Semi-crosslinked network hydrogel based on supergiant glycosaminoglycan Sacran and preparation and application thereof

Abstract

The invention relates to the technical field of polymer hydrogel, in particular to biological bionic design of semi-crosslinked network hydrogel based on supergiant glycosaminoglycan Sacran and application of the hydrogel to sustained-release drugs. The hydrogel material is formed by copolymerization of a polyacrylic acid network, super-huge glycosaminoglycan Sacran and chondroitin sulfate. The hydrogel material prepared by the invention has good water absorption, mechanical strength, oxidation resistance, antibacterial property and excellent cell compatibility, and can control the slow release of cationic drugs through pH or time. And the preparation method is simple, efficient, environment-friendly, low in equipment requirement and easy to industrialize.

Description

Technical Field

[0001] The present invention relates to the technical field of polymer hydrogels, and in particular to a semi-crosslinked network hydrogel material based on supergiant glycosaminoglycan and applications thereof. Background Art

[0002] Glycosaminoglycans (GAGs) are a class of long-chain negatively charged polysaccharide molecules that are widely present in the extracellular matrix and cell surfaces of animals. GAGs are negatively charged and form proteoglycans by covalently binding to proteins in core proteins, ultimately forming giant aggregates. They play a key role in maintaining tissue structure, regulating cell signals, and mediating physiological functions.

[0003] Sacran is an ultra-high molecular weight anionic polysaccharide (molecular weight over 10 7 Da, containing about 10 5 The presence of hydroxyl, carboxylic acid and sulfate groups makes its structure similar to GAG, and it belongs to glycosaminoglycan-like substances. Sacran, as a naturally derived polymer material, has high hydration capacity and good biocompatibility.

[0004] Berberine (BBR) is a quaternary ammonium isoquinoline alkaloid nitrogen compound with broad-spectrum pharmacological activity. It is a core drug in traditional Chinese medicine for the treatment of diarrhea and gastroenteritis. However, its clinical application is limited by its poor water solubility, limited intestinal absorption, and low oral bioavailability due to rapid metabolism. These limitations result in only trace amounts of the drug entering the systemic circulation during clinical use, severely limiting the therapeutic efficacy of oral administration of this drug.

[0005] Hydrogels are materials with three-dimensional network structures formed by physical or chemical crosslinking. They possess excellent hydrophilicity and can fully swell in water without dissolving. In recent years, their application in a variety of fields, including drug delivery, tissue engineering, and wound dressings, has garnered widespread attention. Due to their excellent biocompatibility, tunable hydration, and superior mechanical properties, hydrogels have gained widespread application in the pharmaceutical field, particularly in sustained-release drug systems. However, conventional hydrogel drug delivery systems suffer from issues such as overly rapid or slow drug release, which can affect therapeutic efficacy. Furthermore, existing hydrogels also have deficiencies in their antibacterial and antioxidant properties, which directly impact their stability and efficacy in vivo. In particular, in drug-loaded systems, the hydrophilicity, swelling properties, and zwitterionic properties of the hydrogel surface can significantly reduce bacterial adsorption while enhancing their antioxidant and antibacterial properties, thereby extending the drug's shelf life and improving its bioavailability.

[0006] In order to effectively control the release rate of drugs, it is crucial to develop hydrogel materials with tunable swelling properties and biocompatibility. Summary of the Invention

[0007] To overcome the uncontrollable release rate and insufficient stability of existing hydrogel drug-release systems, the present invention provides a semi-crosslinked network hydrogel material based on the supergiant glycosaminoglycan Sacran. This hydrogel material exhibits excellent water absorption, high mechanical strength, antioxidant and antibacterial properties, and excellent cytocompatibility. It can control the slow release of drugs by pH or time, ensuring sustained and stable drug release in vivo.

[0008] The invention provides a semi-crosslinked network hydrogel material based on supergiant glycosaminoglycan Sacran. The material is formed by free radical polymerization of a polyacrylic acid network, supergiant glycosaminoglycan Sacran and chondroitin sulfate.

