A device and method of use for forming a self-expanding, self-propelled hydrogel hemostatic dressing

Abstract

The application discloses a device for forming a self-expanding and self-propelling hydrogel hemostatic dressing and an application method, belongs to the technical field of biomedical materials, selects a functionalized modified aminated polymer and a functionalized modified aldehyde-based polymer as main components, and the selected polymers all have good biocompatibility; the polymers are loaded in different bearing devices, each device is loaded with a substance to be reacted, and the substances in the two devices are pushed out and mixed in a mixing device, and a rapid reaction is simultaneously performed; the reaction does not need a catalyst, and a Schiff base reaction is formed to generate a basic network structure of a hydrogel which can be degraded under physiological conditions. The hydrogel can be expanded (self-expanding) and pushed forward (self-propelling) to fill various irregular wound cavities under the action of calcium carbonate continuously generating carbon dioxide.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials technology, specifically relating to a device and application method for forming a self-expanding and self-propelled hydrogel hemostatic dressing. Background Technology

[0002] Bleeding is a leading cause of death from traumatic injuries because massive blood loss often leads to serious complications, including hypotension and multiple organ dysfunction. Most deaths occur within the first few hours after a traumatic injury, as bleeding control is extremely time-sensitive, as evidenced by the "golden time" concept in trauma care. For penetrating wounds caused by firearms or explosive devices, traditional hemostatic materials are often inadequate for managing the non-compressible bleeding resulting from these wounds, which is common in everyday life and accounts for 30-40% of all bleeding incidents. Furthermore, arterial bleeding from traffic accidents is also a significant cause of death in everyday life. However, arteries are usually located inside tissues or deep within muscles to avoid easy injury, but once an artery is damaged, it results in significant blood loss that cannot be stopped by effective pressure or traditional hemostatic materials. Therefore, arterial bleeding is one of the most difficult types of non-compressible bleeding to manage, and rapid and effective control of arterial bleeding is crucial.

[0003] Currently, the main types of hemostatic materials include gauze, sponges, powders, and hydrogels. However, gauze and sponges are difficult to use for wounds with non-pressable arterial bleeding because they cannot penetrate deep into the bleeding site, while traditional hemostatic powders cannot form a stable hemostatic barrier and may even dissolve in the blood, thus failing to control arterial bleeding. Adhesive hydrogels can act as a physical barrier, adhering to the bleeding wound. However, most commercial bioadhesives have limitations, including slow adhesion, weak adhesion, poor biocompatibility, and poor mechanical compatibility with tissues. Furthermore, blood often weakens the adhesion between the hydrogel and tissue, affecting its hemostatic effect. Therefore, there is a strong desire to develop novel hemostatic materials that overcome these shortcomings for controlling non-pressable arterial bleeding on the battlefield or elsewhere. Summary of the Invention

[0004] The purpose of this invention is to overcome the shortcomings of the prior art and provide an apparatus and application method for forming a self-expanding and self-propelled hydrogel hemostatic dressing, so as to solve the technical problems of existing wound dressings being unable to effectively control non-pressable bleeding, bleeding due to coagulation disorders, bleeding under blind vision, and arterial bleeding.

[0005] To achieve the above objectives, the present invention employs the following technical solution:

[0006] An apparatus for forming a self-expanding, self-propelled hydrogel hemostatic dressing, comprising:

[0007] The first carrier device is loaded with a mixed solution of a functionalized modified aminated polymer and a first reactant, wherein the first reactant is an acid or hydrogen peroxide;

[0008] The second carrier device is loaded with a mixed dispersion of a functionalized aldehyde-modified polymer and a second reactant, wherein the second reactant is a carbonic compound, catalase, or nanoparticles with catalase activity.

[0009] A mixing device is used to mix the substances output from the first carrier device and the substances output from the second carrier device and then transport them to the target area.

[0010] When the two substances are mixed, the functionalized aminated polymer and the functionalized aldehyde polymer react to form a hydrogel. The first reactant and the second reactant react to produce gas. The hydrogel expands during the reaction, and the gas propels the hydrogel to fill the target area.

[0011] A further improvement of the present invention is that:

[0012] Preferably, in the mixed solution of the first carrier device, the mass fraction of the functionalized modified aminated polymer is 0.5% to 20%, and the concentration of the first reactant is 1 to 200 μL / mL.

[0013] Preferably, in the mixed solution of the second carrier device, the mass fraction of the functionalized aldehyde-modified polymer is 0.5% to 40%, and the concentration of the second reactant is 1 to 100 mg / mL.

[0014] Preferably, both the first and second carrier devices are needle tubes, and the mixing device is a spiral needle.

[0015] Preferably, the functional modification of the aminated polymer is quaternary ammonium salt modification, hydrophobic segment modification or polyphenol group modification, and the functional modification of the aldehyde polymer is quaternary ammonium salt modification, hydrophobic segment modification or polyphenol group modification.

[0016] Preferably, the aminated polymer is chitosan, gelatin, aminated gelatin, aminated sodium alginate, aminated hyaluronic acid, or aminated poly(ethylene glycol-glycerol-sebacic acid).

[0017] Preferably, the aldehyde-modified polymer is oxidized dextran, oxidized hyaluronic acid, oxidized sodium alginate, oxidized pullulan, or aldehyde-modified poly(ethylene glycol-glycerol-sebacic acid).

