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

Abstract

The present application discloses a hemostatic sponge and a preparation method thereof. The hemostatic sponge of the present application is composed of a functionalized polymer and a thickener, or a photoinitiator may be added; the functionalized polymer is a natural polymer and / or a synthetic polymer modified with a functional group, and the hemostatic sponge is formed by crosslinking through interaction between functional groups or crosslinking initiated by a photoinitiator; the functional group is at least one of hydroxyl, aldehyde, carboxyl, amino, thiol, hydrazone bond, hydrazide, olefin, alkynyl, polyphenol, succinimide ester active ester, maleimide, and isocyanate. The hemostatic sponge of the present application has the advantages of shape memory ability, high expansion rate, good mechanical strength, adjustable physical and chemical properties, compressibility and injectability; the hemostatic sponge of the present application has good biocompatibility, is degradable, has a high water absorption rate and water absorption rate, and has a fast volume expansion, and can adsorb and enrich red blood cells and platelets, promote coagulation, and reduce hemostasis time; the hemostatic sponge also has high compression strength and can be pressed to stop bleeding.

Description

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 are traditional ligation, suturing, electrocoagulation, absorbable hemostatic clips and tourniquets. These methods are not only inefficient and difficult to operate, but also affect the surgical field of view and cause hidden medical accidents. In recent years, various material formulations have been developed for hemostatic closure of trauma, including hemostatic powder, hemostatic gel, hemostatic bandage and hemostatic sponge. Among them, hemostatic powder is easily washed away by blood flow, and it is easy to form thrombus when entering blood vessels driven by blood flow, and it is difficult to remove later; hemostatic gel is difficult to apply on the wound surface under high-pressure blood flow environment, resulting in low hemostatic efficiency; hemostatic bandage is not suitable for irregular wounds and cannot block bleeding from deeper wounds. In comparison, expandable hemostatic sponge has attracted widespread attention because of its simple operation and ability to handle heavy bleeding and deeper wounds. The compressed sponge placed on the wound will absorb blood and tissue fluid and expand in volume to seal the wound. During the expansion process, it can adsorb and enrich red blood cells, platelets and coagulation factors in the blood, thereby increasing the coagulation rate and achieving the purpose of 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 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 be automatically degraded is still 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 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 inducing 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 initiate functional group reaction and cross-linking to form a hemostatic sponge under light in the presence of a photoinitiator; in the absence of a photoinitiator, the hemostatic sponge is formed by self-reaction and cross-linking between functionalized polymer groups.

[0009] It should also be noted that the hemostatic sponge of the present application uses the interaction between functional groups to achieve cross-linking, which not only has good biocompatibility, high water absorption rate, fast water absorption speed, and rapid expansion, but also can be degraded, which can better meet different clinical use needs. In addition, the components contained in the hemostatic sponge of the present application can adsorb and enrich red blood cells and platelets, promote coagulation, and reduce hemostasis time; and it has a high compression strength, meeting the requirements of pressing 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 the present application is to achieve cross-linking through the interaction between functional groups. As for the functionalized polymer, either functionalized natural polymer or functionalized synthetic polymer can be used. Considering the biocompatibility of the material, functionalized natural polymer is 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 polymers and synthetic polymers are currently known polymers that can be used to form a gel structure. The key to this application is to use different cross-linking methods to obtain the hemostatic sponge with a special structure of this application. Therefore, it is not excluded that other natural polymers 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) when the pressure is stable and the volume of the precursor liquid no longer changes, a cross-linking reaction of the precursor liquid itself is used to form a gel network, or light is irradiated to cross-link the precursor liquid 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 inter-group interactions of functionalized polymers, without the need for salt immersion 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, and 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 the use of 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 functional polymers and thickeners, allowing the precursor liquid to expand stably during the subsequent decompression treatment and ultimately form 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 the actual situation.

[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 make the precursor liquid expand uniformly and stably. It is understandable that if the vacuum degree is too low, the expansion speed is slow and it is difficult to achieve the desired expansion effect; if the vacuum degree is too high, the bubbles are easy to rupture and it is difficult to form a stable expansion structure. Therefore, the present application preferably uses a vacuum degree of 20-300mbar for 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 the illumination mainly initiates 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 a 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 down the expanded precursor liquid so as to better fix the shape of the sample.