[0009] The first aspect of the present invention provides a semi-crosslinked network hydrogel drug delivery system, wherein the hydrogel material is mainly composed of a polyacrylic acid network and copolymerized with supergiant glycosaminoglycan Sacran and chondroitin sulfate.

[0010] Furthermore, the semi-cross-linked network hydrogel material is formed by copolymerization of a polyacrylic acid network, supergiant glycosaminoglycan Sacran and chondroitin sulfate, wherein the polyacrylic acid network provides the mechanical strength and stability of the hydrogel, the supergiant glycosaminoglycan Sacran gives the material good biocompatibility and high water absorption properties, and chondroitin sulfate further improves the biocompatibility and drug loading capacity of the material.

[0011] The unique properties of Sacran can significantly improve the structure and performance of hydrogels. In the field of drug sustained release, Sacran can effectively control drug release and prolong the drug release time through its hydrophilicity and physical cross-linking structure. 4 The anions distributed along the main chain (order of magnitude) form a negative potential well similar to that of GAG aggregates; the semi-IPN hydrogel containing Sacran has significant cationic regulation ability.

[0012] The second aspect of the present invention provides a method for preparing the semi-crosslinked network hydrogel drug delivery system, which specifically comprises the following steps:

[0013] S1. A mixed solution containing Sacran, acrylic acid monomer, chondroitin sulfate, a crosslinker, an initiator, and a co-initiator is prepared;

[0014] S2 preparation of pre-liquid: the mixed solution obtained in step S1 was deoxygenated and the pre-liquid was obtained after removing bubbles;

[0015] S3. Drug loading: Add the drug to the pre-liquid obtained in step S2, and after the cross-linking reaction is completed, wash and dry to obtain the drug-loaded hydrogel material.

[0016] Furthermore, in step S1, the preparation process is to dissolve Sacran, acrylic acid, a cross-linking agent and an initiator / coinitiator in a solvent and then stir them evenly, and the solvent is water.

[0017] In some embodiments, in step S1, the mass concentration of Sacran is 0.1-0.3 wt%; the mass concentration of acrylic acid monomer is 12-28 wt%;

[0018] Furthermore, the mass concentration of the chondroitin sulfate is 0.5-2 wt %, preferably 1 wt %.

[0019] In some embodiments, in step S1, the mass concentration of the cross-linking agent is: 0.5 to 1.5 wt%;

[0020] Furthermore, the mass concentration of the initiation system is 0.2-0.4 wt %, preferably 0.3 wt %.

[0021] In a preferred embodiment, the initiation system comprises an initiator and a co-initiator;

[0022] In some embodiments, in step S1, the cross-linking agent is ethylene glycol dimethacrylate; in a preferred embodiment, the cross-linking agent is ethylene glycol dimethacrylate with a molecular weight of 198.22.

[0023] Furthermore, the initiation system is a thermal initiation system, wherein the thermal initiator is selected from ammonium persulfate or potassium persulfate;

[0024] Furthermore, the co-initiator is selected from at least one of sodium bisulfite, sodium sulfite, tetramethylethylenediamine, ascorbic acid, thiourea or ferrous sulfate.

[0025] In a preferred embodiment, in step S1, ammonium persulfate is used as an initiator and sodium bisulfite is used as a co-initiator to give the hydrogel a higher initiation rate.

[0026] In some embodiments, in step S2, the deoxygenation method is to introduce an inert gas into the mixed liquid, wherein the inert gas includes but is not limited to one or a combination of nitrogen, argon, and helium. In some embodiments, the defoaming method is ultrasonic defoaming.

[0027] Furthermore, in step S3, the drug is positively charged drug particles, including but not limited to berberine nanoparticles.

[0028] In some embodiments, the drug concentration is 0.5-3 mg / mL; in a preferred embodiment, the drug concentration is 1 mg / mL.

