Hemostatic sponge with high liquid absorption capacity and preparation method therefor

Abstract

Disclosed in the present application are a hemostatic sponge and a preparation method therefor. The hemostatic sponge of the present application is composed of a functionalized polymer and a thickening agent, and may optionally comprise a photoinitiator. The functionalized polymer is a functional group-modified natural polymer and / or synthesized polymer. The hemostatic sponge is formed by means of crosslinking via interaction between functional groups or crosslinking induced by the photoinitiator. The functional groups include at least one of hydroxyl, aldehyde group, carboxyl, amino, sulfydryl, hydrazone bond, hydrazide, olefin, alkynyl, polyphenol, succinimidyl active ester, maleimide, and isocyanate. The hemostatic sponge of the present application exhibits the following advantages: shape memory capability, high expansion rate, good mechanical strength, adjustable physical and chemical properties, being compressible, and being injectable. The hemostatic sponge of the present application demonstrates good biocompatibility, biodegradability, rapid water absorption rate and high water uptake capacity, and fast volumetric expansion, and it can adsorb and enrich red blood cells and platelets, thereby promoting blood coagulation and shortening hemostasis time. The hemostatic sponge also has high compression strength and enables pressing hemostasis.

Description

A hemostatic sponge with high liquid absorption capacity and preparation method thereof Technical Field

[0001] The present application relates to the technical field of hemostatic sponge systems, and in particular to a hemostatic sponge with high liquid absorption capacity and a preparation method thereof. Background Art

[0002] Commonly used hemostatic methods in clinical practice include traditional ligation, suturing, electrocoagulation, absorbable hemostatic clips, and tourniquets. These methods are inefficient, difficult to perform, and can obstruct the surgical field of view, posing a significant risk of medical malpractice. In recent years, a variety of materials and formulations have been developed for wound hemostasis and closure, including hemostatic powders, hemostatic gels, hemostatic bandages, and hemostatic sponges. Hemostatic powders are easily washed away by blood flow, entering blood vessels and forming thrombi that are difficult to remove. Hemostatic gels are difficult to apply to wound surfaces under high-pressure blood flow, resulting in ineffective hemostasis. Hemostatic bandages are unsuitable for irregular wounds and cannot stop bleeding from deeper wounds. In contrast, expandable hemostatic sponges have attracted widespread attention due to their ease of use and suitability for treating heavy bleeding and deeper wounds. When compressed, the sponge absorbs blood and tissue fluid, expanding to seal the wound. During this expansion, it absorbs and concentrates red blood cells, platelets, and coagulation factors, thereby increasing the coagulation rate and achieving rapid hemostasis. However, existing expandable hemostatic sponges have shortcomings such as complex preparation methods, poor biocompatibility, low porosity, slow expansion rate after contact with blood, and low blood absorption rate. Therefore, there is an urgent need to develop new sponge preparation strategies.

[0003] On March 9, 2022, Southern University of Science and Technology submitted patent application 202210221842.4 for a newly developed hemostatic sponge with good biocompatibility, higher water absorption rate and water absorption rate, and rapid expansion after absorbing water, and has been granted a patent. In this patent, double-bond compounds and photoinitiators are used to cross-link chitosan, and a hemostatic sponge is formed by vacuum foaming technology and freeze-drying. This patented technology provides a new solution and idea for the development of hemostatic sponge systems. However, in practical applications, it was found that the hemostatic sponge disclosed in the 202210221842.4 patent hardly degrades and cannot be used in some clinical scenarios that require the automatic degradation of the hemostatic sponge.

[0004] Therefore, how to develop a hemostatic sponge that has excellent properties such as good biocompatibility, high water absorption rate, fast water absorption speed, rapid expansion, and can also be automatically degraded remains an important research topic in this field. Summary of the Invention

[0005] The purpose of this application is to provide a new hemostatic sponge and a preparation method thereof.

[0006] In order to achieve the above objectives, this application adopts the following technical solutions:

[0007] One aspect of the present application discloses a hemostatic sponge, which is composed of a functionalized polymer and a thickener, or composed of a functionalized polymer, a thickener and a photoinitiator; wherein the functionalized polymer is a natural polymer and / or a synthetic polymer modified with functional groups, and the functionalized polymer is cross-linked through interactions between functional groups or through a photoinitiator that triggers a reaction of functional groups under light to form a hemostatic sponge; the functional group is at least one of a hydroxyl group, an aldehyde group, a carboxyl group, an amino group, a thiol group, a hydrazone bond, a hydrazide, an olefin, an alkynyl group, a polyphenol, a succinimide ester active ester, a maleimide, and an isocyanate.

