Preparation method for improving viscoelasticity of chitosan hydrogel
By preparing quaternized chitosan and end-carboxylated polyoxazoline-bound gelatin, the adhesion and positioning of hemostatic materials are solved, and the rapid hemostatic, antibacterial and temperature-sensitive properties of chitosan hydrogel are achieved. It is suitable for wounds of various wound shapes and is accurately positioned during subcutaneous implantation, reducing the risk of infection and improving the accuracy of biological evaluation.
Patent Information
- Application Number
- CN202510392133.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-31
- Publication Date
- 2025-07-04
AI Technical Summary
During use, existing hemostatic materials have risks such as breeding bacterial infections, producing heat to cause secondary damage to the body, poor wet adhesion, and long-term use may lead to microvascular thrombosis, and subcutaneous implantation samples are difficult to accurately locate during biological evaluation.
By preparing quaternized chitosan and end-carboxylated polyoxazoline combined with gelatin, amidation reaction is carried out to form a quaternized polyoxazolined chitosan/gelatin mixture, which is freeze-dried into a powder after emulsion polymerization, and is prepared with viscoelastic chitosan hydrogel with viscoelasticity.
It achieves rapid hemostasis, excellent antibacterial properties, temperature sensitive properties and good biocompatibility of chitosan gel. It is suitable for wounds of different wound shapes and can be accurately positioned when implanting samples under the skin, reducing the risk of infection and improving the accuracy of biological evaluation.
Smart Images
Figure CN120248378A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of functional gel preparation, and particularly relates to a preparation method for improving the viscoelasticity of chitosan hydrogel. Background Art
[0002] In daily life, the skin surface will be damaged and traumatized due to various factors. Bleeding will further lead to bacterial infection, endangering the health of the body. During the wound healing process, hemostasis and antibacterial are particularly important. In the field of antibacterial dressings, natural polymer materials have been widely studied and applied in improving the wound microenvironment, wound gas-liquid exchange, promoting wound hemostasis and antibacterial, etc. due to their good biocompatibility, solubility and biological activity. As an important raw material for hydrogel preparation, natural polymer materials improve the high antibacterial property, rapid self-healing property and antioxidant property of hemostatic materials through various cross-linking methods such as physical, chemical and hybrid cross-linking. Existing hemostatic materials mainly include inorganic hemostatic materials, polymer hemostatic materials, and biomass hemostatic materials. According to the form, there are gel-like, liquid-like and powder-like dressings. Their products have certain side effects during use, such as breeding bacterial infection, generating heat and causing secondary harm to the body, and long-term use may lead to risks such as microvascular thrombosis. In addition, some materials have poor wet adhesiveness and are difficult to effectively exert the hemostatic and antibacterial effects on the wound surface, which is extremely likely to cause wound infection. Therefore, it is particularly important to increase the adhesiveness of hemostatic materials.
[0003] At the same time, according to Appendix A of GB / T 16886.6-2022 "Biological Evaluation of Medical Devices", the subcutaneous implantation test method for solid test samples is specified. In the actual operation process, due to the fluidity of the subcutaneous fascia layer after the solid sample is cut and implanted, the original implantation site changes, making it difficult to accurately locate the affected site during the final biological evaluation. Summary of the Invention
[0004] The present invention provides a preparation method for improving the viscoelasticity of chitosan hydrogel. By preparing quaternized chitosan and carboxyl-terminated polyoxazoline, and combining with natural polymer gelatin with broad-spectrum adhesiveness, it has good biocompatibility, viscoelasticity and hemostatic property, and can be made into multifunctional gels with different forms according to different uses. It can effectively adhere to the wound surface to accelerate wound antibacterial and hemostasis, and the powder state is suitable for wounds of different shapes. Combining its gel with the sample can also be used for the adhesion positioning of subcutaneous implanted samples, and because of its biocompatibility, it can be biodegradable in the body, improving the accuracy of the implantation test.
[0005] The present invention provides a preparation method for improving the viscoelasticity of chitosan hydrogel, including:
[0006] S1. Dissolve quaternized chitosan in an aqueous solution, stir evenly to obtain a quaternized chitosan solution;
[0007] S2. Dissolve the gelatin powder in the quaternized chitosan solution, stir evenly to obtain a quaternized chitosan / gelatin mixture.
[0008] S3. Add 1,4-dibromo-2-butene to the ultra-dry acetonitrile solvent, carry out a catalytic reaction under anhydrous and anaerobic conditions at 70 °C, and add acrylic acid to terminate the catalytic reaction to obtain carboxyl-terminated polyoxazoline.
