Polyvinyl alcohol reinforced carboxymethyl chitosan hydrogel, preparation method and application thereof

Abstract

The application provides a polyvinyl alcohol reinforced carboxymethyl chitosan hydrogel and a preparation method and application thereof, and the method comprises the following steps: S1, uniformly mixing boric acid, deionized water and aldehyde-modified hyaluronic acid according to a proportion of 0.2g:100mL:3g to obtain a mixed solution A; uniformly mixing polyvinyl alcohol, deionized water and carboxymethyl chitosan according to a proportion of (5-8)g:100mL:2g to obtain a mixed solution B; S2, uniformly mixing the mixed solution A and the mixed solution B according to a volume ratio of 1:10 to obtain a mixed system, and then naturally cooling and shaping the mixed system at room temperature to obtain the polyvinyl alcohol reinforced carboxymethyl chitosan hydrogel. The application solves the problems of poor cell compatibility, poor mechanical property, poor pH responsiveness, poor self-healing performance, poor drug loading capacity and poor drug release effect caused by the non-uniform internal structure of the current hydrogel.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials and relates to a polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogel, its preparation method, and its application. Background Technology

[0002] Aspirin, as a drug that promotes human health, is mainly used as an antipyretic, analgesic, and antirheumatic drug. At low doses, it has a good antithrombotic effect and can be used for the treatment and prevention of cardiovascular diseases. However, ordinary aspirin, after being hydrolyzed into salicylic acid in the body, has an irritating effect on the gastrointestinal mucosa. In order to reduce the frequency of medication for patients, reduce adverse gastrointestinal reactions, improve the bioavailability of the drug, and adapt to the complex pH environment of the human body, the development of suitable high-performance drug carrier materials for application in the biomedical field has become a problem that needs to be solved.

[0003] Hydrogels have many advantages and are considered one of the most promising drug delivery carriers. For example, they are formed through a three-dimensional polymer chain network of physical or chemical cross-links and have a rich macroporous structure. This macroporous structure gives them water-swellable properties, and the swelling process is the drug release process, making them suitable as carrier materials for controlled drug delivery. In addition, they have morphological properties similar to the natural extracellular matrix (ECM), providing a suitable support medium for cell growth and a suitable environment for drug delivery.

[0004] Currently, Chinese patent CN106750398A, entitled "Drug-loaded Chitosan / Sodium Alginate Dual Crosslinked Hydrogel and its Preparation and Application," discloses a hydrogel that can be prepared into biomaterials by sequentially crosslinking chitosan and sodium alginate. Chinese patent CN111317709A, entitled "An Injectable Dual-Drug-Loaded Composite Chitosan Hydrogel and its Preparation Method," describes a hydrogel comprising chitosan solution / liposomes / antibiotics / hydroxyapatite, obtained by crosslinking with calcium ions and glutaraldehyde. Chinese patent CN106729960B, entitled "A Chitosan-based Hydrogel Composite Dressing Loaded with Kaempferol and its Preparation Method," mentions using pentylene glycol to crosslink chitosan / polyvinyl alcohol acrylic acid to obtain a hydrogel film. Chinese patent CN114685815A, entitled "A Polyvinyl Alcohol / Carboxymethyl Chitosan / Nano Silver Dual-Network Hydrogel with Antibacterial Effect and its Preparation Method," describes using the photoinitiator genipin for crosslinking and curing to obtain carboxymethyl chitosan / polyvinyl alcohol / nano silver. However, in addition to adding some toxic cross-linking agents during the hydrogel formation process, these materials also suffer from poor cell compatibility, poor mechanical properties, poor pH responsiveness, poor self-healing properties, and poor drug loading capacity due to uneven internal structure. Summary of the Invention

[0005] To overcome the shortcomings of the prior art, this invention provides a polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogel, its preparation method, and its application. Aldehyde-modified hyaluronic acid and boric acid are used as crosslinking agents, which solves the problems of poor cell compatibility, poor mechanical properties, poor pH response, poor self-healing properties, poor drug loading capacity, and poor drug release effect caused by uneven internal structure of current hydrogels.