[0008] It should be noted that the hemostatic sponge of the present application can, in the presence of a photoinitiator, initiate a reaction of functional groups to crosslink under light to form a hemostatic sponge; in the absence of a photoinitiator, the hemostatic sponge is formed by self-reaction and crosslinking between functional polymer groups.

[0009] It should also be noted that the hemostatic sponge of this application utilizes cross-linking through interactions between functional groups. This not only provides excellent biocompatibility, high water absorption, rapid water absorption, and rapid expansion, but also allows for degradation, better meeting diverse clinical needs. Furthermore, the components of the hemostatic sponge of this application can adsorb and enrich red blood cells and platelets, promoting coagulation and reducing hemostasis time. Furthermore, the sponge has high compressive strength, meeting the requirements for pressure-assisted hemostasis.

[0010] In one implementation of the present application, the hemostatic sponge is composed of 1-40 parts by weight of a functionalized polymer, 0.1-10 parts by weight of a thickener, and 0-2 parts by weight of a photoinitiator.

[0011] It should be noted that the hemostatic sponge of the present application may contain a photoinitiator or may not contain a photoinitiator; therefore, the weight portion of the photoinitiator is 0-2.

[0012] In one implementation of the present application, the functionalized polymer is at least one of a functionalized natural polymer and a functionalized synthetic polymer; wherein the functionalized natural polymer is a natural polymer modified with functional groups, and the functionalized synthetic polymer is a synthetic polymer modified with functional groups.

[0013] It should be noted that the key to this application is to achieve cross-linking through the interaction between functional groups. As for the functionalized polymer, functionalized natural polymers or functionalized synthetic polymers can be used; considering the biocompatibility of the material, functionalized natural polymers are preferably used.

[0014] In one implementation of the present application, the functionalized natural polymer is hyaluronic acid, chitosan, gelatin, starch, cellulose, alginate, bletilla striata polysaccharide, konjac glucomannan, agarose, dextran, gum arabic, pectin, hemoglobin, keratin, mussel mucin, collagen, phycocyanin, lysozyme, bovine serum albumin, silk fibroin, and at least one of the derivatives of these natural polysaccharides or natural proteins modified with functional groups.

[0015] In one implementation of the present application, the functionalized synthetic polymer is at least one of polyethylene glycol modified with functional groups, polyoxyethylene-polypropylene ether copolymer, polylactic acid-glycolic acid copolymer, polyvinyl alcohol, polyacrylamide, polyacrylic acid, poly-L-lysine, ε-polylysine, poly-L-glutamic acid, γ-polyglutamic acid, poly(N-isopropylacrylamide), silsesquioxane and derivatives of these synthetic polymers.

[0016] It should be noted that the above natural and synthetic polymers are currently known polymers that can be used to form gel structures. The key to this application lies in the use of different cross-linking methods to obtain the hemostatic sponge with a special structure of this application. Therefore, it is not ruled out that other natural and synthetic polymers with similar functions can also be used.

[0017] In one implementation of the present application, the thickener is at least one of starch, gum arabic, agar, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose and carboxymethyl chitosan.

[0018] In one implementation of the present application, the photoinitiator is at least one of photoinitiator 651, photoinitiator 1173, photoinitiator 2959, TPO, α-ketoglutaric acid, and LAP.

[0019] Another aspect of the present application discloses a method for preparing the hemostatic sponge of the present application, comprising the following steps:

[0020] (1) dissolving a functionalized polymer and a thickener, or a functionalized polymer, a thickener, and a photoinitiator in a solvent to prepare a precursor liquid;

[0021] (2) stirring the precursor liquid to generate a large number of relatively uniform bubbles;

[0022] (3) decompressing the precursor liquid containing uniform bubbles to expand the precursor liquid;

[0023] (4) After the pressure stabilizes and the volume of the precursor liquid no longer changes, a gel network is formed by a cross-linking reaction of the precursor liquid itself, or light is irradiated to cause the precursor liquid to cross-link to form a gel network;

[0024] (5) cooling the product of step (4) to fix the network structure;

[0025] (6) Soaking the product of step (5) in pure water;

[0026] (7) The product of step (6) is taken out and freeze-dried to obtain the hemostatic sponge of the present application.