[0018] Preferably, the acid is any one of acetic acid, protonated tranexamic acid, dilute hydrochloric acid or phosphoric acid, and the carbonate compound is a carbonate or bicarbonate.

[0019] The nanoparticles with catalase activity are manganese dioxide particles or cerium dioxide particles.

[0020] Preferably, the acid is acetic acid and the carbonate compound is calcium carbonate.

[0021] A method for using the above-mentioned device loaded with self-expanding and self-propelled hydrogel hemostatic dressing, wherein the mixing solution in the first carrier device and the mixing solution in the second carrier device are simultaneously pushed into the mixing device, and the mixture is output from the mixing device to the target area;

[0022] When the two substances are mixed, the functionalized aminated polymer and the functionalized aldehyde polymer react to form a hydrogel. The first reactant and the second reactant react to generate gas, which promotes the expansion of the hydrogel.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] This invention discloses a device for a self-expanding, self-propelled hydrogel hemostatic dressing, belonging to the field of biomedical materials technology. It selects functionalized aminated and aldehyde-modified polymers as the main components, both exhibiting good biocompatibility. These polymers are loaded into different carrier devices, each containing a substance to be reacted. After being ejected from both devices, the substances are mixed in a mixing device, undergoing a rapid reaction without a catalyst. This reaction generates a Schiff base reaction that degrades under physiological conditions, forming the basic network structure of the hydrogel. The hydrogel expands (self-expanding) under the continuous generation of carbon dioxide from calcium carbonate and propels itself forward (self-propelled) to fill various irregular wound cavities. The optimized hydrogel can expand to three times its own volume within 30 seconds and exhibits good adhesion to porcine skin (9 kPa) and porcine skeletal muscle (8.5 kPa). Furthermore, the hydrogel degrades by more than 50% within 7 days in a phosphate buffered environment (pH = 7.4). In addition, the optimized hydrogel exhibits a lower coagulation index and greater red blood cell / platelet adhesion than gelatin sponges. Importantly, the self-propelled hydrogel can extensively cover intra-abdominal tissues and organs (including bleeding wounds), demonstrating excellent hemostasis in a blind-field model of intra-abdominal hemorrhage (liver and kidney bleeding) (blood loss was reduced by more than 88% compared to the control group). In a porcine subclavian artery and vein complete transection hemorrhage model, the hydrogel group showed a 97% reduction in blood loss and a 95% reduction in hemostasis time compared to the group using medical gauze with 3 minutes of assisted pressure. Therefore, the biodegradable, self-expanding, self-propelled / procoagulant hydrogel has the potential to control arterial bleeding and massive hemorrhage in a blind field.

[0025] Furthermore, a dual-needle injection device is chosen to preserve the hydrogel precursor, allowing even non-professionals to quickly apply it to the bleeding site. The expandable hemostatic material, with its small volume before expansion, can be delivered to deep bleeding sites via a syringe-like delivery device. Once expanded, the hemostatic material exerts significant pressure on the bleeding site, forming a physical barrier conducive to hemostasis and providing effective physical occlusion. This hemostatic material has the potential to address bleeding from arteries that cannot be compressed.

[0026] Furthermore, the acid chosen is acetic acid, and the carbonate chosen is calcium carbonate. The gas generation rate of the reaction between acetic acid and calcium carbonate is similar to that of the Schiff base reaction, which causes the hydrogel to expand during gelation (self-expansion) and propel it into the irregular wound cavity (self-propulsion).

[0027] This invention also discloses an application method for an apparatus for forming a self-expanding, self-propelled hydrogel hemostatic dressing. The method involves pushing a mixed solution from a first carrier device and a mixed solution from a second carrier device into a mixing device, from which the mixture is output to a target area. After the two substances are mixed, the functionalized aminated polymer and the functionalized aldehyde polymer react to form a hydrogel. The first and second reactants react to generate gas, promoting the hydrogel's discharge from the mixing device and its expansion. The hydrogel possesses good physicochemical properties similar to soft tissue, such as flexibility, viscoelasticity, and wettability. Furthermore, before gelation, the hydrogel has a certain fluidity, easily filling wounds of any shape. The self-propelled hydrogel can fill wounds of any shape under gas propulsion, including extensive intra-abdominal wounds, and has the potential to address bleeding in a blind field. Residual hemostatic residues that are difficult to degrade may cause additional damage and affect soft tissue repair, requiring secondary surgery for removal. However, Schiff base-based hydrogels can degrade under physiological conditions, avoiding the need for secondary surgery. The dual-needle injection hydrogel has multiple procoagulant advantages (quaternary ammonium salt modification can enhance erythrocyte adhesion; hydrophobic segment modification can anchor blood cell membranes, thereby promoting blood cell aggregation; polyphenol group modification can enhance tissue adhesion, promote vasoconstriction, and activate the extrinsic coagulation system), and can effectively control complete transection bleeding of the subclavian artery and vein in pigs. Attached Figure Description

[0028] Figure 1 This is a schematic diagram illustrating the synthesis of quaternized chitosan (QCS).

[0029] Figure 2 This is a schematic diagram of the synthesis of quaternized chitosan grafted with gallic acid (QCSG);

[0030] Figure 3 A schematic diagram illustrating the synthesis of quaternized chitosan grafted with lauric acid (QCSL);

[0031] Figure 4 This is a schematic diagram illustrating the synthesis of oxidized dextran (Odex);

[0032] Figure 5 The proton nuclear magnetic resonance spectrum of the polymer synthesized in this invention (NMR spectrum) 1 ¹H NMR spectrum;

[0033] Figure 6 The Fourier transform infrared (FT-IR) spectra of the polymer synthesized in this invention and the hydrogel prepared therefrom.