[0006] To achieve the above objectives, the present invention employs the following technical solution:

[0007] A method for preparing polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogel includes the following steps:

[0008] S1, mix boric acid, deionized water and aldehyde-modified hyaluronic acid evenly in a ratio of 0.2g:100mL:3g to obtain mixture A;

[0009] Polyvinyl alcohol, deionized water and carboxymethyl chitosan were mixed evenly in a ratio of (5-8)g:100mL:2g to obtain mixture B;

[0010] S2, mix mixture A and mixture B at a volume ratio of 1:10 to obtain a mixed system. Then, allow the mixed system to cool naturally at room temperature to form a polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogel.

[0011] Preferably, the aldehyde-modified hyaluronic acid described in S1 is obtained by the following process:

[0012] A 0.3M sodium periodate solution was added to a 10 mg / mL hyaluronic acid solution, with a volume ratio of 100:(5-10). The reaction was carried out at room temperature in the dark for 2-6 hours, and then ethylene glycol was added to stop the reaction, resulting in a reaction solution. The reaction solution was then dialyzed and freeze-dried to obtain aldehyde-modified hyaluronic acid.

[0013] Furthermore, the reaction solution of S1 was dialyzed with deionized water for 48-96 hours, with the deionized water being replaced every 12 hours, and finally freeze-dried.

[0014] Furthermore, the freeze-drying described in S1 is carried out at a temperature of -50°C to -30°C for 40-48 hours.

[0015] Preferably, in step S1, the aldehyde-modified hyaluronic acid is dissolved in an aqueous solution of boric acid to obtain mixture A.

[0016] Preferably, in step S1, the polyvinyl alcohol is first dissolved in deionized water at 85-95°C, and then carboxymethyl chitosan is added and stirred until completely dissolved to obtain mixture B.

[0017] Preferably, in step S2, mixture A is added to mixture B, and then stirred for 1-5 minutes to obtain a mixed system.

[0018] Preferably, S2 stirs mixture A and mixture B at 25-37°C, and the resulting mixture is naturally cooled and formed in a mold.

[0019] A polyvinyl alcohol reinforced carboxymethyl chitosan hydrogel obtained by the preparation method of any one of the above-described polyvinyl alcohol reinforced carboxymethyl chitosan hydrogels.

[0020] Application of polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogel in loaded aspirin.

[0021] Compared with the prior art, the present invention has the following beneficial technical effects:

[0022] This invention discloses a method for preparing polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogel. Using carboxymethyl chitosan and polyvinyl alcohol as the base material, and aldehyde-modified hyaluronic acid and boric acid as crosslinking agents, a hydrogel with good biocompatibility, good mechanical properties, good pH responsiveness, good self-healing properties, and high drug loading capacity is prepared. Hyaluronic acid is a natural non-sulfated mucopolysaccharide and a major component of glycosaminoglycans in the human extracellular matrix. It is widely distributed in the extracellular matrix of connective tissues and various organs, thus exhibiting excellent cell compatibility, biodegradability, non-immunogenicity, and good gelling ability. Studies have shown that hydrogels formed by a single dynamic covalent bond often fail to meet the requirements of drug delivery carriers. For example, hydrogels formed by imine and borosilicate bonds have poor mechanical properties, while hydrogels formed by acetal bonds have poor stability. In the reaction system of this invention, these dynamic chemical bonds are combined to obtain dynamic covalent bonds, forming a cross-penetrating double network and a double dynamic chemical cross-linked hydrogel through various mild cross-linking methods. This can alleviate the problems of poor cell compatibility, toxic cross-linking agents, poor mechanical properties, poor self-healing properties, poor pH responsiveness, and poor drug loading capacity and drug release effect caused by the inhomogeneous internal structure of hydrogels. Therefore, the hydrogel prepared by this invention can meet the material and structural requirements of drug delivery carriers.