[0027] It should be noted that the preparation method of the hemostatic sponge of the present application is completely different from the existing preparation method, especially the preparation method of patent 202210221842.4, in terms of preparation method, process, raw materials and cross-linking method. On the one hand, chitosan is not a necessary component in the preparation method of the present application. In addition, the present application utilizes the cross-linking of intergroup interactions of functionalized polymers, without the need for salt soaking to induce cross-linking, so that the hemostatic sponge of the present application has a higher swelling rate, forming a high-expansion hemostatic sponge with an interconnected macroporous structure, the sponge has a stronger liquid absorption capacity and the sponge material is degradable.

[0028] In one implementation of the present application, the solvent in step (1) is pure water.

[0029] It should be noted that using pure water as a solvent is, on the one hand, more environmentally friendly and low-cost; on the other hand, pure water can effectively dissolve functionalized polymers and thickeners, allowing the precursor liquid to expand stably during subsequent decompression treatment, ultimately forming a macroporous structure.

[0030] In one implementation of the present application, 1-40 parts by weight of a functionalized polymer, 0.1-10 parts by weight of a thickener, and 0-2 parts by weight of a photoinitiator are dissolved in 100 parts by weight of pure water to prepare a precursor liquid.

[0031] In one implementation of the present application, the stirring method of step (2) is manual stirring or stirring with a stirring device.

[0032] It should be noted that the stirring in the present application only needs to stir the precursor liquid to obtain bubbles of relatively uniform size and fineness. As for the specific use of manual stirring or stirring with a stirring device, it can be determined according to actual conditions.

[0033] In one implementation of the present application, the vacuum degree of the decompression treatment in step (3) is 20-300 mbar.

[0034] It should be noted that the purpose of the decompression treatment is to achieve uniform and stable expansion of the precursor liquid. It is understood that if the vacuum level is too low, the expansion rate will be slow and the desired expansion effect will be difficult to achieve; if the vacuum level is too high, the bubbles will easily burst, making it difficult to form a stable expanded structure. Therefore, this application preferably uses a vacuum level of 20-300 mbar for the decompression treatment.

[0035] In one implementation of the present application, the illumination in step (4) uses ultraviolet light with a wavelength of 200-450nm.

[0036] It should be noted that light irradiation mainly refers to the process of initiating crosslinking by ultraviolet light of 200-450 nm in the presence of a photoinitiator.

[0037] In one implementation of the present application, in step (4), the precursor liquid is cross-linked to form a gel network, or light is irradiated to cause the precursor liquid to cross-link to form a gel network, and the time for cross-linking to form the gel network is 1-20 minutes.

[0038] In one implementation of the present application, the cooling treatment in step (5) includes placing the product of step (4) at -180°C to 5°C to rapidly cool it down and fix the shape of the sample.

[0039] It should be noted that the cooling treatment in the present application is mainly to quickly cool the expanded precursor fluid so as to better fix the shape of the sample.

[0040] In one implementation of the present application, in step (6), the time for soaking the product of step (5) in pure water is 0.5-48 hours.

[0041] Due to the adoption of the above technical solution, the beneficial effects of this application are:

[0042] The hemostatic sponge and its preparation method of the present application utilize cross-linking reactions between functional groups of functionalized polymers, resulting in advantages such as shape memory, high expansion rate, good mechanical strength, adjustable physical and chemical properties, compressibility, and injectability. The sponge exhibits excellent biocompatibility, high water absorption rate, rapid water absorption, and rapid expansion, and is also capable of in vitro degradation, better meeting diverse clinical needs. The sponge can also adsorb and enrich red blood cells and platelets, promoting coagulation and reducing hemostasis time. It also possesses high compressive strength, meeting the requirements for pressure-assisted hemostasis. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] FIG1 is a photograph of the appearance of the hemostatic sponge prepared in an embodiment of the present application;

[0044] FIG2 is a SEM image of a hemostatic sponge adsorbing red blood cells in an embodiment of the present application;

[0045] FIG3 is a SEM image of the hemostatic sponge adsorbing platelets in an embodiment of the present application;

[0046] FIG4 is a diagram showing the experimental effect of a hemostatic sponge hemostasis experiment in an embodiment of the present application. DETAILED DESCRIPTION