[0034] Figure 7 The X-ray diffraction (XRD) spectrum and scanning electron microscope (SEM) image of the porous calcium carbonate (CaCO3) particles prepared in this invention;

[0035] Figure 8 (a) pH change of the hydrogel prepared in this invention in phosphate-buffered saline (PBS); (b) rheological behavior of the hydrogel;

[0036] Figure 9 The degradation curve of the hydrogel prepared in this invention in PBS;

[0037] Figure 10 The microstructure of the hydrogel prepared in this invention is shown in the images. (a) SEM image, scale bar: 500 μm; (b) Fluorescence image, scale bar: 400 μm.

[0038] Figure 11 The self-expansion behavior of the hydrogel prepared in this invention; (a) volume expansion rate; (b) gelation time; (c) volume expansion rate;

[0039] Figure 12 The extrusion pressure exerted on the non-deformable surface by the hydrogel prepared in this invention during the expansion process;

[0040] Figure 13 This is a schematic diagram illustrating the expansion mechanism of the hydrogel prepared according to the present invention;

[0041] Figure 14 The self-propulsion properties of the hydrogel prepared in this invention;

[0042] Figure 15 Blood compatibility of the hydrogel prepared in this invention; (a) hemolysis photograph; (b) hemolysis rate;

[0043] Figure 16 Cell compatibility of the hydrogel prepared in this invention; (a) cell viability; (b) Live / dead staining (10 mg / mL), scale bar: 200 μm;

[0044] Figure 17The adhesion properties of the hydrogel prepared in this invention are shown in the figures: (a) adhesion to pig skin; (b) adhesion to pig skeletal muscle; (c) schematic diagram of the adhesion mechanism.

[0045] Figure 18 The burst pressure of the hydrogel prepared in this invention;

[0046] Figure 19 The antibacterial activity of the hydrogel prepared in this invention;

[0047] Figure 20 The antioxidant activity of the hydrogel prepared in this invention;

[0048] Figure 21 The coagulation index of the hydrogel prepared in this invention; (a) whole blood coagulation; (b) ACD anticoagulation whole blood coagulation;

[0049] Figure 22 Platelet and erythrocyte adhesion properties of the hydrogel prepared in this invention; (a) Platelet adhesion; (b) Erythrocyte adhesion, scale bar: 15 μm;

[0050] Figure 23 SEM image of the hydrogel / blood clot complex, scale bar: 15 μm;

[0051] Figure 24 The hemostatic effect of the hydrogel prepared in this invention on a rat liver circular slice model is shown in the figures: (a) blood loss; (b) hemostasis time; (c) schematic diagram of the model; **P<0.01, ***P<0.001;

[0052] Figure 25 The hemostatic effect of the hydrogel prepared in this invention on a rat liver cross-incision model is shown in the figures: (a) blood loss; (b) hemostasis time; (c) schematic diagram of the model; *P<0.05, **P<0.01, ***P<0.001;

[0053] Figure 26 The hemostatic effect of the hydrogel prepared in this invention on a rabbit liver volume defect bleeding model that cannot be compressed; (a) blood loss; (b) hemostasis time; (c) schematic diagram of the model; *P<0.05, **P<0.01, ***P<0.001;

[0054] Figure 27 The hemostatic effect of the hydrogel prepared in this invention on a rabbit liver volume defect model with lethal coagulopathy; (a) blood loss; (b) hemostasis time; (c) schematic diagram of the model; *P<0.05, **P<0.01;

[0055] Figure 28The hemostatic effect of the hydrogel prepared in this invention on a rabbit liver incision model under blind vision; (a) blood loss; (b) schematic diagram of the model; *P<0.05, **P<0.01;

[0056] Figure 29 The hemostatic effect of the hydrogel prepared in this invention on a rabbit kidney incision model under blind vision; (a) blood loss; (b) schematic diagram of the model; *P<0.05, **P<0.01, ***P<0.001;

[0057] Figure 30 The hemostatic effect of the hydrogel prepared in this invention on a rat femoral artery bleeding model is shown in the figures: (a) blood loss; (b) schematic diagram of the model; *P<0.05, **P<0.01, ***P<0.001;

[0058] Figure 31 The hemostatic effect of the hydrogel prepared in this invention on a porcine subclavian artery and vein complete transection model is shown in the figures: (a) blood loss; (b) hemostasis time; (c) application time; (d) schematic diagram of the model. *P<0.05, **P<0.01, ***P<0.001;

[0059] Figure 32 For the in vivo biocompatibility of the hydrogel prepared in this invention, scale bar: 300 μm;

[0060] Figure 33 This is a schematic diagram illustrating the preparation and application of the hydrogel obtained by the present invention. Detailed Implementation

[0061] The present invention will now be described in further detail with reference to the accompanying drawings:

[0062] In the description of this invention, it should be noted that the terms "center," "upper," "lower," "left," "right," "vertical," "horizontal," "inner," and "outer," etc., indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings. They are used only for the convenience of describing the invention and for simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, they should not be construed as limitations on the invention. The terms "first," "second," and "third" are used for descriptive purposes only and should not be construed as indicating or implying relative importance. Furthermore, unless otherwise explicitly specified and limited, the terms "installed," "connected," and "linked" should be interpreted broadly. For example, they can refer to a fixed connection or a detachable connection; they can refer to a direct connection or an indirect connection through an intermediate medium; they can refer to the internal connection of two elements. Those skilled in the art can understand the specific meaning of the above terms in this invention based on the specific circumstances.