[0029] In a preferred embodiment, the drug loaded in the semi-cross-linked network hydrogel drug delivery system is berberine, which exists in the hydrogel network structure in the form of nanoparticles, has excellent sustained-release properties, and can continuously and stably release the drug in vivo.

[0030] In some embodiments, the cross-linking method in step S3 is to react at 60-75° C. for 6-18 hours.

[0031] In a preferred embodiment, in step S3, berberine nanoparticles are added to the preliquid for drug loading, and then the drug-containing preliquid is sealed in a light-transmitting glass mold, first placed in a 50°C water bath for reaction for 1 hour, and then the temperature is increased to 65°C and maintained for 6-18 hours to complete the polymerization reaction.

[0032] In a preferred embodiment, in step S3, a light-transmitting glass mold is used as the reaction molding container.

[0033] In one embodiment, the hydrogel is cleaned with an ethanol-water mixture to remove unreacted monomers, crosslinking agents, and other impurities. Preferably, the cleaning solvent is a mixture of ethanol and water (1:1 by volume) to clean the hydrogel.

[0034] In one embodiment, the washed hydrogel is dried at 40° C. to a constant weight to obtain a drug sustained-release hydrogel material with stable performance.

[0035] The third aspect of the present invention is to provide the use of the drug-carrying system for preparing drugs and dressings.

[0036] In drug-loaded systems, the hydrophilicity, swelling, and zwitterionic properties of the hydrogel surface can significantly reduce bacterial adsorption while enhancing its antioxidant and antibacterial properties, thereby extending the drug's shelf life and increasing its bioavailability. Sacran, a key component of the hydrogel, significantly improves its antioxidant and antibacterial properties.

[0037] In some embodiments, the invention is used to prepare a sustained-release drug, wherein the release time of the sustained-release drug is ≥30 h; it can reach 38 h, or even 40 h.

[0038] Beneficial effects:

[0039] (1) The present invention overcomes the problems of uncontrollable release rate and insufficient stability of hydrogel drug sustained-release systems in the prior art, and provides a semi-crosslinked network hydrogel material based on supergiant glycosaminoglycan Sacran; it can control the slow release of drugs by pH or time, and can be taken orally to ensure the sustained and stable release of drugs in the body;

[0040] (2) The semi-cross-linked network hydrogel material based on the supergiant glycosaminoglycan Sacran of the present invention has excellent water absorption and water retention properties, with a maximum swelling ratio of up to 14.2 times; and has good biocompatibility, stable mechanical properties, and stable and long-lasting drug release, and is particularly suitable for long-term sustained release of berberine drugs (up to 38 hours or more);

[0041] (3) The semi-cross-linked network hydrogel drug delivery system of the present invention significantly improves the antioxidant and antibacterial properties of the material due to the loading of berberine nanoparticles, and exhibits obvious inhibitory and killing effects on pathogens such as Staphylococcus aureus and Escherichia coli;

[0042] (4) The preparation method adopted by the present invention has simple process, concise steps, high efficiency, environmental protection, mild conditions, safe and environmentally friendly raw materials, non-toxic and pollution-free preparation process, no need for special equipment in the production process, convenient operation, economical and efficient, and has good industrialization prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] The accompanying drawings are used to provide a further understanding of the present application and constitute a part of the specification. Together with the embodiments of the present application, they are used to explain the present application and do not constitute a limitation of the present application.