[0023] This invention discloses a polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogel that is biodegradable in vivo, with non-toxic degradation products, meeting the material and structural requirements of drug delivery carriers. The hydrogel is primarily composed of dynamic covalent bonds of borate ester bonds, acetal bonds, and imine bonds, with synergistic hydrogen bonding. Polyvinyl alcohol is attached to its surface, making the hydrogel a drug delivery carrier with excellent biocompatibility, mechanical properties, controllable pore structure, strong self-healing ability, good pH responsiveness, high drug loading capacity, and sustained drug release performance.

[0024] This invention relates to the application of a polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogel in loading aspirin. Results show that the hydrogel meets the basic performance requirements for drug release. Cytotoxicity studies, reflecting cell viability values, indicate that the hydrogel has good biocompatibility. In vitro drug release experiments demonstrate that the hydrogel has good loading capacity for the target drug, and the release of the drug-loaded hydrogel follows a non-Fick diffusion mechanism. Furthermore, the drug release can be controlled by changing the concentration of polyvinyl alcohol and the pH of the drug release environment. The release process exhibits good pH responsiveness and sustained release behavior; therefore, this hydrogel shows promise as a drug carrier for clinical treatment. Attached Figure Description

[0025] Figure 1 This is a schematic diagram of the structure of the hydrogel prepared by the preparation method described in this invention.

[0026] Figure 2 This is a physical image of the polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogel obtained in Example 2 of the present invention.

[0027] Figure 3 This is a photograph of the self-healing polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogel obtained in Example 2 of the present invention.

[0028] Figure 4a This is a SEM image of the polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogel obtained in Comparative Example 1 of this invention.

[0029] Figure 4b This is a SEM image of the polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogel obtained in Example 1 of this invention.

[0030] Figure 4c This is a SEM image of the polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogel obtained in Example 2 of this invention.

[0031] Figure 4d This is a SEM image of the polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogel obtained in Example 3 of the present invention.

[0032] Figure 5 These are tensile test diagrams of the polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogels obtained in Examples 1-3 and Comparative Example 1 of this invention.

[0033] Figure 6 These are compression test diagrams of the polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogels obtained in Examples 1-3 and Comparative Example 1 of this invention.

[0034] Figure 7 This is a drug loading diagram of the polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogels obtained in Examples 1-3 and Comparative Example 1 of the present invention.

[0035] Figure 8aThis is a diagram showing the drug release at pH=4 after drug loading in polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogels obtained in Examples 1-3 and Comparative Example 1 of this invention.

[0036] Figure 8b The figure shows the drug release at pH 7.4 after the polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogels obtained in Examples 1-3 and Comparative Example 1 of this invention are loaded with drugs.

[0037] Figure 8c The figure shows the drug release at pH=10 after drug loading in the polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogels obtained in Examples 1-3 and Comparative Example 1 of this invention.

[0038] Figure 9 The graph shows the cell proliferation rate of polyvinyl alcohol-enhanced carboxymethyl chitosan hydrogel obtained from the control group, Examples 1-3 and Comparative Example 1 of this invention. Detailed Implementation

[0039] The present invention will be further described in detail below with reference to specific embodiments. These descriptions are for explanation purposes only and are not intended to limit the scope of the invention.

[0040] This invention discloses a method for preparing polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogel, comprising the following steps:

[0041] Step 1: Dissolve a certain amount of hyaluronic acid in 100 ml of deionized water to obtain 100 ml of hyaluronic acid solution with a concentration of 10 mg / mL. Add 5-10 ml of 0.3 M sodium periodate aqueous solution and react at room temperature in the dark for 2-6 hours. Then add ethylene glycol to stop the reaction and continue stirring for 1 hour. Then, dialysis the reaction product to purify it by dialyzing with deionized water for 48-96 hours, changing the deionized water every 12 hours during the dialysis process. Finally, freeze-dry the dialysate in a freeze dryer at -50℃ to -30℃ for 40-48 hours to obtain aldehyde-modified hyaluronic acid.

