Chitosan-polyurethane composite hemostatic sponge and preparation method therefor

Abstract

The present application relates to the technical field of medical consumables, and in particular, to a chitosan-polyurethane composite hemostatic sponge and a preparation method therefor. The preparation method for a chitosan-polyurethane composite hemostatic sponge provided in the present application comprises: mixing chitosan and polyurethane; reacting under a phase transition condition of the polyurethane to obtain an intermediate; and freeze-drying the intermediate to prepare a composite hemostatic sponge, wherein the polyurethane is prepared by copolymerizing a polyester monomer, a polyol, and an isocyanate monomer; the deacetylation degree of the chitosan is 20-50%; and the phase transition condition of the polyurethane is 0-10 °C. According to the present application, the introduction of the hydrophobic polyester and the hydrophilic polyol into the polyurethane can prevent a decrease in the viscosity of the polyurethane due to high-temperature phase transition conditions, which otherwise causes the chitosan to settle in the polyurethane solution and results in uneven distribution. When the polyurethane reaches the phase transition condition, the chitosan is embedded into the polyurethane molecular chain to form a mixture, which can ensure that the chitosan will not be washed away by blood flow.

Description

A chitosan-polyurethane composite hemostatic sponge and its preparation method

[0001] Cross-reference to related applications

[0002] This application claims priority to Chinese Patent Application No. 202510346180.7, filed on March 24, 2025, entitled "A Chitosan-Polyurethane Composite Hemostatic Sponge and Its Preparation Method", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application relates to the field of medical consumables technology, specifically to a chitosan-polyurethane composite hemostatic sponge and its preparation method. Background Technology

[0004] To accelerate wound healing, hemostatic materials are generally used to stop bleeding. Conventional packing materials, such as petroleum jelly gauze and expandable sponges, achieve hemostasis by expanding, compressing, and absorbing blood. However, these packing materials tend to adhere to the wound surface, causing significant pain and secondary damage when removed. Chitosan, a natural polysaccharide, has positively charged amino groups that interact with negatively charged red blood cells, enabling it to accumulate red blood cells. It is widely used in hemostatic materials for wound hemostasis. Currently, chitosan is often combined with other hemostatic materials to achieve hemostasis, as chitosan alone is not very effective.

[0005] The prior art discloses a polyurethane sponge dressing with anti-adhesion and hemostatic function and its preparation method. The polyurethane sponge is used as an auxiliary material and paraffin oil loaded with nano-chitosan particles through petrolatum. It has the function of preventing adhesion and improving hemostatic effect. However, petrolatum has poor adsorption performance for chitosan. During the hemostatic process, chitosan will flow with the blood and detach from the hemostatic material to enter the body and cause thrombosis. Summary of the Invention

[0006] Therefore, the technical problem to be solved by this application is to overcome the poor connection performance between chitosan and carrier in the existing hemostatic materials, which leads to thrombosis defects caused by chitosan entering the body, thereby providing a chitosan polyurethane composite hemostatic sponge and its preparation method.

[0007] On one hand, this application provides a method for preparing a chitosan-polyurethane composite hemostatic sponge, comprising the following steps: mixing chitosan and polyurethane, reacting under the phase transition conditions of polyurethane to obtain an intermediate, and freeze-drying the intermediate to obtain a composite hemostatic sponge. The polyurethane is obtained by copolymerization of polyester monomer, polypolyol and isocyanate monomer, the degree of deacetylation of the chitosan is 20-50%, and the phase transition conditions of the polyurethane are 0-10℃.

[0008] In some embodiments, the mass ratio of chitosan to polyurethane is (0.1-0.5):1.

[0009] In some embodiments, the chitosan is mixed with polyurethane, and the reaction time is 0.5h-3h under the phase transition conditions of polyurethane.

[0010] In some embodiments, before the chitosan reacts with the polyurethane, the chitosan and polyurethane solution are mixed under stirring at a speed of 100 rpm to 200 rpm for a time of 20 min to 60 min.

[0011] Optionally, the weight-average molecular weight of the polyurethane is 100,000 Da to 1,000,000 Da.

[0012] Optionally, the solvent in the polyurethane solution is at least one of dioxane, dimethyl sulfoxide, and N,N-dimethylformamide, and the concentration of polyurethane in the polyurethane solution is 40 g / L-100 g / L.

[0013] In some embodiments, the freeze-drying process includes an annealing step of the intermediate after freezing and before drying.

[0014] Optionally, the freezing temperature during the freeze-drying process is less than or equal to -30°C, and the freezing time is 3-6 hours. Optionally, the annealing temperature is 5-15°C, and the annealing time is 2-4 hours. Optionally, the drying temperature is -40°C to -20°C, and the drying time is 12-24 hours.

[0015] In some embodiments, the method for preparing chitosan includes dissolving chitosan raw material and mixing it with an organic solvent to form a solution, adding an acid anhydride to the solution to react, adjusting the pH of the solution to 10-13, separating the solid and liquid, and obtaining chitosan with a degree of deacetylation of 20-50%. The ratio of chitosan raw material to acid anhydride is 2-8:1-3, in g:mL. Optionally, the ratio of chitosan raw material to acid anhydride is 15g-36g:6mL-13mL.

[0016] Optionally, the organic solvent includes at least one of methanol, isopropanol, or pyridine.

[0017] Optionally, the acid anhydride includes acetic anhydride.

[0018] In some embodiments, the method for preparing chitosan further includes the step of swelling chitosan with a degree of deacetylation of 20%-50% and then reacting it with a first acid solution, the first acid solution comprising an organic acid.

[0019] Optionally, the mass-to-volume ratio of the chitosan with a degree of deacetylation of 20-50% to the swelling agent is 0.1-0.2g:0.5-1mL.

[0020] Optionally, the organic acid includes at least one of acetic acid, lactic acid, glutamic acid, succinic acid, and citric acid.

[0021] Optionally, the mass ratio of the organic acid to the diacetylated chitosan is 1:1.5-5, and the diacetylated chitosan is chitosan with a degree of deacetylation of 20%-50%.

[0022] In this application, the term diacetylated chitosan refers to chitosan with a degree of deacetylation of 20%-50%.

[0023] Optionally, the swelling solvent for swelling chitosan with a degree of deacetylation of 20%-50% is a C1-C6 alcohol solvent.

[0024] In some embodiments, the degree of deacetylation of the chitosan raw material is 70%-95%, and the weight-average molecular weight is 80,000-300,000 Da.

[0025] Furthermore, the mass-to-volume ratio of the chitosan raw material to the reagent for dissolving the chitosan raw material is 1g:25-100mL.

[0026] Furthermore, the volume ratio of the reagent for dissolving the chitosan raw material to the organic solvent is 1:1-2.

[0027] In some embodiments, the reagent for dissolving the chitosan raw material includes a second acid solution, which includes at least one of formic acid, acetic acid, hydrochloric acid, and sulfuric acid, and the concentration of the second acid solution is 1-3 vol%.