[0044] Figure 1 The infrared spectrum (FTIR) of the hydrogel prepared in the present invention is shown;

[0045] Figure 2 This is a scanning electron microscope image of the hydrogel prepared in an embodiment of the present invention;

[0046] Figure 3 Graphs showing stress-strain curves during compression of the hydrogel samples prepared in Examples 1-3 of the present invention;

[0047] Figure 4 The swelling properties and drug release curve of the hydrogel prepared in Example 1 of the present invention;

[0048] Figure 5 The swelling properties and drug release curve of the hydrogel prepared in Example 2 of the present invention;

[0049] Figure 6 The swelling properties and drug release curve of the hydrogel prepared in Example 3 of the present invention;

[0050] Figure 7 The antioxidant properties of the hydrogels prepared in Examples 1-3 of the present invention, wherein A is a graph showing the scavenging efficiency of the hydrogels on DPPH free radicals; B is a graph showing the scavenging efficiency of the hydrogels on ABTS free radicals;

[0051] Figure 8This is a comparison chart of the antibacterial properties of the hydrogel (CSA-6) prepared in Example 2 of the present invention, where A represents Escherichia coli and B represents Staphylococcus aureus;

[0052] Figure 9 This is the cell compatibility of the hydrogel (CSA-6) prepared in Example 2 of the present invention. DETAILED DESCRIPTION

[0053] In order to make the above-mentioned objects, features and advantages of the present invention more clearly understood, the specific embodiments of the present invention are described in detail below in conjunction with the embodiments of the specification. In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways different from those described herein, and those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0054] The technical solution of the present invention will be further described in detail below through specific embodiments in conjunction with the accompanying drawings.

[0055] In the present invention, unless otherwise specified, all equipment and raw materials can be purchased from the market or are commonly used in the industry. The methods in the following embodiments, unless otherwise specified, are all conventional methods in the art.

[0056] The test method used in the embodiment includes the following aspects:

[0057] (1) Fourier transform infrared spectroscopy characterization: Take a small amount of sample and place it on the ATR accessory of Fourier transform infrared spectrometer (FTIR) at 4000 cm -1 ~400cm -1 The spectra of Sacran semi-crosslinked network hydrogel samples and purified components were analyzed within the scanning range of .

[0058] (2) Scanning electron microscopy test: After the freeze-dried hydrogel is sprayed with gold on the cross section, the pore size distribution and morphology of the cross section are observed under a scanning electron microscope.

[0059] (3) Mechanical properties test: The prepared hydrogel samples were cut into cylindrical specimens of the same size and placed on the platform of a universal testing machine for compression performance testing. During the test, the load was continuously applied at a fixed compression rate until the sample showed significant deformation. The stress-strain curve was recorded and analyzed. The sample size was a disc-shaped sample with a diameter of 20 mm and a height of 15 mm.

[0060] (4) Swelling rate test: The completely dried hydrogel sample was weighed and recorded as K0. The sample was then placed in pH 1.2 and pH 7.4 solutions at 37°C. The hydrogel sample was taken out at predetermined time intervals and weighed and recorded as Kt. The dynamic swelling of the hydrogel sample was calculated using formula (1):

[0061]

[0062] (5) Drug release curve: The hydrogel samples loaded with berberine nanoparticles were placed in 900 mL of pH 1.2 and pH 7.4 buffer solutions, respectively, and drug release experiments were performed in a constant temperature water bath at 37°C. 5 mL of the solution medium was removed at set time intervals, and the absorbance of the solution at 345 nm was measured using an ultraviolet spectrophotometer to plot the drug release curve of the hydrogel.

[0063] (6) Antioxidant test: The hydrogel samples were immersed in DPPH and ABTS free radical solutions, respectively. The DPPH free radical system was reacted at room temperature in the dark for 30 minutes, and the absorbance was measured at 517 nm. The ABTS free radical system was incubated at 37°C for 30 minutes, and the absorbance was measured at 730 nm. The antioxidant properties of the hydrogel were evaluated by the absorbance changes.

[0064] (7) The antibacterial properties of the hydrogel were evaluated by the disk diffusion method. Staphylococcus aureus and Escherichia coli were prepared at a concentration of 10 6 Take 0.1 mL of the bacterial suspension with a CFU / mL and evenly spread it on the agar plate. Then, place the sterilized blank hydrogel, drug-loaded hydrogel, and negative control on the surface of the plate respectively. Incubate at 37°C for 24 hours, measure the diameter of the inhibition zone, and evaluate the antibacterial effect of the hydrogel.