[0047] The hemostatic sponge of the present application, its preparation method mainly includes: after the precursor liquid is stirred to obtain bubbles, the bubbles are expanded and interconnected by controlling the vacuum degree of the system to obtain a macroporous structure, and then the network structure is fixed by cross-linking and cooling treatment of the functionalized polymer groups, and further freeze-drying is performed to obtain a sponge material, as shown in Figure 1. The hemostatic sponge of the present application can be placed in an injection device after compression and injected into the wound site when in use. At this time, the compressed sponge quickly absorbs a large amount of blood and expands in volume; the sponges that have restored their original shape are stacked on each other and physically block the bleeding wound, thereby avoiding being washed away by the blood flow, thereby achieving effective blocking of the bleeding wound. The hemostatic sponge of the present invention has good biocompatibility, is simple to make, and can be made into different shapes and sizes as needed, and is suitable for a variety of tissue injuries.

[0048] The hemostatic sponge obtained by the preparation method of this application has a porous structure, which facilitates blood absorption and volume expansion recovery of the compressed sponge, thereby achieving rapid hemostasis. Furthermore, the sponge's interconnected porous structure and bioactive natural polymers can adsorb and enrich red blood cells, promoting coagulation. This gives the hemostatic sponge of this application advantages such as shape memory, high expansion rate, excellent mechanical strength, adjustable physical and chemical properties, compressibility, and injectability.

[0049] Therefore, compared with the prior art, the hemostatic sponge of the present application has the following advantages:

[0050] (1) The raw materials of the hemostatic sponge of the present application are widely available and have high biocompatibility.

[0051] (2) The preparation method of the hemostatic sponge of the present application is simple, the preparation cycle is short and the performance is adjustable.

[0052] (3) The hemostatic sponge of the present application has a higher liquid absorption capacity than existing products, and its volume can expand rapidly after absorbing liquid; when the hemostatic sponge of the present application is compressed and applied to a bleeding wound, it can quickly seal the wound and achieve effective physical sealing and hemostasis.

[0053] (4) The hemostatic sponge of the present application can adsorb and enrich red blood cells and platelets, as shown in Figures 2 and 3, thereby promoting coagulation and reducing hemostasis time.

[0054] (5) The hemostatic sponge of the present application has high compression strength and meets the requirements of pressing to stop bleeding.

[0055] The present invention is further described in detail below through specific examples and drawings. The following examples are only used to further illustrate the present invention and should not be construed as limiting the present invention.

[0056] The terms used in this application, unless otherwise specified, generally have the meanings commonly understood by those of ordinary skill in the art.

[0057] In the following examples, various processes and methods not described in detail are conventional methods well known in the art.

[0058] Example 1

[0059] Weigh 0.15g of olefin-functionalized chitosan (300kDa), 0.1g of olefin-functionalized gelatin (60kDa), 0.001g of thickener carboxymethyl chitosan, and 0.005g of photoinitiator LAP. Dissolve all ingredients in 1g of ultrapure water and stir the precursor solution to create uniform bubbles. The solution is then placed in a reaction flask, evacuated to 20mbar, and, after the pressure stabilizes, illuminated with 450nm UV light for 20 minutes. After the reaction is complete, cool the flask to 5°C to set the shape. After forming, remove the flask, soak it in ultrapure water for 0.5h, and finally freeze-dry it in a freeze dryer to obtain the sponge material. A photograph of the hemostatic sponge prepared in this example is shown in Figure 1.

[0060] Water absorption performance and water absorption time test: Take a dry sponge with a height of about 10mm and weigh the initial mass as W0. After compression, immerse it in ultrapure water. The time required for the sponge to return to its original shape is recorded as the water absorption time. After that, take out the sponge every 10 minutes, quickly wipe the residual water on the surface with filter paper, and weigh the sponge. Weigh it 5 times and take the average value. After weighing, continue to immerse the sponge in pure water. After absorbing liquid, the mass of the sponge does not change after three consecutive weighings. It is recorded as the mass of the sponge at equilibrium swelling W. t The water absorption performance of the sponge is calculated as follows:

[0061] Where SR is the water absorption rate of the sponge, W t is the mass of the sponge when it absorbs water to reach equilibrium swelling, and W0 is the initial mass of the sponge before absorbing water.

[0062] The water absorption rate of the sponge measured according to the above method is 3800%, and the time taken for water absorption is 15 seconds.