[0009] S4. Dissolve and mix the quaternized chitosan / gelatin mixture prepared in step S2 with the polyoxazoline prepared in step S3, and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide to carry out an amidation reaction to obtain a quaternized polyoxazoline-modified chitosan / gelatin mixture.
[0010] S5. Add a set weight ratio of hydrochloric acid, hydrogen peroxide, N-isopropylacrylamide, and deionized water to the quaternized polyoxazoline-modified chitosan / gelatin mixture prepared in step S4, stir and dissolve, and then carry out an emulsion polymerization reaction to obtain a quaternized polyoxazoline-modified chitosan / gelatin aqueous solution system.
[0011] S6. Freeze-dry the quaternized polyoxazoline-modified chitosan / gelatin aqueous solution system prepared in step S5 and grind it into powder to obtain a quaternized polyoxazoline-modified chitosan / gelatin powder.
[0012] Further, step S1 specifically includes:
[0013] S101. Prepare 5 mL of an aqueous solution of chitosan and hydrochloric acid with a mass fraction of 2-5%.
[0014] S102. Take 3-5 mL of the chitosan hydrochloric acid aqueous solution, add 0.5 mL of glycidyltrimethylammonium chloride, and heat and react for 5-8 hours to obtain quaternized chitosan.
[0015] S103. Dissolve 0.03-0.05 g of the prepared quaternized chitosan in 3 mL of an aqueous solution, stir evenly to obtain a quaternized chitosan solution.
[0016] Further, in step S2, add 0.5-0.8 g of fish gelatin powder to the quaternized chitosan solution prepared in step S103.
[0017] Further, in step S4, after the quaternized chitosan / gelatin mixture and polyoxazoline are dissolved and mixed, they are catalyzed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide for 6-8 hours.
[0018] Further, in the step S5, the set weight ratio is: 1 part of quaternized polyoxazoline chitosan / gelatin mixture, 1 - 2 parts of hydrochloric acid, 1 - 5 parts of hydrogen peroxide, 1 - 10 parts of N-isopropylacrylamide, and 50 - 80 parts of deionized water;
[0019] The emulsion polymerization reaction is carried out for 2 - 4 hours.
[0020] The present invention also provides a gel prepared by a preparation method for improving the viscoelasticity of chitosan hydrogel, which includes chitosan, hydrochloric acid aqueous solution, trimethylammonium glycidyl chloride, gelatin, ultra-dry acetonitrile solvent, 1,4-dibromo-2-butene, acrylic acid, hydrochloric acid, hydrogen peroxide, N-isopropylacrylamide, and deionized water.
[0021] The beneficial effects of the present invention are as follows:
[0022] 1. For the chitosan gel obtained by the preparation method of the present invention, the addition of natural polymer gelatin endows the chitosan gel with strong adhesiveness, which is not only applicable to skin tissues but also to internal organs such as the heart and stomach; in addition, its hydrophilicity provides a moist environment for the wound, avoiding secondary damage caused by wound adhesion.
[0023] 2. For the gel powder obtained by the preparation method of the present invention, due to the addition of quaternized chitosan, it has rapid hemostasis and excellent antibacterial properties, and the powder can be applied to wounds with different wound shapes, which can inhibit the growth of wound bacteria and reduce the risk of infection.
[0024] 3. The gel obtained by the preparation method of the present invention has thermosensitive properties. Its solution can quickly coagulate on the wound surface and is in a liquid state below the skin surface. The use of a spray bottle can achieve the effect of spraying and coagulating immediately.
[0025] 4. When a solid sample is implanted subcutaneously, the gel obtained by the preparation method of the present invention can cover the surface of the sample, enabling the sample to adhere to the implantation site, and having good biocompatibility and degradability. BRIEF DESCRIPTION OF THE DRAWINGS
[0026] Figure 1 It is a flow schematic diagram of the preparation method for improving the viscoelasticity of chitosan hydrogel of the present invention.
[0027] The realization, functional characteristics, and advantages of the object of the present invention will be further described in conjunction with the embodiments with reference to the drawings. DETAILED DESCRIPTION OF THE EMBODIMENTS
[0028] It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.