[0065] (8) In vitro cytotoxicity assay: Raw264.7 cells were cultured at a concentration of 1×10 5 Cells were seeded at a density of 100 μL / well in a 96-well plate and cultured at 37°C for 24 hours. The cells were then replaced with 100 μL of hydrogel extract at different concentrations and cultured for another 24 hours. CCK-8 reagent was then added to each well and incubated for 2 hours. The absorbance was measured at 450 nm using a microplate reader. The absorbance of the untreated cell group was used as a reference to calculate the cell viability percentage as follows:

[0066]

[0067] In formula (2), OD sample Represents the absorbance value measured after cells were incubated with hydrogel extract; OD control OD represents the absorbance value after cells are incubated in the culture medium without hydrogel extract; blankThe absorbance value of the culture medium was measured in the absence of cells and hydrogel extract. Six parallel wells were set up for each sample and independently measured.

[0068] As an example, in an embodiment of the present invention, the initiator used is ammonium persulfate, the co-initiator is sodium bisulfite, the crosslinker used is EGDMA (Mn=198.22), the solvent of the mixed solution is deionized water, and the drug is berberine nanoparticles.

[0069] The amounts of raw materials used in various embodiments of the present invention are shown in Table 1.

[0070] Each of Examples 1-3 includes three experiments, and the hydrogel numbers obtained are shown in Table 1. It should be noted that the samples numbered CSA-1, CSA-5, and CSA-7 were prepared in the same experiment. For the sake of consistency in numbering in different figures, the above three numbers are used respectively.

[0071] It should be further noted that in the performance tests of the hydrogels and drug-carrying systems in the examples, the hydrogel samples used for testing the mechanical / physical properties of the hydrogels were all blank hydrogels. The drug-release performance and antibacterial and antioxidant properties were all tested on drug-carrying hydrogels.

[0072] In each embodiment of the present invention, 0.1 g of berberine nanoparticles was added in the drug loading step to perform drug loading experiments.

[0073] Table 1 Amount of each raw material in Examples 1-3

[0074]

[0075] Example 1

[0076] The method for preparing the semi-crosslinked network hydrogel of the present invention comprises the steps of:

[0077] 1) Chondroitin sulfate 1g, Sacran 0.1g, acrylic acid 20g, APS 0.3g, SHS 0.3g, crosslinker EGDMA (add 0.5g / 1g / 1.5g respectively), add water and stir to dissolve to a total volume of 100ml;

[0078] 2) The mixed solution was deoxygenated by nitrogen for 15 minutes, and then ultrasonicated for 30 minutes to remove bubbles in the mixed solution to obtain a pre-liquid;

[0079] 3) Adding berberine nanoparticles to the pre-liquid for drug loading, then sealing the drug-containing pre-liquid in a mold, first placing it in a 50°C water bath for 1 hour, then raising the temperature to 65°C and maintaining it overnight to complete the polymerization reaction;

[0080] 4) Cooling the polymerized drug-loaded hydrogel material to room temperature, and thoroughly washing the sample with a 1:1 volume ratio ethanol-water mixture solution;

[0081] 5) The washed hydrogel material is dried at 40° C. until it reaches a constant weight, thereby obtaining a drug sustained-release hydrogel material with stable performance.

[0082] Example 2

[0083] The method for preparing the semi-crosslinked network hydrogel of the present invention comprises the steps of:

[0084] 1) Dissolve 1g of chondroitin sulfate, 0.1g of Sacran, 12g / 20g / 28g of acrylic acid, 0.3g of APS, 0.3g of SHS, and 0.5g of EGDMA (crosslinker) in water and stir to a total volume of 100ml.