[0063] Water retention test: Take a dry sponge approximately 10 mm tall and weigh its initial mass, W0. Immerse it in ultrapure water until fully swelled. Remove and centrifuge at 500 rpm for 3 minutes. The mass is recorded as W1. The water retention of the sponge is calculated using the following formula:

[0064] Where WRV is the water retention rate of the sponge, W1 is the mass of the sponge after saturation with water and further centrifugation, and W0 is the initial mass of the sponge before water absorption.

[0065] The water retention rate of the sponge measured according to the above method is 920%.

[0066] Compression performance test: After the sponge has reached equilibrium with water absorption and swelling and has been centrifuged, samples with a diameter to height ratio of 1:0.33-1:0.67 are cut out and subjected to 80% cyclic compression at a speed of 5 mm / min using a universal testing machine to obtain the maximum compression strength δ c .

[0067] The compressive strength of the sponge measured according to the above method is 56 kPa.

[0068] Porosity and density measurements:

[0069] Take a piece of dried sponge and weigh its initial mass as W s ; Place the sponge in a container and add a certain amount of ethanol to weigh the total mass W of the container, ethanol, and sponge a After ultrasonicating the container for 2 minutes, remove the sponge and weigh the total mass W of the container and the remaining ethanol. b Fill a graduated cylinder with a certain amount of ethanol and weigh the total mass W1. Mark the scale at this point. Place the removed sponge back into the graduated cylinder, remove the excess ethanol to return the liquid level to the original scale, and weigh the total mass W2. The porosity (P) of the sponge is calculated using the following formula:

[0070] The density of sponge (ρ) is calculated as follows:

[0071] Among them, ρ E is the density of ethanol.

[0072] The porosity of the sponge measured by the above method is 85% and the density is 0.056 g / cm 3 .

[0073] Measurement of hemostasis time and blood loss:

[0074] Rat femoral artery / vein transection hemostasis test: The rat's right femoral artery was exposed, and a 6mm tissue sampler / punch was used to create a cavity approximately 10mm deep in the femoral artery and surrounding tissue. The compressed sponge was then injected into the cavity. Blood was collected with absorbent cotton and observed for bleeding. The time required for blood to stop flowing was the hemostasis time, and the mass of blood collected was the blood loss. The hemostatic effect is shown in Figure 4. SEM images of the hemostatic sponge adsorbing red blood cells and platelets were observed. The SEM images of the hemostatic sponge adsorbing red blood cells are shown in Figure 2, and the SEM images of the hemostatic sponge adsorbing platelets are shown in Figure 3.

[0075] The hemostasis time measured according to the above method was 189 s, and the blood loss was 2.67 g.

[0076] Degradation time test: Take a dry sponge sample with a height of about 10 mm, place it in a sealed container filled with 1×PBS, and then place the container in a constant temperature shaker at 37±1°C. Observe the changes in the sample at a speed of 100 r / min until it is invisible to the naked eye. This is recorded as the in vitro degradation time of the sponge sample.

[0077] The in vitro degradation time measured according to the above method is 38 days.

[0078] Example 2

[0079] Weigh 0.02g of amino-functionalized hyaluronic acid (15kDa), 0.02g of aldehyde-functionalized poly(lactic-co-glycolic acid) (PLGA-CHO) (10kDa), and 0.02g of the thickener gum arabic. Dissolve all ingredients in 1g of ultrapure water. Stir the precursor solution to create uniform bubbles. Place the solution in a reaction flask and evacuate to 300mbar. Once the pressure stabilizes, wait 10 minutes to allow the groups to react. The reaction flask is then cooled to -40°C to set. After forming, remove the flask, soak it in ultrapure water for 48 hours, and finally freeze-dry it in a freeze dryer to obtain the sponge material.

[0080] According to the test method of Example 1, the sponge has a water absorption rate of 5400%, a water absorption time of 3s, a water retention rate of 1970%, a compressive strength of 29kPa, a porosity of 97%, and a density of 0.024g / cm 3 The hemostasis time was 96s, the blood loss was 1.99g, and the in vitro degradation time was 12d.

[0081] Example 3

[0082] Weigh 0.025g of 100kDa olefin-functionalized gelatin, 0.05g of 12.6kDa olefin-functionalized polyoxyethylene-polypropylene ether copolymer (PF127-C=C), 0.01g of photoinitiator 2959, and 0.03g of 250kDa thickener carboxymethyl cellulose. Dissolve all ingredients in 1g of ultrapure water. Stir the precursor solution to create uniform bubbles. Place the solution in a reaction flask, evacuate to 130mbar, and illuminate with 365nm ultraviolet light for 10 minutes after the pressure stabilizes. The flask is then placed in liquid nitrogen to cool and set. After forming, remove the flask, soak it in ultrapure water for 6 hours, and finally freeze-dry it in a freeze dryer to produce a sponge material.