[0063] One embodiment of the present invention discloses an apparatus for forming a self-expanding, self-propelled hydrogel hemostatic dressing. The apparatus includes a first support device, a second support device, and a mixing device. Both the first and second support devices are used to load a mixed solution or dispersion. The input ends of both the first and second support devices are slidably equipped with a pushing structure, and their output ends are simultaneously connected to the mixing device. The two pushing devices simultaneously push the mixed solution or dispersion in their respective support devices into the mixing device. After the substances in the two support devices are mixed, a corresponding reaction occurs. The outlet of the mixing device delivers the reaction product to the target area.

[0064] Specifically, the first carrier device is loaded with a mixed solution of a functionalized modified aminated polymer and a first reactant, wherein the first reactant is an acid or hydrogen peroxide;

[0065] Specifically, the second carrier device is loaded with a mixed dispersion of a functionalized aldehyde-modified polymer and a second reactant, wherein the second reactant is a carbonic compound, catalase, or nanoparticles with catalase activity.

[0066] A mixing device is used to mix the substances output from the first carrier device and the substances output from the second carrier device and then transport them to the target area.

[0067] After the two substances are mixed, the functionalized aminated polymer and the functionalized aldehyde polymer react to form a hydrogel. The first reactant and the second reactant react to produce gas. The hydrogel expands during the reaction in the mixing device, and the gas propels the hydrogel out of the mixing device and fills the target area.

[0068] The assembly process of this device includes the following steps:

[0069] S1: Identify amination polymers, including but not limited to chitosan, gelatin, amination gelatin, amination sodium alginate, amination hyaluronic acid, and amination poly(ethylene glycol-glycerol-sebacic acid).

[0070] S2: Identify aldehyde-modified polymers, including but not limited to oxidized dextran, oxidized hyaluronic acid, oxidized sodium alginate, oxidized pullulan, and aldehyde-modified poly(ethylene glycol-glycerol-sebacic acid);

[0071] S3: Functional modification of aminated and aldehyde-modified polymers, either individually or simultaneously. The types of functional modification include, but are not limited to, quaternary ammonium salt modification, hydrophobic segment modification, and polyphenol group modification.

[0072] The quaternary ammonium salt modification described in S3 can enhance the water solubility, antibacterial properties, and erythrocyte adhesion of polymers; the hydrophobic segment modified polymers can anchor the cell membrane of blood cells, thereby promoting blood cell aggregation; the polyphenol group modified polymers can enhance tissue adhesion and promote vasoconstriction and activate the extrinsic coagulation system.

[0073] S4: Prepare or prepare a foaming agent capable of generating gas, including a first reactant and a second reactant. The first reactant includes an acid or hydrogen peroxide, and the acid includes, but is not limited to, acetic acid, protonated tranexamic acid, dilute hydrochloric acid, or phosphoric acid, etc., which are moderately strong acids. The second reactant includes carbonates, bicarbonates, catalase, or nanoparticles with catalase activity (manganese dioxide particles or cerium dioxide particles, etc.).

[0074] Acids (acetic acid, protonated tranexamic acid, dilute hydrochloric acid, phosphoric acid, etc.) react with carbonates or bicarbonates to produce carbon dioxide, while hydrogen peroxide reacts with catalase or nanoparticles with catalase activity to produce oxygen.

[0075] S5: Dissolve the functionalized aminated polymer in deionized water containing the first reactant to prepare a solution with a mass fraction of 0.5% to 20% (the concentration of the first reactant is 1 to 200 μL / mL), and then add the solution to one syringe of the double-needle tube;

[0076] S6: Dissolve the functionalized aldehyde polymer in deionized water to prepare a solution with a mass fraction of 0.5% to 40%. Then, add a second reactant with a concentration of 1 to 100 mg / mL that can react with the first reactant to generate gas to the solution. Prepare a mixed dispersion or solution under ultrasonic dispersion or dissolution conditions. Then, add the mixed dispersion or solution to the other syringe of the double syringe.

[0077] The free aldehyde groups in the functionalized aldehyde-modified polymer solution described in S6 should be more than the free amino groups in the functionalized aminated polymer solution described in S5, so that the prepared hydrogel can react with amino groups on the tissue, thereby enhancing tissue adhesion.

[0078] In S5 and S6, the functionalized modifiers and reactants in any syringe must be selected to avoid reacting with each other.

[0079] S7: During the injection process, the components in the two syringes are mixed through the spiral mixing nozzle, and a Schiff base reaction occurs rapidly to form a hydrogel. At the same time, calcium carbonate or sodium carbonate reacts with acid (hydrogen peroxide reacts with catalase or nanoparticles with catalase activity) to rapidly generate a large amount of gas, which causes the hydrogel to expand and propel the hydrogel out of the syringe, thus obtaining a self-expanding and self-propelling hydrogel hemostatic dressing.

[0080] The Schiff base reaction described in S7 can occur rapidly under physiological conditions without the need for a catalyst, and the polymer solution can quickly gel during use.