[0040] In one implementation of the present application, in step (6), the product of step (5) is immersed in pure water for a period of 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 preparation method of the present application utilize the reaction between the functional groups of the functionalized polymer to achieve cross-linking, and have the advantages of shape memory, high expansion rate, good mechanical strength, adjustable physical and chemical properties, compressibility and injectability; not only has good biocompatibility, high water absorption rate, fast water absorption rate, and rapid expansion, but also can be degraded in vitro, and can better meet different clinical use needs. The hemostatic sponge of the present application can also adsorb and enrich red blood cells and platelets, promote coagulation, and reduce hemostasis time; and has a high compression strength, meeting the requirements of pressing hemostasis. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 is a photograph of the appearance of the hemostatic sponge prepared in the examples of the present application;

[0044] Figure 2 This is a SEM image of the hemostatic sponge adsorbing red blood cells in the embodiment of the present application;

[0045] Figure 3 This is a SEM image of the hemostatic sponge adsorbing platelets in the embodiment of the present application;

[0046] Figure 4 This is a diagram showing the experimental effect of a hemostatic sponge hemostasis experiment in an embodiment of the present application. DETAILED DESCRIPTION

[0047] The preparation method of the hemostatic sponge of the present application mainly comprises: 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 using the interaction between the groups of the functionalized polymer, and further freeze-drying to obtain a sponge material, such as Figure 1 As shown. 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 piled up on each other and physically block the bleeding wound, thereby avoiding being washed away by the blood flow, and 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 the present application has a porous structure, which is conducive to the blood absorption and volume expansion recovery of the compressed sponge, thereby achieving rapid hemostasis. In addition, the interconnected porous structure of the sponge and the biologically active natural polymer can also adsorb and enrich red blood cells and promote coagulation. This makes the hemostatic sponge of the present application have the characteristics of shape memory ability, 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 absorb and enrich red blood cells and platelets, such as Figure 2 and Figure 3 As shown, it promotes coagulation and reduces hemostasis time.

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

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

[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] Embodiment 1

[0059] Weigh 0.15g of olefin-functionalized chitosan with a molecular weight of 300kDa, weigh 0.1g of olefin-functionalized gelatin with a molecular weight of 60kDa, weigh 0.001g of thickener carboxymethyl chitosan, weigh 0.005g of photoinitiator LAP, dissolve all the materials in 1g of ultrapure water, and stir the precursor liquid to obtain uniform bubbles. Then place the solution in a reaction bottle, evacuate to 20mbar, and after the pressure stabilizes, illuminate the reaction bottle with 450nm ultraviolet light for 20 minutes. After the reaction is completed, place the reaction bottle at 5°C to cool and shape. After forming, take it out, soak it in ultrapure water for 0.5h, and finally freeze-dry it in a freeze dryer to obtain a sponge material. The appearance photo of the hemostatic sponge prepared in this example is shown in the figure. Figure 1 shown.

[0060] Water absorption performance and water absorption time test: Take a dry sponge with a height of about 10 mm and weigh the initial mass as W 0 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 using the following formula:

[0061]

[0062] Among them, SR is the water absorption rate of the sponge, W t W is the mass of the sponge when it absorbs water and reaches equilibrium swelling. 0 is the initial mass of the sponge before absorbing water.

[0063] The water absorption rate of the sponge measured by the above method is 3800%, and the time taken for water absorption is 15s.

[0064] Water retention performance test: Take a dry sponge with a height of about 10 mm and weigh the initial mass W 0 . Immerse it in ultrapure water and fully swell it to saturation. Take it out and centrifuge it at 500r / min for 3min. The mass is recorded as W 1 The water retention performance of the sponge is calculated using the following formula:

[0065]

[0066] Among them, WRV is the water retention rate of the sponge, W 1 W is the mass of the sponge after further centrifugation after saturation with water. 0 is the initial mass of the sponge before absorbing water.

[0067] The water retention rate of the sponge measured according to the above method is 920%.

[0068] Compression performance test: After the sponge has reached equilibrium and centrifuged, cut out samples with a diameter to height ratio of 1:0.33-1:0.67, and use a universal testing machine to perform 80% cyclic compression at a speed of 5mm / min to obtain the highest compression strength δ c .

[0069] The compression strength of the sponge measured according to the above method is 56 kPa.

[0070] Porosity and density measurements:

[0071] 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 min, take out the sponge and weigh the total mass W of the container and the remaining ethanol. b ; Use a measuring cylinder to fill a certain mass of ethanol and weigh the total mass W 1 , and mark the scale at this time; put the taken out sponge into the measuring cylinder, take out the excess ethanol to restore the liquid level to the original scale, and weigh the total mass W 2 The porosity (P) of the sponge is calculated as follows:

[0072]

[0073] The density of sponge (ρ) is calculated as follows:

[0074]

[0075] Among them, ρ E is the density of ethanol.