[0085] 2) The mixed solution was deoxygenated by nitrogen for 15 minutes, and then ultrasonicated for 30 minutes to remove bubbles in the mixed solution to obtain a pre-liquid;

[0086] 3) Adding berberine nanoparticles to the pre-liquid for drug loading, then sealing the drug-containing pre-liquid in a glass mold, first placing it in a 50°C water bath for 1 hour, then raising the temperature to 65°C and maintaining it overnight to complete the polymerization reaction;

[0087] 4) Cooling the polymerized drug-loaded hydrogel material to room temperature and washing the sample with a 1:1 volume ratio ethanol-water mixture solution;

[0088] 5) The washed hydrogel material is dried at 40° C. until it reaches a constant weight, thereby obtaining a drug sustained-release hydrogel material with stable performance.

[0089] Example 3

[0090] The method for preparing the semi-crosslinked network hydrogel of the present invention comprises the steps of:

[0091] 1) Dissolve 1g of chondroitin sulfate, 0.1g / 0.2g / 0.3g of Sacran, 20g of acrylic acid, 0.3g of APS, 0.3g of SHS, and 0.5g of EGDMA (crosslinker) in water and stir to a total volume of 100ml.

[0092] 2) The mixed solution was deoxygenated by nitrogen for 15 minutes, and then ultrasonicated for 30 minutes to remove bubbles in the mixed solution to obtain a pre-liquid;

[0093] 3) Adding berberine nanoparticles to the pre-liquid for drug loading, then sealing the drug-containing pre-liquid in a glass mold, first placing it in a 50°C water bath for 1 hour, then raising the temperature to 65°C and maintaining it overnight to complete the polymerization reaction;

[0094] 4) Cooling the polymerized drug-loaded hydrogel material to room temperature and washing the sample with a 1:1 volume ratio ethanol-water mixture solution;

[0095] 5) The washed hydrogel material is dried at 40° C. until it reaches a constant weight, thereby obtaining a drug sustained-release hydrogel material with stable performance.

[0096] Performance testing:

[0097] Figure 1 The infrared spectrum of the hydrogel sample (CSA-6) prepared in Example 2 (including drug-loaded hydrogel, blank hydrogel and raw materials) is shown in Figure 2. The infrared spectrum of the blank hydrogel (Blankhydrogel) is at 3330 cm -1 The absorption peak at 1690cm is caused by the stretching vibration of hydroxyl (–OH). -1 The absorption peak at 1427 cm is caused by the stretching vibration of the C=O group in acrylic acid (AA). -1 The absorption peak at 1237 cm is caused by the bending vibration of the –OH group in chondroitin sulfate (CHS). -1 The absorption peak at 1140 cm is caused by the stretching vibration of the S=O group in Sacran. -1 The absorption peaks are caused by the symmetric and asymmetric stretching vibrations of the C═C and C–O groups in the ester chain of the crosslinker ethylene glycol dimethacrylate (EGDMA). Compared to the raw material, the blank hydrogel exhibits new characteristic peaks and functional groups, indicating successful cross-linking of the polymer. Loading the hydrogel with drug nanoparticles reveals slight shifts in the characteristic peaks and changes in some peak intensities, indicating interaction between the drug nanoparticles and the hydrogel matrix, further confirming the successful construction of the drug delivery system.

[0098] Figure 2 This is a scanning electron microscope image of the hydrogel sample (CSA-6) prepared in Example 2. It can be seen from the image that the prepared hydrogel material has an irregular porous structure, which gives it strong water absorption performance.

[0099] Figure 3 The stress-strain curves of the hydrogels prepared in Examples 1-3 during compression show that the hydrogels exhibited a maximum compressive strength of 0.22±0.05 MPa (CSA-3) and a maximum strain exceeding 60% (CSA-9). These results demonstrate that the hydrogels possess high mechanical strength and good elasticity, making them suitable for use as sustained-release drug-loaded materials or dressings in biomedical applications.