[0042] The chemical structural formula of aldehyde-modified hyaluronic acid is shown below:

[0043]

[0044] Step 2: Dissolve 3g of the aldehyde-modified hyaluronic acid obtained in Step 1 in 100mL of a 2mg / mL boric acid solution. After complete dissolution, the concentration of boric acid in the entire system is 2mg / mL, and the concentration of the aldehyde-modified hyaluronic acid is 30mg / mL, thus obtaining a boric acid-aldehyde-modified hyaluronic acid aqueous solution.

[0045] Prepare 4 portions using the same method;

[0046] Step 3: Within the range of 85-95℃, dissolve 0g, 2g, 5g, and 8g of polyvinyl alcohol in 100ml of deionized water, respectively, and stir thoroughly until completely dissolved to obtain polyvinyl alcohol aqueous solutions of 0mg / ml, 20mg / ml, 50mg / ml, and 80mg / ml, respectively. Then, weigh out 4 portions of 2g carboxymethyl chitosan and add them to the solutions, and continue stirring until completely dissolved to obtain polyvinyl alcohol-carboxymethyl chitosan solutions of different concentrations.

[0047] Step 4: Add 4 portions of boric acid-aldehyde-modified hyaluronic acid solution to the 4 different polyvinyl alcohol-carboxymethyl chitosan solutions from Step 3 at a volume ratio of 1:10. Stir at 25-37℃ (at the conventional rate) for 1-5 minutes, then place in a mold and allow to cool naturally at room temperature to form polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogel.

[0048] The polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogel described above can be used in drug delivery carriers.

[0049] See Figure 1 Polyvinyl alcohol (PVA) plays a role in enhancing mechanical properties in this network structure. Because PVA contains abundant hydroxyl groups, it forms acetal bonds with the aldehyde groups on the aldehyde-modified hyaluronic acid, hydrogen bonds with carboxymethyl chitosan, and borate ester bonds with boric acid. These hydrogen bonds, acetal bonds, and borate ester bonds interweave within the network structure formed by the aldehyde-modified hyaluronic acid and carboxymethyl chitosan. Simultaneously, the -CHO group on the aldehyde-modified hyaluronic acid reacts with the -NH2 group on the carboxymethyl chitosan through a Schiff base reaction, generating imine bonds. These dynamic chemical bonds combine to form a cross-penetrating network structure, giving the hydrogel good mechanical properties, pH responsiveness, self-healing ability, and high drug loading and release capacity.

[0050] Comparative Example 1

[0051] This invention discloses a method for preparing carboxymethyl chitosan hydrogel, comprising the following steps:

[0052] Step 1: Dissolve 1.0 g of hyaluronic acid in 100 ml of deionized water and mix thoroughly to obtain a hyaluronic acid solution with a concentration of 10 mg / mL. Add 5 ml of 0.3 M sodium periodate aqueous solution dropwise and react the mixture at 25 °C in the dark for 6 hours. Then, add 1 ml of ethylene glycol to stop the reaction and continue stirring for 1 hour. Dialyze the solution with deionized water for 72 hours, changing the deionized water every 12 hours during the dialysis process. Finally, freeze-dry the dialysate in a freeze dryer at -40 °C for 48 hours to obtain aldehyde-modified hyaluronic acid.

[0053] Step 2: Weigh 3g of the aldehyde-modified hyaluronic acid from Step 1 (freeze-dried) and dissolve it in 100mL of a 2mg / mL boric acid solution to obtain a boric acid-aldehyde-modified hyaluronic acid solution.

[0054] Step 3: At 90℃, dissolve 2g of carboxymethyl chitosan in 100ml of deionized water and stir until completely dissolved to obtain a carboxymethyl chitosan solution.

[0055] Step 4: Add the solution obtained in Step 2 to the solution obtained in Step 3 at a volume ratio of 1:10. Stir and react at 37°C for 1 minute, then transfer to a mold and allow to cool naturally at room temperature to form a carboxymethyl chitosan hydrogel.