[0028] In some embodiments, the acid-modified chitosan has a particle size of 1-80 μm, preferably 5-50 μm.

[0029] In some embodiments, the method for preparing the polyurethane includes the following steps: S1, under the protection of an inert gas and in the presence of a catalyst, a polyester monomer and a polypolyol react to generate a random copolyester; S2, under the protection of an inert gas and in the presence of an organic solvent, the random copolyester obtained in step S1 is polymerized with an isocyanate monomer to generate a prepolymer; S3, in the presence of a solvent, the prepolymer generated in step S2 reacts with a chain extender, and solid-liquid separation is performed to obtain polyurethane.

[0030] In some embodiments, the polyester monomer in step S1 includes D,L-lactide and caprolactone, and the polyol includes polyethylene glycol. Optionally, the caprolactone includes ε-caprolactone.

[0031] Optionally, the random copolyester obtained in step S1 has an average molecular weight of 2000 Da-4500 Da and a glass transition temperature of -40℃ to -60℃.

[0032] In some embodiments, when the random copolyester and isocyanate monomer polymerize to form a prepolymer in step S2, a catalyst is also included in the reaction system.

[0033] Optionally, the mass of the catalyst accounts for 0.05‰-0.4‰ of the mass of the reactant mixture.

[0034] Optionally, the catalyst in step S1 and / or step S2 includes at least one of stannous octoate, bismuth isooctanoate, or bismuth neodecanoate.

[0035] In some embodiments, the isocyanate monomer in step S2 includes a diisocyanate monomer, and the organic solvent includes at least one of dimethyl sulfoxide and N,N-dimethylformamide.

[0036] In some embodiments, the molecular weight distribution of the prepolymer obtained in step S2 is 1.0 ≤ Mw / Mn ≤ 2.5.

[0037] In some embodiments, the chain extender in step S3 includes a hydroxyl-terminated isocyanate.

[0038] In some of these embodiments, the solvent in step S3 includes dioxane.

[0039] Optionally, the chain extender comprises the product obtained by heat treatment, washing, and drying of 1,4-butanediol and isocyanate, wherein the molar ratio of 1,4-butanediol to isocyanate is 10-25:1, the heat treatment temperature is 70-100°C, and the heat treatment time is 5-7 hours.

[0040] Optionally, the molar ratio of D,L lactide and caprolactone in the polyester monomer is 1:0.5-2.

[0041] Optionally, the molar ratio of polyester monomer to polyol is 1-8:1.

[0042] Optionally, the mass ratio of isocyanate monomer to copolyester is 0.5-2:1.

[0043] Optionally, the isocyanate monomer includes at least one of dicyclohexylmethane diisocyanate, hexamethylene diisocyanate, lysine diisocyanate, and 1,4-butanediisocyanate.

[0044] Optionally, the polyester monomer may further include at least one of glycolide, trimethylene carbonate, or p-dioxanone.

[0045] In some embodiments, the reaction temperature of step S1 is 110℃-150℃, and the reaction time is 20h-24h.

[0046] In some embodiments, the specific steps of generating the prepolymer in step S2 include reacting the random copolyester obtained in step S1 with the isocyanate monomer at 60°C-100°C for 4-10 hours, adding a catalyst, and continuing the reaction for another 4-8 hours.

[0047] In some embodiments, the reaction temperature of step S3 is 60°C-100°C, and the reaction time is 10h-20h.

[0048] On the other hand, this application provides a composite hemostatic sponge prepared by the above-mentioned chitosan-polyurethane composite hemostatic sponge preparation method.

[0049] The technical solution of this application has the following advantages:

[0050] 1. This application provides a method for preparing a chitosan-polyurethane composite hemostatic sponge, comprising the following steps: mixing chitosan and polyurethane, reacting under the phase transition conditions of polyurethane to obtain an intermediate, and freeze-drying the intermediate to obtain a composite hemostatic sponge, wherein the polyurethane is obtained by copolymerization of polyester monomer, polypolyol and isocyanate monomer, the degree of deacetylation of the chitosan is 20-50%, and the phase transition conditions of the polyurethane are 0-10℃. This application introduces hydrophobic polyester and hydrophilic polyol into polyurethane to obtain polyurethane with a phase transition condition of 0-10℃. On the one hand, the high-temperature phase transition condition leads to a decrease in the viscosity of polyurethane, causing chitosan to settle in the polyurethane solution and resulting in uneven distribution of chitosan. This application utilizes polyurethane with a low-temperature phase transition condition, which does not affect the viscosity of polyurethane and thus improves the uniform distribution of chitosan in the polyurethane solution. On the other hand, when polyurethane reaches the phase transition condition, the polyester polyol undergoes a process of changing from a crystalline state to an amorphous state, making the molecular chains more flexible and even curling, which is conducive to the embedding of chitosan molecules. At the same time, the -OH in chitosan and the -NH in polyurethane are connected by hydrogen bonds, ultimately allowing chitosan to be embedded in the polyurethane molecular chains to form a strong and uniform mixture. This ensures that the chitosan polyurethane composite hemostatic sponge will not be washed away by the blood flow during hemostasis, avoiding the formation of thrombi, and eliminating the need for additional adhesives to connect polyurethane and chitosan.

[0051] Meanwhile, this application uses a freeze-drying process to form the chitosan-polyurethane composite material into a sponge state, which not only provides expansion and compression at the wound site but also rapidly absorbs fluid. Furthermore, since the hemostatic effect of chitosan mainly utilizes the interaction between the positive charge formed by the protonation of amino groups and the positive charge of red blood cells, a higher degree of deacetylation inevitably increases the interaction between hydroxyl and amino groups in chitosan, leading to a reduction in protonated amino groups. This inhibits blood aggregation and affects the hemostatic effect. Therefore, this application uses chitosan with a deacetylation degree of 20%-50%, which not only ensures a good hemostatic effect but also improves the coagulation effect of the composite hemostatic sponge.

[0052] 2. This application provides a method for preparing a chitosan-polyurethane composite hemostatic sponge, wherein the mass ratio of chitosan to polyurethane is (0.1-0.5):1. The preparation method provided by this application can reduce the amount of chitosan used in the composite hemostatic sponge while still achieving a good hemostatic effect.

[0053] 3. This application provides a method for preparing a chitosan-polyurethane composite hemostatic sponge, wherein the method further includes an annealing step after freezing the intermediate and before drying. This application adds an annealing step to the freeze-drying process of the chitosan-polyurethane composite material, increasing the crystal ratio during the pre-freezing process of the composite hemostatic sponge, resulting in a more stable crystalline structure. This is beneficial for the uniformity of crystal and pore size distribution in the chitosan-polyurethane composite hemostatic sponge, thereby improving its porosity and mechanical properties.

