solution or chitosan derivative solution, and is obtained by electrostatic force adsorption.
7. The hydrogel according to claim 1, which is obtained by mixing 1.3 wt% aqueous hyaluronic acid solution and 2 wt% chitosan solution or chitosan derivative solution, and is obtained by electrostatic force adsorption.
8. A method of preparing a hyaluronic acid/chitosan hydrogel, comprising:
dissolving hyaluronic acid powder in water to obtain 0.3-1.5 wt% hyaluronic acid solution; preparing 0.3-4 wt% of chitosan or chitosan derivative solution;
mixing hyaluronic acid solution and chitosan or chitosan derivative solution, and obtaining the viscous hyaluronic acid/chitosan hydrogel through electrostatic force action.
9. The method according to claim 8, wherein the hyaluronic acid solution is selected from the group consisting of: dissolving hyaluronic acid powder in sterilized deionized water, oscillating at room temperature, and filtering with 0.2-0.25 μm filter membrane; the chitosan solution is prepared by dissolving chitosan powder in acetic acid aqueous solution; the chitosan derivative solution is prepared by dissolving chitosan derivative powder into sterile deionized water and oscillating; the volume ratio of the hyaluronic acid solution to the chitosan or chitosan derivative solution is 1: 1.
10. Use of the hyaluronic acid/chitosan hydrogel of claim 1 for the preparation of a cartilage repair material.
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