[0083] According to the test method of Example 1, the water absorption rate of the sponge was measured to be 11000%, the time taken for water absorption was 27s, the water retention rate was 2700%, the compressive strength was 11.5kPa, the porosity was 96%, and the density was 0.021g / cm 3The hemostasis time was 105s, the blood loss was 2.4g, and the in vitro degradation time was 5d.

[0084] Example 4

[0085] Weigh 0.1g of 100kDa succinimidyl ester-functionalized poly (L-glutamic acid) (L-PGA-NHS), 0.03g of 100kDa amino-functionalized poly (vinyl alcohol) (PVA-NH2), and 0.005g of 100kDa thickener starch and dissolve all ingredients in 1g of ultrapure water. Stir the precursor solution to create uniform bubbles. Place the solution in a reaction flask and evacuate to 120mbar. Wait 15 minutes for the pressure to stabilize, then cool the flask to -100°C to set the shape. After forming, remove the flask, soak it in ultrapure water for 3 hours, and finally freeze-dry it in a freeze dryer to obtain the sponge material.

[0086] According to the test method of Example 1, the water absorption rate of the sponge was measured to be 4900%, the time taken for water absorption was 16s, the water retention rate was 2300%, the compressive strength was 96kPa, the porosity was 88%, and the density was 0.031g / cm 3 The hemostasis time was 165s, the blood loss was 2.56g, and the in vitro degradation time was 42d.

[0087] Example 5

[0088] Weigh 0.08g of phenolic hydroxyl-functionalized mussel mucin (a molecular weight greater than 400kDa), 0.05g of phenolic hydroxyl-functionalized polyacrylic acid (PAA-DOPA) (a molecular weight of 1kDa), and 0.05g of hydroxyethyl cellulose (a thickener with a molecular weight of 100kDa) and dissolve all ingredients in 1g of ultrapure water. Stir the precursor solution to create uniform bubbles. Place the solution in a reaction flask and evacuate to 250mbar. Wait 15 minutes for the pressure to stabilize before cooling the flask to -20°C to set the shape. After forming, remove the flask, soak it in ultrapure water for 24 hours, and finally freeze-dry it in a freeze dryer to obtain the sponge material.

[0089] According to the test method of Example 1, the water absorption rate of the sponge was measured to be 12000%, the time taken for water absorption was 3s, the water retention rate was 3400%, the compressive strength was 6kPa, the porosity was 86%, and the density was 0.04g / cm 3 The hemostasis time was 127s, the blood loss was 1.46g, and the in vitro degradation time was 29d.

[0090] Example 6

[0091] Weigh 0.15g of amino-functionalized gelatin (15kDa or greater), 0.15g of 10kDa succinimidyl ester-functionalized four-arm polyethylene glycol (4-arm-PEG-NHS), and 0.01g of a 10kDa thickener, carboxymethyl chitosan. Dissolve all ingredients in 1g of ultrapure water. Stir the precursor solution to create uniform bubbles. Place the solution in a reaction flask and evacuate to 200mbar. Wait for 1 minute for the pressure to stabilize, then cool the flask to -80°C to set. After forming, remove the flask, soak it in ultrapure water for 0.5h, and finally freeze-dry it in a freeze dryer to obtain the sponge.

[0092] According to the test method of Example 1, the water absorption rate of the sponge was measured to be 8700%, the time taken for water absorption was 2.7s, the water retention rate was 2200%, the compressive strength was 154kPa, the porosity was 91%, and the density was 0.036g / cm 3 The hemostasis time was 92s, the blood loss was 1.69g, and the in vitro degradation time was 1d.

[0093] Example 7

[0094] Weigh 0.1g of 100kDa γ-polyglutamic acid, 0.1g of 100kDa carboxyl-functionalized alginate, and 0.008g of 100kDa thickener methylcellulose and dissolve all ingredients in 1g of ultrapure water. Stir the precursor solution to form uniform bubbles. Place the solution in a reaction flask and evacuate to 150mbar. Wait for 2 minutes after the pressure stabilizes. Then, place the flask in liquid nitrogen to cool and set the sponge. After forming, remove the sponge and soak it in ultrapure water for 5 hours. Finally, freeze-dry it in a freeze dryer to obtain the sponge.