[0054] 4. This application provides a method for preparing a chitosan-polyurethane composite hemostatic sponge. The method includes dissolving chitosan raw material and mixing it with an organic solvent to form a solution, adding an acid anhydride to the solution for reaction, adjusting the pH of the solution to 10-13, and performing solid-liquid separation to obtain chitosan with a degree of deacetylation of 20%-50%. The ratio of chitosan raw material to acid anhydride is 10-40:5-15, in g:mL. This application uses chitosan as raw material, removes residual proteins and endotoxins from chitosan by alkali soaking to improve the safety of chitosan, and better controls the degree of deacetylation of chitosan by controlling the molar ratio of acid anhydride to chitosan raw material.

[0055] 5. This application provides a method for preparing a chitosan-polyurethane composite hemostatic sponge. The reagent for dissolving the chitosan raw material is an acid solution, wherein the acid solution includes at least one of formic acid, acetic acid, hydrochloric acid, or sulfuric acid, and the concentration of the acid solution is 1-3 vol%. By optimizing the concentration of the acid solution for dissolving the chitosan raw material, this application can effectively prevent chitosan from gelling.

[0056] 6. This application provides a method for preparing a chitosan-polyurethane composite hemostatic sponge, wherein the chitosan is a product of chitosan modified with organic acid. The method further includes an acidification step of chitosan with a degree of deacetylation of 20-50%, specifically involving swelling the chitosan with a degree of deacetylation of 20-50% and mixing it with an acid solution, wherein the acid solution is an organic acid. This application utilizes organic acid to modify chitosan, which protonates the -NH2 group in the chitosan, giving it a positively charged property. During hemostasis, this enhances the interaction with platelets and erythrocytes, further improving hemostasis and coagulation effects.

[0057] 7. This application provides a method for preparing a chitosan-polyurethane composite hemostatic sponge. The acid-modified chitosan has a particle size of 1-80 μm, preferably 5-50 μm. By controlling the particle size of the modified chitosan particles, this application ensures that the chitosan does not settle when mixed with polyurethane and can be uniformly distributed in the polyurethane solution. This allows the chitosan to be uniformly bonded to the polyurethane during phase transition. Furthermore, chitosan within this particle size range acts as a nucleating agent for ice crystals during freeze-drying, further enhancing the uniformity of the pore size of the chitosan-polyurethane composite hemostatic sponge.

[0058] 8. This application provides a method for preparing a chitosan-polyurethane composite hemostatic sponge. The polyurethane preparation method includes the following steps: S1, under the protection of an inert gas and in the presence of a catalyst, polyester monomers and polypolyols react to generate a random copolyester; S2, under the protection of an inert gas and in the presence of an organic solvent and a catalyst, the random copolyester obtained in step S1 is polymerized with isocyanate to generate a prepolymer; S3, in the presence of a solvent, the prepolymer generated in step S2 reacts with a chain extender, and solid-liquid separation is performed to obtain polyurethane. This application uses a stepwise synthesis method of prepolymer to achieve controlled polymerization, which facilitates the purification and structural control of the product at each step, reduces the occurrence of side reactions such as transesterification during the reaction process, and achieves controlled polymerization.

[0059] 9. This application provides a method for preparing a chitosan-polyurethane composite hemostatic sponge, wherein the chain extender in step S3 is a hydroxyl-terminated isocyanate. This application uses a structurally uniform hydroxyl-terminated isocyanate as a chain extender, which can improve the mechanical properties of the polyurethane.

[0060] 10. The chitosan-polyurethane composite hemostatic sponge provided in this application has the functions of absorbing liquid, expanding and compressing, and stopping bleeding. It is suitable for rapid hemostasis of surgical wounds and will not cause the risk of thrombosis. Attached Figure Description

[0061] To more clearly illustrate the technical solutions in the specific embodiments of this application or the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this application. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0062] Figure 1 is a microscopic morphology diagram of the composite hemostatic sponge prepared in Example 1 of this application;

[0063] Figure 2 is another microscopic morphology diagram of the composite hemostatic sponge prepared in Example 1 of this application. Detailed Implementation

[0064] The following embodiments are provided to better understand this application and are not limited to the preferred embodiments described herein. They do not constitute a limitation on the content and scope of protection of this application. Any product that is the same as or similar to this application, derived by anyone under the guidance of this application or by combining features of this application with other prior art, falls within the scope of protection of this application.

[0065] For experiments not specifically described in the examples, the procedures or conditions should be followed according to the conventional experimental procedures described in the literature in this field. Reagents or instruments whose manufacturers are not specified are all commercially available conventional reagent products.

[0066] Preparation Example 1

[0067] This preparation example provides a method for modifying chitosan, with the specific steps and parameters as follows:

[0068] (1) Dissolve 20g of chitosan powder (70% degree of deacetylation, 80,000 Da weight average molecular weight) in 500mL of 2.5 vol% acetic acid solution, then add 750mL of pure methanol solvent, stir and mix to form a homogeneous solution, slowly add 8.22mL of acetic anhydride, and react for 6 hours. After the reaction is complete, add 4M NaOH dropwise to the solution until the pH of the solution is 10. After the chitosan precipitates, continue soaking for 2 hours, filter to obtain the precipitate, soak the precipitate in ethanol for 2 hours to remove impurities, wash the precipitate repeatedly with ethanol, and vacuum dry.

[0069] The degree of deacetylation of the prepared chitosan was determined to be 20% by acid-base titration.

[0070] (2) Take 10g of chitosan with a degree of deacetylation of 20% obtained in step (1), add 50mL of 95%vol ethanol and stir to swell overnight, then add 1.42mL of glacial acetic acid and continue to react for 2h. Wash the precipitate with ethanol 3 times and dry it at 50℃ to obtain a solid. Grind the obtained solid with a ball mill to obtain acid-modified chitosan with a particle size of 5-15μm for later use.

[0071] Preparation Example 2

[0072] This preparation example provides a method for modifying chitosan, with the specific steps and parameters as follows:

[0073] (1) Dissolve 15g of chitosan powder with a weight average molecular weight of 150000Da and a degree of deacetylation of 95% in 500mL of 1.0vol% formic acid solution, then add 900mL of pyridine and stir to form a homogeneous solution. Slowly add 9.16mL of acetic anhydride and react for 8 hours. After the reaction is complete, add 4M NaOH dropwise to the solution to adjust the pH of the solution to 11. After the chitosan precipitates, continue to soak for 2 hours, then filter out the precipitate, soak it in ethanol for 2 hours, wash the precipitate repeatedly, and then vacuum dry it.

[0074] The degree of deacetylation of the prepared chitosan was determined to be 30% by acid-base titration.

[0075] (2) Take 10g of the dried solid from step (1), add 70mL of 95% ethanol and stir to swell overnight. Add 2.08mL of lactic acid and continue the reaction for 3h. Wash the precipitate three times with ethanol and dry at 50℃. Grind the obtained solid with a ball mill to obtain acid-modified chitosan with a particle size of 20-30μm for later use.