[0029] Biomass materials have excellent hemostatic properties and good biocompatibility. Such materials mainly include proteins and polysaccharides. Chitosan belongs to natural polymer biomass polysaccharides and is the product of the deacetylation of chitin. It has characteristics such as biocompatibility, antibacterial hemostasis, and degradability, and is considered to be the most promising raw material for wound dressings. The cationic clusters formed by it can interact with red blood cells, and effective hemostasis can be achieved without relying on the body's coagulation mechanism.
[0030] Quaternized chitosan can significantly improve its water solubility, and its antibacterial performance is better than that of pure chitosan. As a polymer with a polypeptide-like structure, polyoxazoline has good biocompatibility and has currently been applied in the field of medical biomaterials. N-isopropylacrylamide and its polymers belong to thermosensitive materials and can be grafted onto chitosan through polymerization reactions to achieve its thermosensitive properties. It is in a liquid state below the human body surface temperature and in a gel state when covering the human body surface. Gelatin belongs to natural polymer proteins and is widely applicable to fields such as food and medicine. It has broad-spectrum bioadhesion, and when combined with the application of chitosan and adhered to the skin surface, it can achieve rapid hemostasis and antibacterial effects.
[0031] The present invention belongs to a preparation method of functional gels, specifically related to rapid hemostasis and antibacterial of skin wounds, and can also be applied to the intradermal positioning and release of subcutaneous implanted samples. It has good hemostatic antibacterial, biocompatible, and degradable properties. The method of the present invention prepares a quaternized polyoxazoline-modified chitosan / gelatin mixture by subjecting quaternized chitosan and carboxyl-terminated polyoxazoline to an amidation reaction and combining with the highly adhesive polymer protein gelatin. Finally, an aqueous solution of viscoelastic quaternized polyoxazoline-modified chitosan / gelatin is obtained through an emulsion polymerization reaction, and further freeze-dried to form a powder, and different forms of gels can be prepared according to actual uses. It is an adhesive gel that can be biodegradable in the body, can accurately fix the implanted sample at the implantation site when implanted, and can improve the accuracy of tissue sampling evaluation.
[0032] As Figure 1 shown, the present invention provides a preparation method for improving the viscoelasticity of chitosan hydrogels, including:
[0033] Example 1
[0034] S1. Dissolve quaternized chitosan in an aqueous solution and stir evenly to obtain a quaternized chitosan solution.
[0035] S101. Prepare 5 mL of an aqueous solution of chitosan and hydrochloric acid with a mass fraction of 5%.
[0036] S102. Take 5 mL of the chitosan hydrochloric acid aqueous solution, add 0.5 mL of trimethylammonium glycidyl chloride, and heat and react for 5 hours. Dissolve the prepared 0.05 g of quaternized chitosan in 3 mL of an aqueous solution and stir evenly to obtain a quaternized chitosan solution.
[0037] S2. Add 0.5 g of fish gelatin powder to the quaternized chitosan solution and stir evenly to obtain a quaternized chitosan / gelatin mixture.
[0038] S3. Add 1,4-dibromo-2-butene to the ultra-dry acetonitrile solvent, react under the conditions of anhydrous and anaerobic heating at 70 °C, and add acrylic acid to terminate the catalytic reaction to obtain carboxyl-terminated polyoxazoline.
[0039] S4. Catalyze the prepared quaternized chitosan / gelatin mixture and carboxyl-terminated polyoxazoline with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide for 6 hours for further amidation reaction to obtain a quaternized polyoxazoline-modified chitosan / gelatin mixture;
[0040] S5. Mix the quaternized polyoxazoline-modified chitosan / gelatin mixture, hydrochloric acid, hydrogen peroxide, N-isopropylacrylamide, and deionized water prepared in step S4 in a weight ratio of 1:2:5:10:80, and carry out emulsion polymerization reaction for 2 hours to obtain a quaternized polyoxazoline-modified chitosan / gelatin aqueous solution system.
[0041] S6. Further freeze-dry and grind into powder the quaternized polyoxazoline-modified chitosan / gelatin aqueous solution system prepared in step S5 to obtain a quaternized polyoxazoline-modified chitosan / gelatin powder.
[0042] Example 2
[0043] S1. Dissolve quaternized chitosan in an aqueous solution and stir evenly to obtain a quaternized chitosan solution.
[0044] S101. Prepare 5 mL of an aqueous solution of chitosan and hydrochloric acid with a mass fraction of 2%.
[0045] S102. Take 3 mL of the chitosan hydrochloric acid aqueous solution, add 0.5 mL of trimethylammonium glycidyl chloride, and heat and react for 6 hours. Dissolve the prepared 0.03 g of quaternized chitosan in 3 mL of aqueous solution and stir evenly to obtain a quaternized chitosan solution.