[0056] Example 1

[0057] This invention discloses a method for preparing polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogel, comprising the following steps:

[0058] Step 1: Dissolve 1.0 g of hyaluronic acid in 100 ml of deionized water and mix thoroughly to obtain a hyaluronic acid solution with a concentration of 10 mg / mL. Add 5 ml of 0.3 M sodium periodate aqueous solution dropwise and react the mixture at 25°C in the dark for 6 hours. Then, add 1 ml of ethylene glycol to stop the reaction and continue stirring for 1 hour. Dialyze the solution with deionized water for 72 hours, changing the deionized water every 12 hours during the dialysis process. Finally, freeze-dry the dialysate at -40°C for 48 hours to obtain aldehyde-modified hyaluronic acid.

[0059] Step 2: Weigh 3g of the aldehyde-modified hyaluronic acid from Step 1 (freeze-dried) and dissolve it in 100mL of a 2mg / mL boric acid solution to obtain a boric acid-aldehyde-modified hyaluronic acid solution.

[0060] Step 3: At 90℃, dissolve 2g of polyvinyl alcohol in 100ml of deionized water to obtain a polyvinyl alcohol aqueous solution with a concentration of 20mg / ml. Add 2g of carboxymethyl chitosan to the solution and stir until completely dissolved to obtain a polyvinyl alcohol-carboxymethyl chitosan solution.

[0061] Step 4: Add the solution obtained in Step 2 to the solution obtained in Step 3 at a volume ratio of 1:10. Stir and react at 37°C for 1 minute, then transfer to a mold and allow to cool naturally at room temperature to form polyvinyl alcohol reinforced carboxymethyl chitosan hydrogel.

[0062] Example 2

[0063] This invention discloses a method for preparing polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogel, comprising the following steps:

[0064] Step 1: Dissolve 1.0 g of hyaluronic acid in 100 ml of deionized water and mix thoroughly to obtain a hyaluronic acid solution with a concentration of 10 mg / mL. Add 5 ml of 0.3 M sodium periodate aqueous solution dropwise and react the mixture at 25°C in the dark for 6 hours. Then, add 1 ml of ethylene glycol to stop the reaction and continue stirring for 1 hour. Dialyze the solution with deionized water for 72 hours, changing the deionized water every 12 hours during the dialysis process. Finally, freeze-dry the dialysate at -40°C for 48 hours to obtain aldehyde-modified hyaluronic acid.

[0065] Step 2: Weigh 3g of the aldehyde-modified hyaluronic acid from Step 1 (freeze-dried) and dissolve it in 100mL of a 2mg / mL boric acid solution to obtain a boric acid-aldehyde-modified hyaluronic acid solution.

[0066] Step 3: At 90℃, dissolve 5g of polyvinyl alcohol in 100ml of deionized water to obtain a polyvinyl alcohol aqueous solution with a concentration of 50mg / ml. Add 2g of carboxymethyl chitosan to the solution and stir until completely dissolved to obtain a polyvinyl alcohol-carboxymethyl chitosan solution.

[0067] Step 4: Add the solution obtained in Step 2 to the solution obtained in Step 3, with a mixing volume ratio of 1:10. Stir and react at 37°C for 1 minute, then transfer to a mold and allow to cool naturally at room temperature to form polyvinyl alcohol reinforced carboxymethyl chitosan hydrogel.

[0068] Figure 2 The image shows a circular sheet formed from hydrogel, which has a relatively complete structure and good elasticity.

[0069] Figure 3 The image shows a self-healing hydrogel. As can be seen from the image, the hydrogel was cut into two identical pieces, one of which was stained with methylene blue. Then, two semicircles of different colors were placed in the original mold for a period of time. After the two cut hydrogel pieces were in contact for 360 minutes, the ends of the stained hydrogel could be clamped and stretched with tweezers without breaking, indicating that the hydrogel has good self-healing properties.

[0070] Figure 4c The image shows a scanning electron microscope (SEM) image of the hydrogel. The SEM reveals that the hydrogel exhibits a uniform porous structure, which enables it to have a high drug loading capacity and sustained drug release capability. (The following...) Figure 7 and Figure 8a , Figure 8b , Figure 8c There are descriptions of hydrogels having high drug loading capacity and sustained drug release capability.