[0076] The sponge porosity measured by the above method is 85% and the density is 0.056 g / cm 3 .

[0077] Measurement of hemostasis time and blood loss:

[0078] Rat femoral artery / vein transection hemostasis performance test: The right femoral artery of the rat was exposed, and a 6mm tissue sampler / punch was used to create a cavity with a depth of about 10mm in the femoral artery and surrounding tissues. The compressed sponge was then injected into the cavity. The outflowing blood was collected with absorbent cotton and the bleeding was observed. The time required for the blood to stop flowing was the hemostasis time, and the mass of the collected blood was the blood loss. The hemostasis effect was as follows: Figure 4 SEM was used to observe the adsorption of red blood cells and platelets by the hemostatic sponge. The SEM images of the hemostatic sponge adsorbing red blood cells are shown in the figure. Figure 2 As shown, the SEM image of the hemostatic sponge adsorbing platelets is shown in Figure 3 shown.

[0079] The hemostasis time measured by the above method was 189 s and the blood loss was 2.67 g.

[0080] Degradation time test: Take a dry sponge sample with a height of about 10 mm, put it into a sealed container filled with 1×PBS, and then place the container in a constant temperature shaker at 37±1℃, and observe the changes of the sample at a speed of 100r / min until it is invisible to the naked eye. This is recorded as the in vitro degradation time of the sponge sample.

[0081] The in vitro degradation time measured according to the above method is 38 days.

[0082] Embodiment 2

[0083] Weigh 0.02g of amino-functionalized hyaluronic acid with a molecular weight of 15kDa, weigh 0.02g of aldehyde-functionalized polylactic acid-glycolic acid copolymer (PLGA-CHO) with a molecular weight of 10kDa, weigh 0.02g of thickener gum arabic, and dissolve all the materials in 1g of ultrapure water. Stir the precursor liquid to obtain uniform bubbles, then place the solution in a reaction bottle, evacuate to 300mbar, wait for 10min after the pressure stabilizes, and allow the groups to react. Then place the reaction bottle at -40℃ to cool and shape. After molding, take it out, soak it in ultrapure water for 48h, and finally freeze-dry it in a freeze dryer to obtain a sponge material.

[0084] According to the test method of Example 1, the water absorption rate of the sponge was measured to be 5400%, the time taken for water absorption was 3s, the water retention rate was 1970%, the compression strength was 29kPa, the porosity was 97%, and the density was 0.024g / cm 3 The hemostasis time was 96s, the blood loss was 1.99g, and the in vitro degradation time was 12d.

[0085] Embodiment 3

[0086] Weigh 0.025g of olefin functionalized gelatin with a molecular weight of 100kDa, weigh 0.05g of olefin functionalized polyoxyethylene-polypropylene ether copolymer (PF127-C=C) with a molecular weight of 12.6kDa, weigh 0.01g of photoinitiator 2959, weigh 0.03g of thickener carboxymethyl cellulose with a molecular weight of 250kDa, and dissolve all the materials in 1g of ultrapure water. Stir the precursor liquid to obtain uniform bubbles, then place the solution in a reaction bottle, evacuate to 130mbar, and irradiate with 365nm ultraviolet light for 10min after the pressure stabilizes. Then place the reaction bottle in liquid nitrogen to cool and shape. After shaping, take it out, soak it in ultrapure water for 6h, and finally freeze-dry it in a freeze dryer to obtain a sponge material.

[0087] 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 compression strength was 11.5kPa, the porosity was 96%, and the density was 0.021g / cm 3 The hemostasis time was 105s, the blood loss was 2.4g, and the in vitro degradation time was 5d.

[0088] Embodiment 4

[0089] Weigh 0.1 g of succinimidyl ester functionalized poly (L-glutamic acid) (L-PGA-NHS) with a molecular weight of 100 kDa, weigh 0.03 g of amino functionalized poly (vinyl alcohol) (PVA-NH 2 ), weigh 0.005g of thickener starch with a molecular weight of 100kDa, and dissolve all the materials in 1g of ultrapure water. Stir the precursor liquid to obtain uniform bubbles, then place the solution in a reaction bottle, evacuate to 120mbar, wait for 15min after the pressure stabilizes, and then place the reaction bottle at -100℃ to cool and shape. After shaping, take it out, soak it in ultrapure water for 3h, and finally freeze-dry it in a freeze dryer to obtain a sponge material.