[0076] Preparation Example 3

[0077] This preparation example provides a method for modifying chitosan, with the specific steps and parameters as follows:

[0078] (1) Dissolve 30g of chitosan powder with a weight average molecular weight of 300,000 Da and a degree of deacetylation of 88% in 750mL of 2.5vol% hydrochloric acid solution, then add 1312.5mL of isopropanol and stir to form a homogeneous solution. Slowly add 12.68mL of acetic anhydride and react for 7 hours. After the reaction is complete, add 4M NaOH dropwise to the solution to adjust the pH to 12. After the chitosan precipitates, continue soaking for 2 hours, then filter out the precipitate, soak it in ethanol for 2 hours, wash the precipitate repeatedly with ethanol, and dry it under vacuum.

[0079] The degree of deacetylation of the prepared chitosan was determined to be 40% by acid-base titration.

[0080] (2) Take 15g of the dried solid from step (1), add 150mL of 95vol% ethanol and stir to swell overnight. Add 3.77mL of succinic acid and continue the reaction for 4h. Wash the precipitate three times with ethanol and dry at 50℃. Grind the obtained solid with a ball mill to obtain acid-modified chitosan with a particle size of 30-40μm for later use.

[0081] Preparation Example 4

[0082] This preparation example provides a method for modifying chitosan, with the specific steps and parameters as follows:

[0083] (1) Dissolve 36g of chitosan powder with a weight average molecular weight of 200,000 Da and a degree of deacetylation of 92% in 2700mL of 1.5% acetic acid solution, then add 4050mL of methanol and stir to form a homogeneous solution. Slowly add 6.9mL of acetic anhydride and react for 9 hours. After the reaction is complete, add 4M NaOH dropwise to the solution to adjust the pH to 13, so that the chitosan can precipitate completely. Wash the precipitate repeatedly with ethanol and dry it under vacuum.

[0084] The degree of deacetylation of the prepared chitosan was determined to be 50% by acid-base titration.

[0085] (2) Take 20g of the dried solid from step (1), add 80mL of 95% ethanol and stir to swell overnight. Add 5.34mL of glutamic acid and continue the reaction for 4h. Wash the precipitate three times with ethanol and dry at 50℃. Grind the obtained solid with a ball mill to obtain acid-modified chitosan with a particle size of 20-30μm for later use.

[0086] Preparation Example 5

[0087] This preparation example provides a method for modifying chitosan. The specific steps and parameters are the same as in preparation example 1, except that the concentration of acetic acid in step (1) is 0.05 vol%.

[0088] Preparation Example 6

[0089] This preparation example provides a method for modifying chitosan. The specific steps and parameters are the same as in preparation example 1, except that the concentration of acetic acid in step (1) is 3.5 vol%.

[0090] Preparation Example 7

[0091] This preparation example provides a method for modifying chitosan. The specific steps and parameters are the same as in preparation example 1, except that step (2) is not included, that is, the deacetylated chitosan is not acidified.

[0092] Preparation Example 8

[0093] This preparation example provides a method for modifying chitosan. The specific steps and parameters are the same as those in preparation example 1. The difference is that in step (2), the obtained solid is ground with a ball mill to obtain acid-modified chitosan with a particle size range of 5-50 μm.

[0094] Preparation Example 9

[0095] This preparation example provides a method for modifying chitosan. The specific steps and parameters are the same as those in preparation example 1. The difference is that in step (2), the obtained solid is ground with a ball mill to obtain acid-modified chitosan with a particle size range of 1-80 μm.

[0096] Preparation Example 10

[0097] This preparation example provides a method for preparing polyurethane, with the specific steps and parameters as follows:

[0098] (1) Add 18g of polyethylene glycol (molecular weight 600 Da), 5g of D,L-lactide, 3g of ε-caprolactone, 5g of p-dioxane, and 0.005g of stannous octoate to a reaction flask and mix well. Vacuum the flask to ensure that it is oxygen-free and anhydrous. Under nitrogen protection, heat the reaction flask to 130°C and react for 21 hours. The product is repeatedly washed and purified with dichloromethane and acetone to obtain a random copolyester with an average molecular weight of 2170 Da and a glass transition temperature of -45°C. After vacuum drying, it is ready for use.

[0099] (2) Take 3.8g of dry random copolyester and 2.6g of dicyclohexylmethane diisocyanate (HMDI) and add them to the reaction flask. Add dimethyl sulfoxide to the reaction flask to dissolve it. Vacuum the flask to remove oxygen and water, and introduce nitrogen gas. Then heat the reaction flask to 80°C under nitrogen protection and stir to continue the reaction for 8 hours. Add 0.003g of stannous octoate to the reaction flask and continue stirring to maintain the reaction for 6 hours to complete the synthesis of polyurethane single-component prepolymer. Wash the obtained product repeatedly with n-hexane and dry it under vacuum at 60°C. The molecular weight distribution coefficient of the prepolymer is 2.2.

[0100] (3) Take 10g of 1,4-diol and 1.8g of dicyclohexylmethane diisocyanate (HMDI) and react them at 90℃ for 6 hours. Wash the product with acetone and filter it 3 times to obtain the BDO-terminated chain extender.

[0101] (4) The polyurethane one-component prepolymer and chain extender were dissolved in dioxane solvent at a molar ratio of 2:3 and reacted at 70°C for 15 hours. The product was washed and dried to obtain polyurethane solid with a weight average molecular weight of 190,000 Da.

[0102] Preparation Example 11

[0103] This preparation example provides a method for preparing polyurethane, with the specific steps and parameters as follows:

[0104] (1) 42g of polyethylene glycol (800 Da), 16g of D,L-lactide, 13g of ε-caprolactone, 15g of trimethylene carbonate, and 0.005g of stannous octoate were added to a reaction flask and mixed thoroughly. The flask was then evacuated to ensure an oxygen-free and anhydrous environment. Under nitrogen protection, the reaction flask was heated to 110°C and reacted for 24 hours. The resulting product was repeatedly washed and purified with dichloromethane and acetone to obtain a random copolyester with an average molecular weight of 3200 Da and a glass transition temperature of -50°C. After vacuum drying, it was ready for use.

[0105] (2) 10g of dried random copolyester and 6.5g of hexamethylene diisocyanate (HDI) were added to a reaction flask, and dimethyl sulfoxide was added to dissolve them. The mixture was evacuated to remove oxygen and water, and nitrogen gas was introduced. The reaction flask was then heated to 100°C under nitrogen protection, and the reaction was stirred for 4 hours. 0.006g of stannous octoate was added to the reaction flask, and the reaction was maintained at 100°C for 8 hours to complete the synthesis of the polyurethane one-component prepolymer. The resulting product was repeatedly washed with n-hexane and then dried under vacuum at 60°C to obtain a prepolymer with a molecular weight distribution coefficient of 1.9.

[0106] (3) Take 15g of 1,4-diol and 2.0g of hexamethylene diisocyanate (HDI) and react them at 100℃ for 5 hours. Wash the product with acetone and filter it three times to obtain the BDO-terminated chain extender.