[0071] Example 3

[0072] This invention discloses a method for preparing polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogel, comprising the following steps:

[0073] Step 1: Dissolve 1.0 g of hyaluronic acid in 100 ml of deionized water and mix thoroughly to obtain a hyaluronic acid solution with a concentration of 10 mg / mL. Add 5 ml of 0.3 M sodium periodate aqueous solution dropwise and react the mixture at 25°C in the dark for 6 hours. Then, add 1 ml of ethylene glycol to stop the reaction and continue stirring for 1 hour. Dialyze the solution with deionized water for 72 hours, changing the deionized water every 12 hours during the dialysis process. Finally, freeze-dry the dialysate at -40°C for 48 hours to obtain aldehyde-modified hyaluronic acid.

[0074] Step 2: Dissolve 3g of the aldehyde-modified hyaluronic acid that was freeze-dried in Step 1 in 100mL of a 2mg / mL boric acid solution to obtain a boric acid-aldehyde-modified hyaluronic acid solution.

[0075] Step 3: At 90℃, dissolve 8g of polyvinyl alcohol in 100ml of deionized water to obtain a polyvinyl alcohol aqueous solution with a concentration of 80mg / ml. Add 2g of carboxymethyl chitosan to the solution and stir until completely dissolved to obtain a polyvinyl alcohol-carboxymethyl chitosan solution.

[0076] Step 4: Add the solution obtained in Step 2 to the solution obtained in Step 3 at a volume ratio of 1:10. Stir and react at 37°C for 1 minute, then transfer to a mold and allow to cool naturally at room temperature to form polyvinyl alcohol reinforced carboxymethyl chitosan hydrogel.

[0077] Figure 5 Tensile testing and Figure 6 The compression test was performed using a universal testing machine at sensor values ​​of 500 N and 3000 N, with a speed of 5 mm / min, yielding stress-tensile strain curves and stress-compressive strain curves. Comparative Example 1, Example 1, Example 2, and Example 3 represent polyvinyl alcohol concentrations of 0 mg / ml, 20 mg / ml, 50 mg / ml, and 80 mg / ml, respectively. Figure 5 and Figure 6 As can be seen, with the increase of polyvinyl alcohol concentration, the stress-tensile strain curve and stress-compressive strain curve of the hydrogel show an upward trend, indicating that the addition of polyvinyl alcohol has a significant improvement on the tensile and compressive properties of the hydrogel material.

[0078] See Figure 7Comparative Example 1, Example 1, Example 2, and Example 3 represent hydrogels synthesized with polyvinyl alcohol concentrations of 0 mg / ml, 20 mg / ml, 50 mg / ml, and 80 mg / ml, respectively. Aspirin was loaded onto the hydrogels via solvent adsorption. The specific process is as follows: First, a series of aspirin solutions of different masses were accurately weighed and dissolved in PBS solution at pH 7.4 to obtain aspirin solutions with concentrations of 5 μg / ml, 8 μg / ml, 10 μg / ml, 20 μg / ml, 25 μg / ml, 40 μg / ml, 50 μg / ml, 80 μg / ml, 100 μg / ml, 160 μg / ml, and 200 μg / ml, respectively. The absorbance at 296 nm was measured, and the standard curve of the aspirin solution was calculated. The freeze-dried hydrogel sample was then immersed in an aspirin solution with a concentration of 200 μg / ml obtained according to the above procedure and stored at room temperature until the hydrogel reached maximum expansion. The expanded hydrogel sample was then removed, and the absorbance of the aspirin solution after removing the expanded hydrogel sample was measured at 296 nm using a UV spectrophotometer. The residual aspirin content in the aspirin solution was calculated based on the standard curve of the aspirin solution. The difference between the initial and residual values ​​was determined by the amount of aspirin loaded onto the hydrogel. Finally, the aspirin-loaded hydrogel was freeze-dried to obtain the aspirin-loaded hydrogel sample. As shown in the figure, the aspirin loading capacity of the hydrogel at different polyvinyl alcohol concentrations all exceeded 105 mg / g, indicating that the hydrogel has a good aspirin loading capacity. However, as the polyvinyl alcohol concentration increased, the aspirin loading gradually decreased. This is because when the polyvinyl alcohol concentration was 0 mg / ml and 20 mg / ml, the hydrogel had a lower degree of cross-linking and a larger internal pore size (see...). Figure 4a and Figure 4b Therefore, drug molecules are more easily loaded into it, resulting in higher drug loading at low polyvinyl alcohol concentrations (0 mg / ml and 20 mg / ml). At a polyvinyl alcohol concentration of 50 mg / ml, the internal pore structure is uniform (…). Figure 4c As the PVA concentration increased to 80 mg / ml, the integrity and size of the internal pore structure of the hydrogel gradually deteriorated. Figure 4d This is not conducive to drug release.