[0095] According to the test method of Example 1, the sponge has a water absorption rate of 4900%, a water absorption time of 23s, a water retention rate of 2000%, a compressive strength of 51kPa, a porosity of 89%, and a density of 0.051g / cm 3 The hemostasis time was 131s, the blood loss was 2.24g, and the in vitro degradation time was 9d.

[0096] Example 8

[0097] Weigh 0.1g of thiol-functionalized Bletilla striata polysaccharide (6.5kDa or greater), 0.15g of thiol-functionalized polyacrylamide (PAAM-SH) (1kDa), and 0.1g of hydroxyethyl cellulose (150kDa thickener) and dissolve all ingredients in 1g of ultrapure water. Stir the precursor solution to create uniform bubbles. Place the solution in a reaction flask and evacuate to 130mbar. Wait for 5 minutes after the pressure stabilizes, then cool the flask to -60°C to set. After forming, remove the flask, soak it in ultrapure water for 2 hours, and finally freeze-dry it in a freeze dryer to obtain the sponge.

[0098] According to the test method of Example 1, the sponge has a water absorption rate of 6900%, a water absorption time of 16s, a water retention rate of 1800%, a compressive strength of 68kPa, a porosity of 94%, and a density of 0.029g / cm 3 The hemostasis time was 127s, the blood loss was 1.95g, and the in vitro degradation time was 14d.

[0099] Embodiment 9

[0100] Weigh 0.1g of 610kDa thiolated dextran, 0.5g of 12.6kDa alkynyl-functionalized polyoxyethylene-polypropylene ether copolymer (PF127-C≡C), 0.05g of 250kDa thickener agar, and 0.01g of photoinitiator α-ketoglutaric acid. Dissolve all ingredients in 1g of ultrapure water. Stir the precursor solution to create uniform bubbles. Then, place the solution in a reaction flask, evacuate to 280mbar, and illuminate the flask with 284nm UV light for 8 minutes after the pressure stabilizes. After the reaction is complete, cool the flask to -120°C to set the shape. After forming, remove the flask, soak it in ultrapure water for 8 hours, and finally freeze-dry it in a freeze dryer to obtain the sponge.

[0101] According to the test method of Example 1, the sponge has a water absorption rate of 7100%, a water absorption time of 9.8s, a water retention rate of 1900%, a compressive strength of 39kPa, a porosity of 92%, and a density of 0.034g / cm 3 The hemostasis time was 134s, the blood loss was 2.01g, and the in vitro degradation time was 18d.

[0102] Example 10

[0103] Weigh 0.05g of 40kDa phycocyanin, 0.05g of 1kDa aldehyde-functionalized silsesquioxane (POSS-CHO), and 0.01g of 50kDa thickening starch and dissolve all ingredients in 1g of ultrapure water. Stir the precursor solution to create uniform bubbles. Place the solution in a reaction flask and evacuate to 180mbar. Wait 18 minutes for the pressure to stabilize before cooling the flask to -150°C to set the shape. After forming, remove the flask, soak it in ultrapure water for 10 hours, and finally freeze-dry it in a freeze dryer to obtain the sponge.

[0104] According to the test method of Example 1, the sponge has a water absorption rate of 4600%, a water absorption time of 8.6s, a water retention rate of 1560%, a compressive strength of 69kPa, a porosity of 91%, and a density of 0.039g / cm 3 The hemostasis time was 145s, the blood loss was 2.21g, and the in vitro degradation time was 11d.

[0105] Example 11

[0106] Weigh 0.2g of 50kDa carboxyl-functionalized starch, 0.1g of 200kDa hydroxyl-functionalized polyvinyl alcohol (PVA), and 0.002g of 500kDa thickener methylcellulose and dissolve all ingredients in 1g of ultrapure water. Stir the precursor solution to create uniform bubbles. Place the solution in a reaction flask and evacuate to 80mbar. Wait for 3 minutes after the pressure stabilizes, then cool the flask to -20°C to set. After forming, remove the flask, soak it in ultrapure water for 0.5h, and finally freeze-dry it in a freeze dryer to obtain a sponge.

[0107] According to the test method of Example 1, the sponge has a water absorption rate of 4100%, a water absorption time of 7.6s, a water retention rate of 2100%, a compressive strength of 84kPa, a porosity of 87%, and a density of 0.049g / cm 3 The hemostasis time was 119s, the blood loss was 1.74g, and the in vitro degradation time was 37d.