[0081] Preferably, the reaction of calcium carbonate or sodium carbonate, etc., described in S7 with acid can rapidly release a large amount of gas, and the reaction rate is similar to that of Schiff base reaction. Therefore, it can promote the expansion of hydrogel precursor during gelation, and the reaction is mild and the generated gas is harmless.

[0082] The hydrogel hemostatic dressing prepared using the above preparation method can expand (self-expand) under the action of carbon dioxide continuously generated by calcium carbonate / sodium carbonate and propel itself forward (self-propulsion) to fill various irregular wound cavities.

[0083] The Schiff base crosslinked hydrogel prepared by the above method can be degraded under physiological conditions.

[0084] The self-expanding hydrogel prepared by the above method can effectively control non-pressable bleeding such as liver volume defects in rabbits.

[0085] The procoagulant hydrogel prepared by the above method can effectively control hemorrhage caused by liver volume defects in rabbits with coagulation dysfunction.

[0086] The self-propelled hydrogel prepared by the above method has fluidity and can effectively control intra-abdominal bleeding under blind vision.

[0087] The self-expanding, self-propelling, procoagulant hydrogel prepared by the above method can effectively control bleeding from complete transection of the subclavian artery and vein in pigs.

[0088] Example 1

[0089] Preparation of OD+C / QGQL+A30 self-expanding and self-propelling hydrogel: Equal masses of QCSG and QCSL were dissolved in deionized water, and 60 μL / mL of acetic acid was added to form a mixed solution containing 5 wt% QCSG and 5 wt% QCSL. Odex was dissolved in deionized water to form a 15 wt% solution, and then CaCO3 particles (35 mg / mL) were dispersed in the Odex solution under ultrasound to form an Odex / CaCO3 mixture. The QCSG / QCSL mixture and the Odex / CaCO3 mixture were mixed uniformly at a 1:1 ratio using a shaker or a dual-syringe syringe. Schiff base crosslinking occurred immediately after mixing, generating carbon dioxide (CO2), which promoted the continuous expansion of the sol during gelation, thus preparing the self-expanding and self-propelling hydrogel. The hydrogel was named OD+C / QGQL+An, where OD represents oxidized dextran (Odex), C represents calcium carbonate (CaCO3), QGQL represents the same concentration of (quaternized chitosan grafted with gallic acid) QCSG and (quaternized chitosan grafted with lauric acid) QCSL, A represents acetic acid, and n after A represents the volume (μL) of acetic acid in 1 mL of the hydrogel precursor.

[0090] QCS (quaternization of chitosan with glycidyltrimethylammonium chloride) was used to synthesize a product with good water solubility, antibacterial activity, and procoagulant activity. Figure 1 ).

[0091] QCS was further modified with gallic acid and lauric acid respectively to obtain QCSG and QCSL. Figure 2 and Figure 3 Hydrophobic lauric acid can insert into the cell membrane of blood cells, thereby capturing blood cells, promoting blood cell aggregation, and enhancing coagulation ability. Gallic acid can promote the activation of erythrocytes and platelets, while also endowing the hydrogel with antioxidant activity and improving the tissue adhesion of the hydrogel.

[0092] Odex (a glycoside rich in aldehyde groups) was synthesized by oxidizing dextran with sodium periodate. Figure 4 ).

[0093] The chemical structures of QCSG, QCSL, and Odex are derived from 1 HNMR ( Figure 5 ) and FT-IR ( Figure 6 Spectroscopic confirmation. In QCS, QCSG, and QCSL... 1In the ¹H NMR spectra, two distinct proton characteristic peaks were observed at 3.1 ppm and 3.3 ppm, corresponding to the trimethylammonium group and -NH-CH₂-, respectively. Furthermore, compared to QCS, a new peak of 6.8–7.3 ppm appeared in the QCSG spectrum, corresponding to the catechol-like group of gallic acid. A peak of approximately 2.4 ppm was observed in the QCSL spectrum, corresponding to the -CH₂- group of lauric acid. For the ¹H NMR spectrum of Odex, several additional peaks were observed in the range of 4.2–5.8 ppm, corresponding to the protons of the hemiacetal structure. For the FT-IR spectra of QCS, QCSG, and QCSL, a peak was observed at approximately 1475 cm⁻¹. -1 There is a distinct characteristic peak at 1736 cm⁻¹, corresponding to the methyl band of GTMAC. -1 The peak appearing at [location] is an amide bond, which may be related to lauric acid grafting onto the QCS or gallic acid grafting onto the QCS. Additionally, peaks appearing at 1600-1450 cm⁻¹... -1 (C=C stretching vibration of the benzene ring) and 880-680 cm⁻¹ -1 The wavelength range (CH bending vibration of the benzene ring) also indicates that gallic acid was successfully grafted onto the amino group of QCS. Furthermore, in the Odex FT-IR spectrum, at 1731 cm⁻¹... -1 A weak absorption peak corresponding to the aldehyde functional group was observed at [value missing]. These results indicate the successful synthesis of QCS and Odex, and the grafting of gallic acid and lauric acid onto QCS, respectively. Furthermore, the FT-IR spectra of QCSL and QCSG show [value missing] in the 3200–3500 cm⁻¹ range. -1 The region exhibits strong absorption, attributed to the stretching vibrations of NH and OH, and at 1595 cm⁻¹. -1 A primary amine NH bending vibration corresponding to this vibration appears at a certain point. Compared to QCSL and QCSG, the primary amine NH bending vibration (1595 cm⁻¹) in the hydrogel sample... -1 The height of 3200-3500cm has disappeared. -1 The absorption intensity in the region also decreased significantly. Meanwhile, the 1731 cm⁻¹ corresponding to the aldehyde group... -1 The peak also disappeared, while at 1634cm -1 A new peak appeared at C=N, indicating that the hydrogel underwent Schiff base crosslinking.