[0079] Combination Figure 5 , Figure 6It can be seen that the mechanical properties (tensile and compressive properties) of polyvinyl alcohol at concentrations of 0 mg / ml and 20 mg / ml are relatively low, failing to meet the requirements for use as a drug carrier. At a polyvinyl alcohol concentration of 80 mg / ml, the presence of numerous hydroxyl groups hinders cross-linking between other substances, leading to incomplete and uneven cross-linking, and a decrease in the tensile and compressive properties of the hydrogel. The highest tensile and compressive properties are achieved at a polyvinyl alcohol concentration of 50 mg / ml, with a uniform internal pore structure and a drug loading of 117.54 mg / g, making it more suitable as a carrier for the release of aspirin.

[0080] Figure 8a , Figure 8b , Figure 8c The hydrogels prepared in Examples 1-3 and Comparative Example 1 were demonstrated to exhibit sustained drug release behavior at pH 4, 7.4, and 10, respectively, with drug release occurring in a water bath shaker at 37°C and 120 rpm. Aspirin-loaded hydrogels were placed in PBS solutions at pH 4, 7.4, and 10. Every one hour, 2 ml of the released mixture was taken, and the amount of aspirin released was determined by UV spectroscopy. Simultaneously, 2 ml of PBS solution was added to maintain a constant solution volume. Due to the very rapid hydrolysis rate of imine and acetal bonds in acidic environments, the highest drug release rate was observed at pH 4, followed by pH 7.4 and pH 10.

[0081] Figure 9 The proliferation of mouse fibroblasts (L929) was observed using the MTT direct contact method. It can be seen that the cell viability values ​​of the experimental group with the hydrogel of this invention added after 1, 3 and 5 days of cell culture were not significantly different from those of the control group without the hydrogel of this invention, indicating that the hydrogel has good biocompatibility.

Claims

1. The application of a polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogel in loaded aspirin, characterized in that, Aspirin is loaded onto the hydrogel using a solvent adsorption method, wherein a PBS solution with pH=7.4 is used to dissolve the aspirin. The preparation method of the hydrogel includes the following steps: S1. Add a 0.3 M sodium periodate solution to a 10 mg / mL hyaluronic acid solution, wherein the volume ratio of the hyaluronic acid solution to the sodium periodate solution is 100:(5-10). After reacting at room temperature in the dark for 2-6 h, add ethylene glycol to stop the reaction and obtain a reaction solution. Then, dialyze the reaction solution with deionized water for 48-96 h, changing the deionized water every 12 h. Then freeze-dry at -50℃ to -30℃ for 40-48 h to obtain aldehyde-modified hyaluronic acid. Dissolve the aldehyde-modified hyaluronic acid in an aqueous solution of boric acid, wherein the ratio of boric acid, deionized water and aldehyde-modified hyaluronic acid is 0.2 g:100 mL:3 g, to obtain mixture A. At 85-95℃, the polyvinyl alcohol was first dissolved in deionized water, and then carboxymethyl chitosan was added and stirred until completely dissolved. The ratio of polyvinyl alcohol, deionized water and carboxymethyl chitosan was (5-8) g: 100 mL: 2 g, to obtain mixture B. S2, add mixture A to mixture B at a volume ratio of 1:10, and stir at 25-37℃ for 1-5 minutes to obtain a mixed system. Then, allow the mixed system to cool naturally in a mold at room temperature to form a polyvinyl alcohol-reinforced carboxymethyl chitosan hydrogel.

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