[0100] like Figure 4-6As shown in the swelling curves in , the hydrogel (CSA-6) prepared in the present invention can achieve swelling rates of approximately 7.1 times and 14.2 times at pH 1.2 and pH 7.4, respectively, exhibiting obvious pH-responsive swelling characteristics, indicating that the material can dynamically adjust the degree of swelling according to changes in the environmental pH and is suitable for drug sustained release and other pH-sensitive biomedical applications.

[0101] The 48-hour drug release curves of the hydrogel prepared by the present invention at pH 1.2 and pH 7.4 are as follows: Figure 4-6 The drug release curves are shown in Figure 2 . As can be seen from the figure, after drug loading into the hydrogel, the maximum release rates reached 33.20% and 40.80% in pH 1.2 and pH 7.4 environments, respectively, within the first hour of release. After sustained release, equilibrium was reached around 40 hours later, with maximum cumulative drug release reaching 56.36% and 72.89%, respectively. This demonstrates that the hydrogel prepared by the present invention exhibits excellent sustained drug release properties and is suitable for controlled drug release and related biopharmaceutical applications.

[0102] The antioxidant properties of the drug-loaded hydrogels prepared in Examples 1-3 are as follows: Figure 7 As shown, Figures A and B are the scavenging efficiency curves of the hydrogel for DPPH and ABTS free radicals, respectively. The blank hydrogel also showed excellent antioxidant capacity; the antioxidant capacity of the hydrogel was significantly improved after loading the drug; the drug-loaded hydrogel showed obvious scavenging effects on DPPH and ABTS free radicals. This result shows that the drug-loaded hydrogel has excellent antioxidant properties. Among them, the antioxidant rates of (CSA-6) reached 71.66% and 65.59%, respectively, which were significantly higher than those of other groups. It shows a relatively obvious synergistic effect. It reflects its good application potential in antioxidant drug carriers and related biomedicine fields.

[0103] The antibacterial effect of the hydrogel (CSA-6) prepared in Example 2 is as follows Figure 8 As shown, A and B represent the inhibitory effects of the hydrogel on Escherichia coli and Staphylococcus aureus, respectively. As can be seen from the figure, the drug-loaded hydrogel exhibits significant antibacterial effects against both Escherichia coli and Staphylococcus aureus. The unloaded blank hydrogel also exhibits a certain degree of antibacterial ability, which may be due to the inherent antibacterial properties of the sacran in the hydrogel. This further illustrates that the antibacterial effect of the drug-loaded system of the present invention is achieved through the synergistic effect of the hydrogel material and the loaded drug, indicating that the hydrogel has good application potential in the fields of drug carriers and antibacterial materials.

[0104] The cell compatibility of the hydrogel (CSA-6) prepared in Example 2 is as follows Figure 9As shown in the figure, A and B represent the cell survival rates after 24 and 48 hours of co-culture in the hydrogel extract, respectively. As can be seen from the figure, the cell survival rates after treatment with the hydrogel extract were both above 95%, indicating that the hydrogel prepared by this invention has good cytocompatibility and is non-toxic to cells, making it suitable as a safe and reliable biopharmaceutical material for drug delivery and tissue engineering applications.

[0105] Table 2. Network parameters of the semi-crosslinked network hydrogel prepared in the present invention (pH 7.4)

[0106]

[0107]

[0108] Note: In the table, Ve represents cross-linking density; Mc represents average molecular weight; Mr represents molar mass of repeating unit; N represents number of cross-linking units; D represents diffusion coefficient.

[0109] The network parameters of the hydrogels prepared in Examples 1-3 of the present invention are shown in Table 2. Among them, the CSA-6 hydrogel exhibited the best overall performance. Particularly noteworthy was its lowest repeating unit molar mass and exceptionally high number of crosslinking units; a high number of crosslinking units is typically associated with increased network rigidity and decreased swelling capacity. However, CSA-6 forms a unique structure characterized by high crosslinking points but low crosslink density, exhibiting both high swelling and high strength. This can be attributed to the unique structure of saccharin, an ultra-high molecular weight polysaccharide, which increases the distance between crosslinking points. Its abundant sugar units further contribute to the large number of crosslinking points.