[0108] The above content is a further detailed description of the present application in conjunction with specific implementation methods, and the specific implementation of the present application cannot be considered to be limited to these descriptions. For ordinary technicians in the technical field to which the present application belongs, several simple deductions or substitutions can be made without departing from the concept of the present application.

Claims

1. A method for preparing a hemostatic sponge, characterized in that: It includes the following steps: (1) Dissolve the functionalized polymer and the thickener, or the functionalized polymer, the thickener and the photoinitiator in a solvent to prepare a precursor solution. (2) Stir the precursor solution to generate a large number of relatively uniform bubbles. (3) Subject the precursor solution with uniform bubbles to a pressure reduction treatment to expand the precursor solution. (4) Wait until the pressure is stable and the volume of the precursor solution no longer changes, and wait for the precursor solution to crosslink to form a gel network, or perform light irradiation to make the precursor solution crosslink to form a gel network. (5) Cool the product of step (4) to fix the network structure. (6) Immerse the product of step (5) in pure water. (7) Take out the product of step (6) and freeze-dry it to obtain the hemostatic sponge. In step (3), the vacuum degree of the pressure reduction treatment is 20 - 300 mbar. In step (5), the cooling treatment includes placing the product of step (4) at -180°C to 5°C to rapidly cool it and fix the sample shape. In step (6), the product of step (5) is immersed in pure water for 0.5 - 48 h. The hemostatic sponge is composed of a functionalized polymer and a thickener, or composed of a functionalized polymer, a thickener and a photoinitiator. The functionalized polymer is a natural polymer and / or a synthetic polymer modified with functional groups. The functionalized polymer crosslinks through the interaction between functional groups or is further crosslinked by adding a photoinitiator and light irradiation to form a hemostatic sponge. The functional groups are at least one of hydroxyl group, aldehyde group, carboxyl group, amino group, mercapto group, hydrazone bond, hydrazide, alkene, alkyne group, polyphenol, succinimidyl active ester, maleimide, isocyanate.

2. The preparation method according to claim 1, wherein: In step (1), the solvent is pure water.

3. The preparation method according to claim 2, characterized in that: Dissolve 1 - 40 parts by weight of the functionalized polymer, 0.1 - 10 parts by weight of the thickener and 0 - 2 parts by weight of the photoinitiator in 100 parts by weight of pure water to prepare a precursor solution.

4. The preparation method according to claim 1, wherein: In step (2), the stirring method is manual stirring or stirring with a stirring device.

5. The preparation method according to any one of claims 1-4, characterized in that: In step (4), the light irradiation uses ultraviolet light with a wavelength of 200 - 450 nm.

6. The preparation method according to claim 5, wherein: In step (4), the precursor solution crosslinks to form a gel network, or, light irradiation is performed to make the precursor solution crosslink to form a gel network, and the time for crosslinking to form a gel network is 1 - 20 min.

7. The preparation method according to any one of claims 1-4, characterized in that: The natural polymer is at least one of hyaluronic acid, chitosan, gelatin, starch, cellulose, alginate, bletilla striata polysaccharide, konjac glucomannan, agarose, dextran, arabic gum, pectin, hemoglobin, keratin, mussel adhesive protein, collagen, phycocyanin, lysozyme, bovine serum albumin, silk fibroin, and derivatives of these natural polysaccharides or natural proteins.

8. The preparation method according to any one of claims 1-4, characterized in that: The synthetic polymer is at least one of polyethylene glycol, polyoxyethylene - polypropylene ether copolymer, poly(lactic - glycolic acid) copolymer, polyvinyl alcohol, polyacrylamide, polyacrylic acid, poly(L - lysine), ε - polylysine, poly(L - glutamic acid), γ - polyglutamic acid, poly(N - isopropylacrylamide), silsesquioxane and derivatives of these synthetic polymers.

9. The preparation method according to any one of claims 1-4, characterized in that: The thickener is at least one of starch, arabic gum, agar, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose and carboxymethyl chitosan.

10. The preparation method according to any one of claims 1-4, characterized in that: The photoinitiator is at least one of photoinitiator 651, photoinitiator 1173, photoinitiator 2959, TPO, α-ketoglutaric acid, and LAP.

11. A hemostatic sponge prepared by the preparation method according to any one of claims 1-10.

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