[0046] S2. Add 0.8 g of fish gelatin powder to the quaternized chitosan solution and stir evenly to obtain a quaternized chitosan / gelatin mixture.
[0047] S3. Add 1,4-dibromo-2-butene to the ultra-dry acetonitrile solvent, react under the conditions of anhydrous and anaerobic heating at 70 °C, and add acrylic acid to terminate the catalytic reaction to obtain carboxyl-terminated polyoxazoline.
[0048] S4. Mix the prepared quaternized chitosan / gelatin mixture with carboxyl-terminated polyoxazoline under the catalysis of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide for 8 hours for further amidation reaction to obtain a quaternized polyoxazolinized chitosan / gelatin mixture;
[0049] S5. Mix the quaternized polyoxazolinized chitosan / gelatin mixture prepared in step S4, hydrochloric acid, hydrogen peroxide, N-isopropylacrylamide, and deionized water in a weight ratio of 1:1:3:10:80, and carry out emulsion polymerization reaction for 3 hours to obtain a quaternized polyoxazolinized chitosan / gelatin aqueous solution system.
[0050] S6. Further freeze-dry and grind into powder the quaternized polyoxazolinized chitosan / gelatin aqueous solution system prepared in step S5 to obtain a quaternized polyoxazolinized chitosan / gelatin powder.
[0051] Example 3
[0052] S1. Dissolve quaternized chitosan in an aqueous solution and stir evenly to prepare a quaternized chitosan solution.
[0053] S101. Prepare 5 mL of an aqueous solution of chitosan and hydrochloric acid with a mass fraction of 3%.
[0054] S102. Take 3 mL of the chitosan hydrochloric acid aqueous solution, add 0.5 mL of trimethylammonium glycidyl chloride, and heat for reaction for 8 hours. Dissolve the prepared 0.05 g of quaternized chitosan in 3 mL of an aqueous solution and stir evenly to obtain a quaternized chitosan solution.
[0055] S2. Add 0.8 g of fish gelatin powder to the quaternized chitosan solution and stir evenly to obtain a quaternized chitosan / gelatin mixture.
[0056] S3. Add 1,4-dibromo-2-butene to an ultra-dry acetonitrile solvent, react under the conditions of anhydrous and anaerobic heating at 70 °C, and add acrylic acid to terminate the catalytic reaction to obtain carboxyl-terminated polyoxazoline.
[0057] S4. Mix the prepared quaternized chitosan / gelatin mixture with carboxyl-terminated polyoxazoline under the catalysis of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide for 8 hours for further amidation reaction to obtain a quaternized polyoxazolinized chitosan / gelatin mixture;
[0058] S5. Mix the quaternized polyoxazolinized chitosan / gelatin mixture prepared in step S4, hydrochloric acid, hydrogen peroxide, N-isopropylacrylamide, and deionized water in a weight ratio of 1:2:3:8:80, and carry out emulsion polymerization reaction for 4 hours to obtain a quaternized polyoxazolinized chitosan / gelatin aqueous solution system.
[0059] S6. The quaternized polyoxazolinylated chitosan / gelatin aqueous solution system prepared according to step S5 is further freeze-dried and ground into powder to obtain a quaternized polyoxazolinylated chitosan / gelatin powder.
[0060] The present invention also provides a gel prepared by a preparation method for improving the viscoelasticity of chitosan hydrogel, which includes chitosan, hydrochloric acid aqueous solution, trimethylammonium glycidyl chloride, gelatin, ultra-dry acetonitrile solvent, 1,4-dibromo-2-butene, acrylic acid, hydrochloric acid, hydrogen peroxide, N-isopropylacrylamide, and deionized water.
[0061] The present invention achieves the following technical effects:
[0062] (1) For the chitosan gel provided by the present invention, the addition of natural polymer gelatin endows the chitosan gel with strong adhesiveness, which is applicable not only to skin tissues but also to internal organs such as the heart and stomach. In addition, its hydrophilicity provides a moist environment for the wound, avoiding secondary damage caused by wound adhesion.
[0063] (2) For the gel powder provided by the present invention, due to the addition of quaternized chitosan, it has rapid hemostasis and excellent antibacterial properties, and the powder can be applied to wounds with different wound shapes, which can inhibit the growth of wound bacteria and reduce the risk of infection.