[0107] (4) The polyurethane one-component prepolymer and chain extender were dissolved in dioxane solvent at a molar ratio of 2:3 and reacted at 60°C for 20 hours. The product was washed and dried to obtain polyurethane solid with a weight average molecular weight of 400,000 Da.

[0108] Preparation Example 12

[0109] This preparation example provides a method for preparing polyurethane, with the specific steps and parameters as follows:

[0110] (1) 30g of polyethylene glycol with a molecular weight of 1000 Da, 3.0g of D,L-lactide, 2.8g of ε-caprolactone, 1.0g of p-lysine diisocyanate (LDI), and 0.005g of bismuth isooctanoate were added to a reaction flask and mixed thoroughly. The flask was then evacuated to ensure an oxygen-free and anhydrous environment. Under nitrogen protection, the reaction flask was heated to 150℃ and reacted for 20 hours. The resulting product was repeatedly washed and purified with dichloromethane and acetone to obtain a random copolyester with an average molecular weight of 3700 Da and a glass transition temperature of -54℃. After vacuum drying, it was ready for use.

[0111] (2) 12g of dried random copolyester and 14g of lysine diisocyanate (LDI) were added to a reaction flask, and dimethyl sulfoxide was added to the reaction flask to dissolve them. Vacuum was applied to remove oxygen and water, and nitrogen was introduced. The reaction flask was then heated to 60°C under nitrogen protection, and the reaction was stirred for 10 hours. 0.008g of bismuth isooctanoate was added to the reaction flask, and the reaction was stirred for 4 hours to complete the synthesis of the polyurethane one-component prepolymer. The obtained product was repeatedly washed with n-hexane and then dried under vacuum at 60°C to obtain a prepolymer with a molecular weight distribution coefficient of 2.2.

[0112] (3) Take 20g of 1,4-diol and 2.2g of lysine diisocyanate (LDI) and react them at 70℃ for 7 hours. Wash the product with acetone and filter it three times to obtain BDO-terminated chain extender K3.

[0113] (4) The prepolymer and chain extender were dissolved in dioxane solvent at a molar ratio of 2:3 and reacted at 100°C for 10 hours. The product was washed and dried to obtain polyurethane solid with a weight average molecular weight of 680,000 Da.

[0114] Preparation Example 13

[0115] This preparation example provides a method for preparing polyurethane, with the specific steps and parameters as follows:

[0116] (1) 40g of polyethylene glycol with a molecular weight of 3000 Da, 3g of D,L-lactide, 1.5g of ε-caprolactone, 1.6g of lactide, and 0.05g of bismuth neocaprate were added to a reaction flask and mixed thoroughly. The flask was then evacuated to ensure an oxygen-free and anhydrous environment. Under nitrogen protection, the reaction flask was heated to 130℃ and reacted for 20 hours. The resulting product was repeatedly washed and purified with dichloromethane and acetone to obtain a random copolyester with an average molecular weight of 4400 Da and a glass transition temperature of -58℃. After vacuum drying, it was ready for use.

[0117] (2) Add 3g of dry random copolyester and 2g of 1,4-butanediisocyanate (BDI) to a reaction flask, and add dimethyl sulfoxide to the reaction flask to dissolve it. Vacuum the flask to remove oxygen and water, and purge with nitrogen. Add 0.008g of bismuth neodecanoate to the reaction flask, and then heat the reaction flask to 100°C under nitrogen protection. Stir the reaction for 8 hours to complete the synthesis of the polyurethane one-component prepolymer. Wash the obtained product repeatedly with n-hexane and then vacuum dry it at 60°C to obtain a prepolymer with a molecular weight distribution coefficient of 1.6.

[0118] (3) Take 30g of 1,4-diol and 3.3g of 1,4-butanediisocyanate (BDI) and react them at 100℃ for 6 hours. Wash the product with acetone and filter it three times to obtain the BDO-terminated chain extender.

[0119] (4) The prepolymer and chain extender were dissolved in dioxane solvent at a molar ratio of 2:3 and reacted at 80°C for 20 hours. The product was washed and dried to obtain polyurethane solid with a weight average molecular weight of 880,000 Da.

[0120] Example 1

[0121] This embodiment provides a method for preparing a chitosan-polyurethane composite hemostatic sponge, the specific steps and parameters of which are as follows:

[0122] (1) Take 16g of the polyurethane solid prepared in Preparation Example 10 and dissolve it in 400mL of dioxane solution to form a dioxane solution of polyurethane. Add 1.6g of the acid-modified chitosan prepared in Preparation Example 1 and stir at 150rpm for 30 minutes to obtain a mixture.

[0123] (2) Pour the mixture obtained in step (1) of this embodiment into a mold, react at 0°C for 0.5h, freeze at -30°C under normal pressure for 6 hours, then anneal at 5°C for 2 hours, and then vacuum dry at -20°C for 24 hours. Finally, package the obtained freeze-dried product and sterilize it by cobalt-60 irradiation to obtain chitosan polyurethane composite hemostatic sponge.

[0124] Figures 1 and 2 show electron microscope images of the chitosan-polyurethane composite hemostatic sponge prepared in this embodiment at different magnifications. As can be seen from Figures 1 and 2, chitosan particles are embedded in the pore edges of the polyurethane sponge and are distributed relatively evenly.

[0125] Example 2

[0126] This embodiment provides a method for preparing a chitosan-polyurethane composite hemostatic sponge, the specific steps and parameters of which are as follows:

[0127] (1) Take 20g of the polyurethane solid obtained in Preparation Example 11 and dissolve it in 330mL of dimethyl sulfoxide (DMSO) to form a dimethyl sulfoxide solution of polyurethane. Add 4g of the acid-modified chitosan obtained in Preparation Example 2 and stir at 100rpm for 40 minutes to obtain a polyurethane mixture.

[0128] (2) The mixture obtained in step (1) of this embodiment is poured into a mold and reacted at 5°C for 1.5 hours. Then it is frozen at -35°C under normal pressure for 4.5 hours, followed by annealing at 8°C for 3 hours, and then vacuum dried at -30°C for 18 hours. Finally, the obtained freeze-dried product is packaged and sterilized by cobalt-60 irradiation to obtain chitosan polyurethane composite hemostatic sponge.

[0129] Example 3

[0130] This embodiment provides a method for preparing a chitosan-polyurethane composite hemostatic sponge, the specific steps and parameters of which are as follows:

[0131] (1) Take 30g of the polyurethane solid obtained in Preparation Example 12 and dissolve it in 380mL of N,N-dimethylformamide (DMF) to form a polyurethane dimethylformamide solution. Add 10g of the chitosan succinate particles obtained in Preparation Example 3 to the solution and stir at 200rpm for 20 minutes to obtain a polyurethane mixture.