[0094] The successful synthesis of porous CaCO3 microparticles was confirmed by XRD spectroscopy and SEM images. Figure 7 The results showed a CaCO3 calcite structure, confirmed by a strong peak at 2θ around 30°.

[0095] Examples 2 to 6

[0096] The acetic acid concentration in Example 1 was controlled at 10 μL / mL, 30 μL / mL, 60 μL / mL, 90 μL / mL, and 120 μL / mL, respectively, and other conditions were the same as in Example 1, so that OD+C / QGQL+A5, OD+C / QGQL+A15, OD+C / QGQL+A45, and OD+C / QGQL+A60 hydrogels could be obtained.

[0097] The release of H from the hydrogel in PBS at 37°C was evaluated. + Caused pH changes ( Figure 8 a) The pH of the PBS soaking solutions of the four hydrogels almost reached equilibrium after 1.5 h. During soaking, the OD+C / QGQL+A5 hydrogel showed the least pH change, with a ΔpH of 0.25. With increasing acetic acid content in the hydrogels, the ΔpH of the OD+C / QGQL+A15, OD+C / QGQL+A30, and OD+C / QGQL+A45 hydrogels increased to 0.96, 1.51, and 2.05, respectively, with final soaking solution pH values ​​of 6.6, 6.1, and 5.6. The decrease in pH with increasing acetic acid content in the hydrogel precursor affects the rate and efficiency of the Schiff base reaction, thereby reducing the crosslinking density of the hydrogel. The resulting hydrogel also releases more H+ during soaking. + Furthermore, the increase in acetic acid produces more CO2, leading to more pores in the same mass of hydrogel, thus further increasing the hydrogel's swelling rate while decreasing its mechanical properties. To evaluate the mechanical properties of the hydrogel, rheological property tests were performed. Figure 8 b). After complete gelation, the storage modulus and loss modulus (G′ and G″) of the hydrogels were tested. Except for OD+C / QGQL+A45, the G′ of the other hydrogels was higher than that of G″ across the entire angular frequency range (1–50 rad / s), indicating that they can maintain their original hydrogel network structure in the low / mid frequency region. For the hydrogel OD+C / QGQL+A45, at angular frequencies above 20 rad / s, G' is lower than G'", indicating that its hydrogel network is disrupted. Furthermore, the OD+C / QGQL+A5 hydrogel has the highest G' at 8.3 kPa, while the G' of OD+C / QGQL+A15 and OD+C / QGQL+A30 hydrogels decreases slightly to 5.6 and 4.2 kPa, respectively. However, the G' of the OD+C / QGQL+A45 hydrogel drops sharply to 0.8 kPa. The results show that the hydrogel exhibits higher strength when the acid content in the hydrogel precursor is low. When the acid content in the hydrogel precursor is excessive, the strength of the hydrogel decreases significantly.

[0098] Degradable hemostatic materials can avoid the need for secondary surgery to remove residual material after hemostasis. Therefore, an in vitro degradation test was conducted on a representative sample, OD+C / QGQL+A30 hydrogel, in PBS (pH=7.4). Figure 9 As shown, the mass loss of the hydrogel gradually increases with time. After 7 days, the dry weight loss of the hydrogel increases to 59%, demonstrating its good degradability. This is because the hydrogel based on Schiff base dynamic cross-linking can be hydrolyzed. Therefore, the OD+C / QGQL+A hydrogel is degradable and can be used for in vivo hemostasis.

[0099] SEM images of all hydrogels ( Figure 10 a) All hydrogels exhibited intact porous structures without network collapse. Furthermore, with increasing acetic acid content, the pore sizes of the OD+C / QGQL+A5, OD+C / QGQL+A15, OD+C / QGQL+A30, and OD+C / QGQL+A45 hydrogels gradually increased from 147 μm to 198 μm, 267 μm, and 312 μm, respectively. To confirm that the hydrogel swelling was caused by CO2, the state of air bubbles in the fluorescently labeled swollen hydrogels was observed using confocal laser scanning microscopy. Figure 10 b shows that the hydrogel portion exhibits green fluorescence, with numerous air bubbles (non-fluorescent) uniformly dispersed within it. As the acetic acid content increases from 5 μL to 30 μL, the air bubble coverage in the hydrogel significantly increases. There is no significant difference in air bubble coverage between the OD+C / QGQL+A30 and OD+C / QGQL+A45 hydrogels. Furthermore, the OD+C / QGQL+A5 hydrogel contains very few air bubbles, while the other three hydrogels contain a large number of air bubbles.

[0100] Figure 11 (a) to (c) show the volume expansion ratio, gelation time, and expansion rate of the hydrogels, respectively. With increasing acetic acid content, the volume expansion ratios of the OD+C / QGQL+A15, OD+C / QGQL+A30, and OD+C / QGQL+A45 hydrogels were 2, 3.3, and 4, respectively. Furthermore, they exhibited similar gelation times of 33 s, 30 s, and 28 s, respectively. The expansion rates of the four hydrogels increased from 0.77% / s to 3.65% / s, 7.95% / s, and 10.80% / s with increasing acetic acid content. Therefore, higher acetic acid and CaCO3 contents resulted in larger hydrogel volumes and faster expansion rates.