[0090] 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 compression 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.

[0091] Embodiment 5

[0092] Weigh 0.08g of phenolic hydroxyl functionalized mussel mucin with a molecular weight higher than 400kDa, weigh 0.05g of phenolic hydroxyl functionalized polyacrylic acid (PAA-DOPA) with a molecular weight of 1kDa, weigh 0.05g of thickener hydroxyethyl cellulose with a molecular weight of 100kDa, and dissolve all materials in 1g of ultrapure water. Stir the precursor liquid to obtain uniform bubbles, then place the solution in a reaction bottle, evacuate to 250mbar, wait for 15min after the pressure stabilizes, and then place the reaction bottle at -20℃ to cool and shape. After molding, take it out, soak it in ultrapure water for 24h, and finally freeze-dry it in a freeze dryer to obtain a sponge material.

[0093] According to the test method of Example 1, the water absorption rate of the sponge was measured to be 12000%, the water absorption time was 3s, the water retention rate was 3400%, the compression 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.

[0094] Embodiment 6

[0095] Weigh 0.15g of amino-functionalized gelatin with a molecular weight of more than 15kDa, weigh 0.15g of succinimidyl ester functionalized four-arm polyethylene glycol (4-arm-PEG-NHS) with a molecular weight of 10kDa, weigh 0.01g of thickener carboxymethyl chitosan with a molecular weight of 10kDa, and dissolve all the materials in 1g of ultrapure water. Stir the precursor liquid to obtain uniform bubbles, then place the solution in a reaction bottle, evacuate to 200mbar, wait for 1min after the pressure stabilizes, and then place the reaction bottle at -80℃ to cool and shape. After forming, take it out, soak it in ultrapure water for 0.5h, and finally freeze-dry it in a freeze dryer to obtain a sponge.

[0096] 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 compression 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.

[0097] Embodiment 7

[0098] Weigh 0.1g of γ-polyglutamic acid with a molecular weight of 100kDa, weigh 0.1g of carboxyl functionalized alginate with a molecular weight of 100kDa, weigh 0.008g of thickener methylcellulose with a molecular weight of 100kDa, and dissolve all the materials in 1g of ultrapure water. Stir the precursor liquid to obtain uniform bubbles, then place the solution in a reaction bottle, evacuate to 150mbar, wait for 2 minutes after the pressure stabilizes, and then place the reaction bottle in liquid nitrogen to cool and shape. After forming, take it out, soak it in ultrapure water for 5h, and finally freeze-dry it in a freeze dryer to obtain a sponge.

[0099] 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 23s, the water retention rate was 2000%, the compression strength was 51kPa, the porosity was 89%, and the density was 0.051g / cm 3 The hemostasis time was 131s, the blood loss was 2.24g, and the in vitro degradation time was 9d.

[0100] Embodiment 8

[0101] Weigh 0.1g of thiol-functionalized Bletilla striata polysaccharide with a molecular weight of more than 6.5kDa, weigh 0.15g of thiol-functionalized polyacrylamide (PAAM-SH) with a molecular weight of 1kDa, weigh 0.1g of thickener hydroxyethyl cellulose with a molecular weight of 150kDa, and dissolve all the materials in 1g of ultrapure water. Stir the precursor liquid to obtain uniform bubbles, then place the solution in a reaction bottle, evacuate to 130mbar, wait for 5min after the pressure stabilizes, and then place the reaction bottle in -60℃ to cool and shape. After forming, take it out, soak it in ultrapure water for 2h, and finally freeze-dry it in a freeze dryer to obtain a sponge.

[0102] According to the test method of Example 1, the water absorption rate of the sponge was measured to be 6900%, the time taken for water absorption was 16s, the water retention rate was 1800%, the compression strength was 68kPa, the porosity was 94%, and the density was 0.029g / cm 3 The hemostasis time was 127s, the blood loss was 1.95g, and the in vitro degradation time was 14d.

[0103] Embodiment 9

[0104] 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, 0.01g of photoinitiator α-ketoglutaric acid, and dissolve all materials in 1g of ultrapure water. Stir the precursor liquid to obtain uniform bubbles, then place the solution in a reaction bottle, evacuate to 280mbar, and illuminate the reaction bottle with 284nm ultraviolet light for 8min after the pressure stabilizes. After the reaction is completed, place the reaction bottle at -120℃ to cool and shape. After forming, take it out, soak it in ultrapure water for 8h, and finally freeze-dry it in a freeze dryer to obtain a sponge.