[0132] (2) Pour the mixture obtained in step (4) into a mold, react at 10°C for 3 hours, freeze at -40°C under normal pressure for 3 hours, then anneal at 15°C for 4 hours, and then vacuum dry at -40°C for 12 hours. Finally, package the obtained freeze-dried product and sterilize it by cobalt-60 irradiation to obtain chitosan polyurethane composite hemostatic sponge.

[0133] Example 4

[0134] This embodiment provides a method for preparing a chitosan-polyurethane composite hemostatic sponge, the specific steps and parameters of which are as follows:

[0135] (1) Take 20g of the polyurethane solid obtained in Preparation Example 13 and dissolve it in 200mL of 1,4-dioxane to form a dioxane solution of polyurethane. Add 10g of the acid-modified chitosan obtained in Preparation Example 4 to the solution and stir at 150rpm for 60 minutes to obtain a polyurethane mixture.

[0136] (2) Pour the mixture obtained in step (4)3 into a mold, react at 5°C for 1 hour, freeze at -40°C under normal pressure for 3 hours, then anneal at 15°C for 4 hours, and then vacuum dry at -40°C for 12 hours. Finally, package the obtained freeze-dried product and sterilize it by cobalt-60 irradiation to obtain chitosan polyurethane composite hemostatic sponge.

[0137] Example 5

[0138] This embodiment provides a method for preparing a chitosan-polyurethane composite hemostatic sponge. The specific steps and parameters are the same as in Example 1, except that the mass ratio of chitosan to polyurethane in step (1) is 0.5:1.

[0139] Example 6

[0140] This embodiment provides a method for preparing a chitosan-polyurethane composite hemostatic sponge. The specific steps and parameters are the same as in Example 1, except that the mass ratio of chitosan to polyurethane in step (1) is 0.05:1.

[0141] Example 7

[0142] This embodiment provides a method for preparing a chitosan-polyurethane composite hemostatic sponge. The specific steps and parameters are the same as in Example 1, except that the mass ratio of chitosan to polyurethane in step (1) is 0.6:1.

[0143] Example 8

[0144] This embodiment provides a method for preparing a chitosan-polyurethane composite hemostatic sponge. The specific steps and parameters are the same as in Example 1, except that the annealing step is not set between freezing and drying in step (2). That is, in step (2), the mixture obtained in step (1) of this embodiment is poured into a mold and reacted at 5°C for 1.5 hours, then frozen at -35°C under normal pressure for 4.5 hours, and then vacuum dried at -30°C for 18 hours. Finally, the obtained freeze-dried product is packaged and sterilized by cobalt-60 irradiation to obtain the chitosan-polyurethane composite hemostatic sponge.

[0145] Example 9

[0146] This embodiment provides a method for preparing a chitosan-polyurethane composite hemostatic sponge. The specific steps and parameters are the same as in Example 1. The difference is that the acid-modified chitosan obtained in Preparation Example 5 is used instead of the acid-modified chitosan obtained in Preparation Example 1 in step (1).

[0147] Example 10

[0148] This embodiment provides a method for preparing a chitosan-polyurethane composite hemostatic sponge. The specific steps and parameters are the same as in Example 1. The difference is that the acid-modified chitosan obtained in Preparation Example 6 is used instead of the acid-modified chitosan obtained in Preparation Example 1 in step (1).

[0149] Example 11

[0150] This embodiment provides a method for preparing a chitosan-polyurethane composite hemostatic sponge. The specific steps and parameters are the same as in Example 1. The difference is that the acid-modified chitosan obtained in Preparation Example 7 is used instead of the acid-modified chitosan obtained in Preparation Example 1 in step (1).

[0151] Example 12

[0152] This embodiment provides a method for preparing a chitosan-polyurethane composite hemostatic sponge. The specific steps and parameters are the same as in Example 1. The difference is that the acid-modified chitosan obtained in Preparation Example 8 is used instead of the acid-modified chitosan obtained in Preparation Example 1 in step (1).

[0153] Example 13

[0154] This embodiment provides a method for preparing a chitosan-polyurethane composite hemostatic sponge. The specific steps and parameters are the same as in Example 1. The difference is that the acid-modified chitosan obtained in Preparation Example 9 is used instead of the acid-modified chitosan obtained in Preparation Example 1 in step (1).

[0155] Comparative Example 1

[0156] This comparative example provides a method for preparing a chitosan-polyurethane composite hemostatic sponge. The specific steps and parameters are the same as in Example 1, except that an equal mass of acid-modified chitosan with a degree of deacetylation of 10% is used to replace the acid-modified chitosan in step (1).

[0157] Comparative Example 2

[0158] This comparative example provides a method for preparing a chitosan-polyurethane composite hemostatic sponge. The specific steps and parameters are the same as in Example 1, except that an equal mass of acid-modified chitosan with a degree of deacetylation of 60% is used to replace the acid-modified chitosan in step (1).

[0159] Comparative Example 3

[0160] This comparative example provides a method for preparing a chitosan-polyurethane composite hemostatic sponge. The specific steps and parameters are the same as in Example 1, except that an equal mass of commercially available polyurethane (TECOPHILIC™ SP-80A-150, which does not contain polyester) is used to replace the polyurethane in step (1).

[0161] Comparative Example 4

[0162] This comparative example provides a method for preparing a chitosan-polyurethane composite hemostatic sponge. The specific steps and parameters are the same as in Example 1. The difference is that the reaction temperature in step (2) is 15°C. In step (5), the mixture obtained in step (4) is poured into a mold and reacted at 15°C for 0.5 hours. Then, it is frozen at -30°C under normal pressure for 6 hours. Next, it is annealed at 15°C for 2 hours and then vacuum dried at -20°C for 24 hours. Finally, the freeze-dried product is packaged and sterilized by cobalt-60 irradiation to obtain the chitosan-polyurethane composite hemostatic sponge.

[0163] Comparative Example 5

[0164] This comparative example provides a method for preparing a chitosan polyurethane composite hemostatic sponge. The specific steps and parameters are the same as those in Example 1. The difference is that step (2) does not include the freeze-drying step. That is, in step (2), the mixture obtained in step (1) of this example is poured into a mold, placed at 0°C for 0.5 h, and then vacuum dried at 40°C for 24 h. The obtained product is packaged and sterilized by cobalt-60 irradiation to obtain the chitosan polyurethane composite hemostatic sponge.

[0165] Experimental Example 1

[0166] The porosity, water absorption, compressive strength, in vitro coagulation index, and degradation properties of the chitosan polyurethane composite hemostatic sponges prepared in Examples 1-13 and Comparative Examples 1-5, as well as commercially available hemostatic products, were tested. Among them, Nasopore, a commercially available biodegradable ear and nose hemostatic sponge produced by Stryker, was selected as product 1. The test results are shown in Table 1.