[0101] The extrusion pressure of the OD+C / QGQL+A30 hydrogel on the non-deformable surface was tested during the expansion process when there was a 1 mm gap between the 8 mL cylindrical container containing 4 mL of hydrogel precursor and the non-deformable surface. Figure 12During the expansion of the hydrogel, the hydrogel precursor is squeezed outwards due to obstruction at the top surface, and the axial pressure at the top surface gradually increases. However, the maximum pressure does not exceed 45 kPa, which is lower than the ultimate pressure that soft tissue can withstand.

[0102] For the swelling mechanism of hydrogels, see Figure 13 When the QCSG / QCSL / acetic acid solution and the Odex / CaCO3 dispersion are injected using a dual-needle syringe, the mixed acetic acid and CaCO3 rapidly undergo a metathesis reaction, generating a large amount of CO2 around the porous CaCO3 particles and dispersing it within the hydrogel precursor. Because a Schiff base reaction is also rapidly occurring within the hydrogel precursor, its viscosity increases rapidly until gelation occurs. Therefore, the CO2 does not escape in a short time but is locked within the stable hydrogel network, thus promoting the expansion of the hydrogel.

[0103] The self-propulsion properties of the hydrogel were evaluated through filling experiments with irregular cavities. The results are as follows: Figure 14 As shown, an irregular wound cavity was simulated using a specially treated glove. After the hydrogel precursor was injected, the hydrogel precursor expanded continuously under the impetus of CO2 and propelled into all parts of the cavity. When the glove was cut open, it was found that the hydrogel completely filled the entire cavity.

[0104] The hemolysis rate of hydrogels is evaluated by direct contact between red blood cells and the surface of the hydrogel. Figure 15 (a) and (b) show the macroscopic color of the supernatant from the four hydrogel groups, the Triton X-100 positive control group, and the PBS negative control group. All hydrogel groups exhibited a pale yellow color similar to the PBS group, while the supernatant from the Triton X-100 group was bright red, indicating that no significant hemolysis occurred with any of the four hydrogels. Quantitative data showed that the hemolysis rate of all four hydrogels was less than 5%, consistent with the macroscopic supernatant color results. Therefore, the hemolysis results indicate that none of the four hydrogels caused significant hemolysis upon contact with red blood cells, demonstrating good blood compatibility.

[0105] The cell compatibility of the hydrogel was assessed using a leaching assay in which L929 cells were co-cultured with the hydrogel leachate. Figure 16As shown, when the leachate concentrations of the OD+C / QGQL+A5, OD+C / QGQL+A15, and OD+C / QGQL+A30 hydrogels ranged from 2.5 mg / mL to 5.0 mg / mL and 10 mg / mL, the cell viability in the hydrogel groups exceeded 83% compared to the TCP group. Live / dead staining results were consistent with the cell viability results; L929 cells in all four hydrogel groups were green and spindle-shaped, with only a small number of cells turning red due to cell metabolism, similar to the TCP control group. All results indicate that all hydrogels have good cell compatibility and can be used as hemostatic agents.

[0106] The adhesive strength of the hydrogel to fresh pig skin and pig skeletal muscle was evaluated using an overlap shear test. Figure 17 As shown in Figure a, the OD+C / QGQL+A5 hydrogel exhibited the lowest skin tissue adhesion strength at 3.1 kPa. With increasing acetic acid content in the hydrogel precursor, the skin tissue adhesion strength of the OD+C / QGQL+A15 hydrogel slightly increased to 4.1 kPa, while the OD+C / QGQL+A30 hydrogel showed the highest skin tissue adhesion strength at 9 kPa. However, the skin tissue adhesion strength of the OD+C / QGQL+A45 hydrogel, which had the highest acid content, decreased to 7.6 kPa. Furthermore, the OD+C / QQL+A30 hydrogel (QCS instead of QCSG), lacking catechol-like groups, also showed a lower skin tissue adhesion strength than the OD+C / QGQL+A30 hydrogel, at 5.7 kPa, indicating that catechol groups contribute to the tissue adhesion properties of the hydrogel. For skeletal muscle tissue adhesion, the hydrogel adhesion strength showed a similar pattern to that of skin tissue. Figure 17 b). The skeletal muscle tissue adhesion strength of OD+C / QGQL+A5 hydrogel was 3.5 kPa, while that of OD+C / QGQL+A15 hydrogel increased slightly to 4.1 kPa. OD+C / QGQL+A30 hydrogel showed the highest skeletal muscle tissue adhesion strength (8.5 kPa), while that of OD+C / QGQL+A45 hydrogel decreased to 6.2 kPa. Regarding the tissue adhesion mechanism ( Figure 17 c) The adhesive properties of the hydrogel mainly originate from the Schiff base dynamic covalent cross-linking between the aldehyde groups of Odex and the amino groups on the tissue surface. In addition, the abundant catechol-like groups in the OD+C / QGQL+A30 hydrogel can form physical adhesion on the tissue surface (including hydrogen bonding, cation-π, π-π interactions, etc.), and the positively charged quaternary ammonium groups of QCSL and QCSG can also provide electrostatic interactions on the tissue surface.