[0064] (3) The gel provided by the present invention has thermosensitive properties. Its solution can quickly coagulate on the wound surface and is in a liquid state below the skin surface. The use of a spray bottle can achieve the effect of spraying and coagulating immediately.
[0065] (4) When a solid sample is implanted subcutaneously, the gel provided by the present invention can cover the surface of the sample, enabling the sample to adhere to the implantation site, and having good biocompatibility and degradability.
[0066] It should be noted that in this article, the terms "include", "comprise" or any other variant thereof are intended to cover non-exclusive inclusion, so that a process, device, article or method including a series of elements not only includes those elements but also includes other elements not expressly listed, or also includes elements inherent to such process, device, article or method. Without further limitation, an element defined by the statement "including one..." does not exclude the existence of additional identical elements in the process, device, article or method including that element.
[0067] The above are only the preferred embodiments of the present invention, and do not limit the patent scope of the present invention accordingly. Any equivalent structural or equivalent process transformation made by using the description and drawings of the present invention, or directly or indirectly applied in other related technical fields, shall be equally included in the patent protection scope of the present invention.
Claims
1. A preparation method for improving the viscoelasticity of chitosan hydrogel, characterized in that, Including: S1. Dissolve quaternized chitosan in an aqueous solution, stir evenly to obtain a quaternized chitosan solution; S2. Dissolve gelatin powder in the quaternized chitosan solution, stir evenly to obtain a quaternized chitosan / gelatin mixture; S3. Add 1,4-dibromo-2-butene to an ultra-dry acetonitrile solvent, carry out a catalytic reaction under anhydrous and anaerobic conditions at 70 °C, and add acrylic acid to terminate the catalytic reaction to obtain a carboxyl-terminated polyoxazoline; S4. Dissolve and mix the quaternized chitosan / gelatin mixture prepared in step S2 with the polyoxazoline prepared in step S3, and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide to carry out an amidation reaction to obtain a quaternized polyoxazoline-modified chitosan / gelatin mixture; S5. Add hydrochloric acid, hydrogen peroxide, N-isopropylacrylamide, and deionized water in a set weight ratio to the quaternized polyoxazoline-modified chitosan / gelatin mixture prepared in step S4, stir to dissolve and then carry out an emulsion polymerization reaction to obtain a quaternized polyoxazoline-modified chitosan / gelatin aqueous solution system; S6. Freeze-dry the quaternized polyoxazoline-modified chitosan / gelatin aqueous solution system prepared in step S5 and grind it into powder to obtain a quaternized polyoxazoline-modified chitosan / gelatin powder.
2. The preparation method for improving the viscoelasticity of chitosan hydrogel according to claim 1, wherein The specific steps of step S1 include: S101. Prepare 5 mL of an aqueous solution of chitosan and hydrochloric acid with a mass fraction of 2-5%; S102. Take 3-5 mL of the chitosan hydrochloric acid aqueous solution, add 0.5 mL of trimethylammonium glycidyl chloride, and heat and react for 5-8 hours to obtain quaternized chitosan; S103. Dissolve 0.03-0.05 g of the prepared quaternized chitosan in 3 mL of an aqueous solution, stir evenly to obtain a quaternized chitosan solution.
3. The preparation method for improving the viscoelasticity of chitosan hydrogel according to claim 2, characterized in that, In step S2, add 0.5-0.8 g of fish gelatin powder to the quaternized chitosan solution prepared in step S103.
4. The preparation method for improving the viscoelasticity of chitosan hydrogel according to claim 3, characterized in that, In step S4, after the quaternized chitosan / gelatin mixture and polyoxazoline are dissolved and mixed, they are catalyzed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide for 6-8 hours.
5. The preparation method for improving the viscoelasticity of chitosan hydrogel according to claim 4, characterized in that, In step S5, the set weight ratio is: 1 part of the quaternized polyoxazoline-modified chitosan / gelatin mixture, 1-2 parts of hydrochloric acid, 1-5 parts of hydrogen peroxide, 1-10 parts of N-isopropylacrylamide, and 50-80 parts of deionized water; The emulsion polymerization reaction is carried out for 2-4 hours.
6. A gel prepared by a preparation method for improving the viscoelasticity of chitosan hydrogel, characterized in that, Including chitosan, hydrochloric acid aqueous solution, trimethylammonium glycidyl chloride, gelatin, ultra-dry acetonitrile solvent, 1,4-dibromo-2-butene, acrylic acid, hydrochloric acid, hydrogen peroxide, N-isopropylacrylamide, deionized water.