[0167] Porosity and water absorption rate were tested using a MAY-ME104E sponge porosity and water absorption rate analyzer from Miaozhun Technology; compressive strength was tested using a CTM2050 universal testing machine from Shanghai Xieqiang Company; the in vitro coagulation index (BCI) was determined as follows:

[0168] Fresh sodium citrate anticoagulated rabbit whole blood (100 μL) and CaCl2 (0.2 M, 10 μL) were added dropwise to the surface of the sample (0.02 g), and incubated at 37 °C for 5 min. Deionized water (25 mL) was then added, and the mixture was incubated for another 5 min at 37 °C in a constant-temperature shaker. The absorbance of the supernatant at 540 nm was measured using a UV-Vis spectrophotometer (UV8000) from Shanghai Yuanxi Instrument Co., Ltd. (absorbance value denoted as A). 540nmsample No sample group was used as a reference (absorbance value denoted as A). 540nmcontrol ).

[0169] Calculate BCI using the following formula: BCI(%) = A 540nmsample / A 540nmcontrol ×100%;

[0170] The degradation performance testing methods are as follows:

[0171] A phosphate buffer solution with pH = 7.4 ± 0.3 was prepared by mixing 1 / 15 mol / L potassium dihydrogen phosphate and 1 / 15 mol / L disodium hydrogen phosphate at a volume ratio of 18.2:81.8. No other components were added to the solution, and it was sterilized at high temperature before use.

[0172] 1) Accurately weigh the sample to be tested and place it in a sterilized reagent bottle. Add (25±0.5) mL of test solution, cover the sample in the bottle with phosphate buffer, seal, and place in a constant temperature water bath at (37±1)℃ for the preset time. 2) After degradation to the set time point (14 days), remove the container containing the sample. Dry the filter to constant weight under vacuum at 37℃, then filter out sample fragments. Rinse the filter three times with a small amount of deionized water, dry under vacuum at 37℃, and weigh. 3) Calculate the mass difference before and after sample degradation and the percentage of mass loss. Percentage of mass loss % = (Weight of sample before degradation - Weight of sample after degradation) / Weight of sample before degradation × 100%.

[0173] Table 1 Results of hemostatic sponge performance testing

[0174] The test results show that, compared to Comparative Examples 1-5, the chitosan-polyurethane composite hemostatic sponges prepared in Examples 1-4 all have a water absorption rate of over 1800%, a porosity of over 93%, and a compressive strength of over 2.0 N, comparable to commercially available pure polyurethane hemostatic sponges. This demonstrates that the product prepared in this application possesses excellent physical and mechanical properties. This will facilitate rapid blood absorption, resulting in the enrichment of red blood cells and platelets, thereby achieving rapid hemostasis. The good strength also ensures that the product will not break during the hemostasis process.

[0175] Furthermore, as shown in Figures 1 and 2, it can be seen that chitosan particles can be embedded in the pore edges of the polyurethane sponge. Therefore, during hemostasis, the chitosan is bound by the microporous structure of the polyurethane and will not fall off. Moreover, the coagulation index test method used in this experimental example verifies the bonding performance between chitosan and polyurethane on the composite hemostatic sponge through the steps of water washing and shaking. The coagulation index of the composite hemostatic sponges in Examples 1-13 of this application is lower than that of the comparative example, which further proves that the chitosan and polyurethane of the composite hemostatic sponge can be tightly bonded and will not be washed away by liquid, thus exerting a hemostatic effect in the experimental example.

[0176] Meanwhile, the coagulation index (BCI) of the chitosan-polyurethane composite hemostatic sponges prepared in Examples 1-13 of this application was significantly lower than that of Comparative Examples 1-5 and commercially available Product 1, indicating that the modified chitosan exhibited superior coagulation properties, while the commercially available product primarily relied on blood absorption with minimal or no coagulation effect. Comparative Example 4, prepared under non-phase-inversion conditions, had a significantly higher coagulation index than the chitosan-polyurethane composite hemostatic sponges prepared in Examples 1-13 of this application, demonstrating that the mixing conditions in this application significantly impacted product performance. After 14 days of degradation in phosphate buffer solution, the chitosan-polyurethane composite hemostatic sponges prepared in Examples 1-13 of this application showed a mass loss exceeding 70%, similar to commercially available Product 1, meeting the requirements for the in vitro degradation test endpoint in YY / T 0473-2004 "In vitro degradation test of polylactide copolymers and blends for surgical implants". Comparative Example 3, a commercially available thermoplastic polyurethane without a random copolyester structure, exhibited a significantly lower degradation rate than the products in the Examples.

[0177] Experimental Example 2

[0178] The hemostatic effects of the chitosan-polyurethane composite hemostatic sponges prepared in Examples 1-13 and Comparative Examples 1-5, as well as commercially available products, were determined (commercially available product 1 was Nasopore, a biodegradable ear and nose hemostatic sponge manufactured by Stryker Corporation, and commercially available product 2 was Vaseline gauze manufactured by Zhende Medical Supplies Co., Ltd.). The determination methods are as follows:

[0179] Male New Zealand white rabbits, 5 months old, weighing 2-3.5 kg, were used for the first time in animal experiments. During the experiment, the rabbits were anesthetized and fixed on the operating table. Their noses were disinfected with iodine solution. Under nasal endoscopy, a partial removal of the ethmoid turbinate was performed using tissue forceps on the lateral wall of the nasal cavity, approximately 1.5 cm from the anterior nasal opening. Approximately 3×4 mm of the ethmoid turbinate was bitten off with tissue forceps. 2 Organize and create a bleeding wound. After preparing a bleeding model of one side of the rabbit's nasal cavity, immediately pack the bleeding wound with a hemostatic sponge or commercially available product. The packing material should be cut into 0.5cm pieces. 3 Roll it tightly and insert it into the nasal cavity until it is full; after one side is packed, create the same bleeding model in the other nasal cavity.

[0180] Postoperative care: Animals were kept in individual cages after surgery and routine care was provided. The cages were cleaned daily, and the animals' drinking water, mental state, and activity levels were recorded.

[0181] The hemostasis effect was observed under nasal endoscopy. For the first 10 minutes, observations were made every 5 minutes, and after 10 minutes, every 2 minutes. The criterion for stopping bleeding was the absence of blood around the sponge and no active bleeding. Seventy-two hours post-operation, the packing material was removed, and the wound healing and swelling were observed under nasal endoscopy.

[0182] The test sample was fixed to the surface of the wound, and the average hemostasis time of the wound was recorded. The test sample was removed 72 hours after the operation, and the redness and swelling of the wound were observed under nasal endoscopy to determine the degree of wound healing. The results are shown in Table 2. The number of rabbits treated in each treatment group was 10.

[0183] Table 2. Determination of the hemostatic effect of hemostatic sponges

[0184] The above experimental results show that, compared with the chitosan polyurethane composite hemostatic sponges prepared in Comparative Examples 1-5, and commercially available product 1 and product 2, the chitosan polyurethane composite hemostatic sponges prepared in Examples 1-13 of this application can make good contact with the wound, achieve rapid hemostasis, reduce inflammatory response, further accelerate wound healing, and the degree of redness and swelling of the wound is only slight.