[0110] In summary, the present invention provides a biomimetic design of a semi-crosslinked network hydrogel based on supergiant glycosaminoglycan Sacran and its application in sustained-release of cationic drugs.

[0111] The experimental results above demonstrate that the technical solution of the present invention alleviates the high viscosity of Sacran by introducing chondroitin sulfate, resulting in a semi-interpenetrating network with an exceptionally high molecular weight between crosslinks. The resulting semi-crosslinked network hydrogel based on the ultra-giant glycosaminoglycan Sacran exhibits good water absorption (swelling rate up to 14.2 times), high mechanical strength (maximum compressive strength reaches 0.22±0.05MPa, maximum strain reaches over 60%), antioxidant and antibacterial properties, and excellent cytocompatibility. The Sacran and CHS chains in the semi-interpenetrating network effectively regulate the release of BBR cations, enabling the slow release of drugs controlled by pH or time, making it suitable for use as an oral sustained-release drug carrier material.

[0112] It should be noted that the above description is merely a preferred embodiment of the present invention and does not constitute any form of limitation to the present invention. Other variations and modifications are possible without departing from the technical solutions described in the claims. Those skilled in the art will understand that the technical solutions of the present invention may be modified or replaced with equivalents without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications are intended to be encompassed within the scope of the present invention.

Claims

1. A semi-crosslinked network hydrogel drug delivery system, characterized in that: The hydrogel material is mainly composed of a polyacrylic acid network and is copolymerized with supergiant glycosaminoglycan Sacran and chondroitin sulfate.

2. The method for preparing the semi-crosslinked network hydrogel drug delivery system according to claim 1, characterized in that: The following steps are involved: S1. A mixed solution containing Sacran, acrylic acid monomer, chondroitin sulfate, a cross-linking agent, and an initiating substance is prepared; S2 preparation of pre-liquid: the mixed solution obtained in step S1 is deoxygenated and the pre-liquid is obtained after removing bubbles; S3. Drug loading: Add the drug to the pre-liquid obtained in step S2, and after the cross-linking reaction is completed, wash and dry to obtain the drug-loaded hydrogel material.

3. The preparation method according to claim 2, characterized in that In step S1, the mass concentration of Sacran is: 0.1-0.3 wt%; The mass concentration of acrylic acid monomer is: 12-28wt%; The mass concentration of chondroitin sulfate is 0.5-2wt%.

4. The preparation method according to claim 2, characterized in that In step S1, the mass concentration of the cross-linking agent is: 0.5-1.5wt%; The mass concentration of the initiation system is 0.2-0.4 wt%.

5. The preparation method according to claim 2, characterized in that The crosslinking agent is ethylene glycol dimethacrylate; the initiation system includes an initiator and a co-initiator; and / or, the initiator is selected from ammonium persulfate or potassium persulfate; And / or, the co-initiator is selected from at least one of sodium bisulfite, sodium sulfite, tetramethylethylenediamine, ascorbic acid, thiourea or ferrous sulfate.

6. The preparation method according to claim 2, characterized in that In step S2, the deoxygenation method is to introduce an inert gas into the mixed liquid, wherein the inert gas includes but is not limited to one or a combination of nitrogen, argon, and helium; And / or, the defoaming method is ultrasonic defoaming.

7. The preparation method according to claim 2, characterized in that In step S3, the drug is positively charged drug particles, including but not limited to berberine nanoparticles; The drug concentration is 0.5-3 mg / mL.

8. The preparation method according to claim 7, characterized in that The cross-linking conditions in step S3 are 60-75° C. and reaction time of 6-18 hours.

9. Use of the drug delivery system according to claim 1 in preparing drugs and dressings.

10. The use according to claim 9, characterized in that Used for preparing oral sustained-release drugs, wherein the release time of the sustained-release drugs is ≥30h.

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