[0105] According to the test method of Example 1, the water absorption rate of the sponge was measured to be 7100%, the time taken for water absorption was 9.8s, the water retention rate was 1900%, the compression strength was 39kPa, the porosity was 92%, and the density was 0.034g / cm 3 The hemostasis time was 134s, the blood loss was 2.01g, and the in vitro degradation time was 18d.

[0106] Embodiment 10

[0107] Weigh 0.05g of phycocyanin with a molecular weight of 40kDa, weigh 0.05g of aldehyde-functionalized silsesquioxane (POSS-CHO) with a molecular weight of 1kDa, weigh 0.01g of thickening starch with a molecular weight of 50kDa, and dissolve all the materials in 1g of ultrapure water. Stir the precursor liquid to obtain uniform bubbles, then place the solution in a reaction bottle, evacuate to 180mbar, wait for 18min after the pressure stabilizes, and then place the reaction bottle in -150℃ to cool and shape. After forming, take it out, soak it in ultrapure water for 10h, and finally freeze-dry it in a freeze dryer to obtain a sponge.

[0108] According to the test method of Example 1, the water absorption rate of the sponge was measured to be 4600%, the time taken for water absorption was 8.6s, the water retention rate was 1560%, the compression strength was 69kPa, the porosity was 91%, and the density was 0.039g / cm 3 The hemostasis time was 145s, the blood loss was 2.21g, and the in vitro degradation time was 11d.

[0109] Embodiment 11

[0110] Weigh 0.2g of carboxyl functional starch with a molecular weight of 50kDa, weigh 0.1g of hydroxyl functional polyvinyl alcohol (PVA) with a molecular weight of 200kDa, weigh 0.002g of thickener methyl cellulose with a molecular weight of 500kDa, and dissolve all the materials in 1g of ultrapure water. Stir the precursor liquid to obtain uniform bubbles, then place the solution in a reaction bottle, evacuate to 80mbar, wait for 3 minutes after the pressure stabilizes, and then place the reaction bottle in -20℃ to cool and shape. After forming, take it out, soak it in ultrapure water for 0.5h, and finally freeze-dry it in a freeze dryer to obtain a sponge.

[0111] According to the test method of Example 1, the water absorption rate of the sponge was measured to be 4100%, the time taken for water absorption was 7.6s, the water retention rate was 2100%, the compression strength was 84kPa, the porosity was 87%, and the density was 0.049g / cm 3 The hemostasis time was 119s, the blood loss was 1.74g, and the in vitro degradation time was 37d.

[0112] The above contents are further detailed descriptions of the present application in combination with specific implementation methods, and it cannot be determined that the specific implementation of the present application is 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: The following steps are included: (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; (2) stirring the precursor liquid to generate a large number of relatively uniform bubbles; (3) decompressing the precursor liquid with uniform bubbles to expand the precursor liquid; (4) when the pressure is stable and the volume of the precursor liquid no longer changes, the precursor liquid is allowed to cross-link to form a gel network, or light is irradiated to cross-link the precursor liquid to form a gel network; (5) cooling the product of step (4) to fix the network structure; (6) Soaking the product of step (5) in pure water; (7) taking out the product of step (6) and freeze-drying it to obtain the hemostatic sponge; In step (3), the vacuum degree of the decompression 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 down and fix the shape of the sample; In step (6), the product of step (5) is immersed in pure water for 0.5-48 hours; The hemostatic sponge is composed of a functionalized polymer and a thickener, or a functionalized polymer, a thickener and a photoinitiator; The functionalized polymer is a natural polymer and / or a synthetic polymer modified with functional groups, and the functionalized polymer is cross-linked by interaction between functional groups or further cross-linked by adding a photoinitiator to form a hemostatic sponge. The functional group is at least one of hydroxyl, aldehyde, carboxyl, amino, thiol, hydrazone bond, hydrazide, olefin, alkynyl, polyphenol, succinimide ester active ester, maleimide, and isocyanate.

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

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

4. The preparation method according to claim 1, characterized in that: 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 to 4, characterized in that: In step (4), the illumination adopts ultraviolet light with a wavelength of 200-450nm.

6. The preparation method according to claim 5, characterized in that: 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 a gel network is 1-20 minutes.

7. The preparation method according to any one of claims 1 to 4, characterized in that: The 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.

8. The preparation method according to any one of claims 1 to 4, characterized in that: The synthetic polymer is at least one of polyethylene glycol, 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.

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

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

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

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