[0185] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A method for preparing a chitosan-polyurethane composite hemostatic sponge, characterized in that, Includes the following steps, Chitosan and polyurethane were mixed and reacted under the phase transition conditions of polyurethane to obtain an intermediate. The intermediate was then freeze-dried to obtain a composite hemostatic sponge. The polyurethane is prepared by copolymerization of polyester monomers, polyols, and isocyanate monomers. The degree of deacetylation of the chitosan is 20-50%. The phase transition conditions for the polyurethane are 0-10℃.

2. The method for preparing the chitosan-polyurethane composite hemostatic sponge according to claim 1, characterized in that, The mass ratio of chitosan to polyurethane is (0.1-0.5):1; and / or, The chitosan is mixed with polyurethane, and the reaction time under the phase transition conditions of polyurethane is 0.5 h to 3 h; and / or, Before reacting chitosan with polyurethane, the chitosan and polyurethane solution are mixed under stirring at a speed of 100-200 rpm for 20-60 minutes; and / or, In the freeze-drying process, after freezing the intermediate and before drying, the process also includes an annealing step for the intermediate.

3. The method for preparing the chitosan-polyurethane composite hemostatic sponge according to claim 2, characterized in that, The method for preparing chitosan includes dissolving chitosan raw material and mixing it with an organic solvent to form a solution, adding an acid anhydride to the solution to react, adjusting the pH of the solution to 10-13, separating the solid and liquid phases, and obtaining chitosan with a degree of deacetylation of 20-50%, wherein the ratio of chitosan raw material to acid anhydride is 2-8:1-3, in g:mL; and / or, The solvent in the polyurethane solution includes at least one of dioxane, dimethyl sulfoxide, and N,N-dimethylformamide; and / or, The concentration of polyurethane in the polyurethane solution is 40 g / L-100 g / L; and / or, During the freeze-drying process, the freezing temperature is less than or equal to -30°C, and the freezing time is 3-6 hours. Annealing temperature: 5℃-15℃; annealing time: 2h-4h. The drying temperature is -40℃ to -20℃, and the drying time is 12h to 24h.

4. The method for preparing the chitosan-polyurethane composite hemostatic sponge according to claim 3, characterized in that, The method for preparing chitosan further includes the steps of swelling chitosan with a degree of deacetylation of 20%-50% and then reacting it with a first acid solution, wherein the first acid solution comprises an organic acid; and / or, The degree of deacetylation of the chitosan raw material is 70%-95%, and the weight-average molecular weight is 80,000 Da-300,000 Da; and / or, The mass-to-volume ratio of the chitosan raw material to the reagent for dissolving the chitosan raw material is 1 g: 25-100 mL; and / or, The volume ratio of the reagent to the organic solvent for dissolving the chitosan raw material is 1:1-2; and / or, The reagent for dissolving the chitosan raw material is a second acid solution, which includes at least one of formic acid, acetic acid, hydrochloric acid, and sulfuric acid, and the concentration of the second acid solution is 1-3 vol%; and / or, The organic solvent includes at least one of methanol, isopropanol, or pyridine; and / or, The acid anhydride includes acetic anhydride.

5. The method for preparing the chitosan-polyurethane composite hemostatic sponge according to claim 4, characterized in that, The swelling solvent for swelling chitosan with a degree of deacetylation of 20-50% includes C1-C6 alcohol solvents; and / or, The mass-to-volume ratio of chitosan with a degree of deacetylation of 20-50% to the swelling agent is 0.1-0.2 g:0.5-1 mL; and / or, The organic acid includes at least one selected from acetic acid, lactic acid, glutamic acid, succinic acid, and citric acid; and / or, The particle size of acid-modified chitosan is 1-80 μm.

6. The method for preparing the chitosan-polyurethane composite hemostatic sponge according to any one of claims 1-5, characterized in that, The method for preparing the polyurethane includes the following steps: S1, under the protection of an inert gas and in the presence of a catalyst, polyester monomers and polypolyols react to form random copolyesters. S2, Under the protection of an inert gas and in the presence of an organic solvent, the random copolyester obtained in step S1 is polymerized with isocyanate monomers to form a prepolymer. S3, in the presence of a solvent, the prepolymer generated in step S2 reacts with a chain extender, and polyurethane is obtained by solid-liquid separation.

7. The method for preparing the chitosan-polyurethane composite hemostatic sponge according to claim 6, characterized in that, The polyester monomers in step S1 include D,L-lactide and caprolactone. The polyols include polyethylene glycol; and / or, In step S2, when the random copolyester and isocyanate monomer polymerize to form a prepolymer, the reaction system also includes a catalyst; and / or, The isocyanate monomers in step S2 include diisocyanate monomers. Organic solvents include at least one of dimethyl sulfoxide and N,N-dimethylformamide; and / or, The chain extender in step S3 includes hydroxyl-terminated isocyanates; and / or, The solvent in step S3 includes dioxane.

8. The method for preparing the chitosan-polyurethane composite hemostatic sponge according to claim 7, characterized in that, The random copolyester obtained in step S1 has an average molecular weight of 2000 Da-4500 Da and a glass transition temperature of -40 to -60°C; and / or, The catalyst in step S1 and / or step S2 includes at least one of stannous octanoate, bismuth isooctanoate, or bismuth neocaprate; and / or The chain extender comprises a product obtained by heat treatment, washing, and drying of 1,4-butanediol and isocyanate, wherein the molar ratio of 1,4-butanediol to isocyanate is 10-25:1, the heat treatment temperature is 70℃-100℃, and the heat treatment time is 5h-7h; and / or The molar ratio of D,L lactide and caprolactone in the polyester monomer is 1:0.5-2; and / or, The molar ratio of polyester monomer to polyol is 1-8:1; and / or, The mass ratio of isocyanate monomer to copolyester is 0.5-2:1; and / or, The isocyanate monomer comprises at least one selected from dicyclohexylmethane diisocyanate, hexamethylene diisocyanate, lysine diisocyanate, and 1,4-butanediisocyanate; and / or The polyester monomer also includes at least one of glycolide, trimethylene carbonate, or p-dioxanone.

9. The method for preparing the chitosan-polyurethane composite hemostatic sponge according to claim 8, characterized in that, The reaction temperature in step S1 is 110℃-150℃, and the reaction time is 20h-24h; and / or, The specific steps for generating the prepolymer in step S2 include reacting the random copolyester obtained in step S1 with the isocyanate monomer at 60℃-100℃ for 4h-10h, adding a catalyst, and continuing the reaction for 4h-8h; and / or, The reaction temperature in step S3 is 60℃-100℃, and the reaction time is 10h-20h.

10. A chitosan-polyurethane composite hemostatic sponge, characterized in that, It is prepared by the method described in any one of claims 1-9 for the preparation of chitosan-polyurethane composite hemostatic sponge.

Images