[0107] The bursting pressure of OD+C / QGQL+A30 hydrogel adhered to the surface of pigskin was tested. Figure 18The results showed that the burst pressure of the OD+C / QGQL+A30 hydrogel reached 235 mmHg (31.3 kPa), far exceeding the normal systolic blood pressure of the human body (120 mmHg). Furthermore, the burst pressure of the OD+C / QGQL+A30 hydrogel was also significantly higher than that of commercial tissue adhesives, such as Evicel (1.94 ± 0.99 kPa) and Coseal (1.68 ± 0.11 kPa).

[0108] The antibacterial activity of hydrogels against *Escherichia coli* (E. coli) and methicillin-resistant *Staphylococcus aureus* (MRSA) was evaluated. After co-culturing the bacteria with the hydrogels for 2 hours, all hydrogels showed a 100% bactericidal rate against both bacteria. Figure 19 The logarithm of E. coli decreased to 5.77, and the logarithm of MRSA decreased to 5.64.

[0109] The antioxidant activity of the hydrogel was evaluated by testing its DPPH· scavenging rate. Figure 20 As shown, when the concentration of the OD+C / QGQL+A30 hydrogel dispersion increased from 5 mg / mL to 20 mg / mL, the DPPH· scavenging rate gradually increased from 52% to 88%. However, in the control group, when the concentration of the OD+C / QQL+A30 hydrogel dispersion reached 20 mg / mL, the DPPH· scavenging rate was only 42%.

[0110] For whole blood coagulation test ( Figure 21 a) The blank group showed the highest blood clotting index (BCI) at 120 s, at 66%, indicating the slowest clotting rate (P<0.05). Compared to the blank group, the BCI of the gelatin sponge group decreased by approximately 7% at 120 s (P<0.05). The combat gauze group showed a lower BCI at 120 s, approximately 43%, and was significantly lower than the blank group and the gelatin sponge group at every time point (P<0.001). However, all hydrogels showed better clotting ability than combat gauze and gelatin sponge. Furthermore, the BCI of the OD+C / QGQL+A5, OD+C / QGQL+A15, and OD+C / QGQL+A45 hydrogel groups decreased sequentially (33%, 30%, and 27% at 120 s, respectively). The OD+C / QGQL+A30 hydrogel group had the lowest BCI, at 24% at 120 s. The results of the ACD anticoagulation whole blood clotting test were similar to those of the whole blood clotting test. Figure 21 (b) The OD+C / QGQL+A30 hydrogel still showed the lowest BCI, at 25% at 300s. The results demonstrate that all hydrogels have good coagulation ability, with the OD+C / QGQL+A30 and OD+C / QGQL+A45 hydrogels exhibiting the strongest coagulation ability.

[0111] The adhesion amount of different hemostatic materials to platelets, such as Figure 22 As shown in Figure a, the platelet adhesion content of all hydrogels was higher than that of the two control hemostatic materials. In particular, the platelet adhesion content of the OD+C / QGQL+A15 and OD+C / QGQL+A30 hydrogel groups was higher than that of the OD+C / QGQL+A5 and OD+C / QGQL+A45 hydrogel groups. Therefore, hydrogels can promote platelet aggregation. Figure 22 Figure b shows the adhesion morphology of erythrocytes on the hydrogel surface. All hydrogels showed a large number of erythrocytes adhering to them, and most erythrocytes exhibited morphological changes and irregular aggregation, indicating that the erythrocytes were activated by the hydrogels. In particular, the erythrocytes in the OD+C / QGQL+A30 and OD+C / QGQL+A45 hydrogel groups showed a dense aggregation. Furthermore, the combat gauze group had very few erythrocytes, while the gelatin sponge group showed a slight increase in erythrocyte count. The results indicate that hydrogels can promote erythrocyte aggregation and activation.

[0112] The optimized OD+C / QGQL+A30 hydrogel precursor was further injected into ACD-anticoagulated whole blood using a dual-needle syringe. The hydrogel precursor rapidly swelled in the blood and underwent Schiff base cross-linking, forming a blood clot within approximately 10 seconds. The morphology of erythrocytes on and inside the hydrogel was observed using SEM. Figure 23 As shown, a large number of red blood cells aggregate on the surface of the hydrogel, with most of them deformed and exhibiting an activated state. Furthermore, observation of the hydrogel's internal state revealed that a significant amount of blood components and red blood cells were embedded within the hydrogel, indicating that the hydrogel precursor encapsulates blood during expansion, forming a hydrogel / blood clot complex. Therefore, when blood comes into contact with the hydrogel precursor, blood coagulation is enhanced, which is crucial for sealing bleeding wounds.

[0113] The results are as follows Figure 24 As shown, in the rat liver circular section model, the blood loss was highest in the blank group (1081 mg, P < 0.05), while the blood loss in the combat gauze group decreased to 464 mg (P < 0.05). The blood loss in the gelatin sponge group was further reduced to 385 mg. All hydrogel groups had less blood loss than the combat gauze and hemostatic sponge groups, and with increasing acetic acid content, the blood loss in the hydrogel groups was 141 mg, 32 mg, 21 mg, and 141 mg, respectively. Regarding hemostasis time, the blank group had a time of 2.4 min. The hemostasis time in the gelatin sponge group and the combat gauze group decreased to 1.8 min and 1.9 min, respectively. However, with increasing acetic acid content, the hemostasis time in the hydrogel groups was 0.8 min, 0.2 min, 0.3 min, and 0.8 min, respectively, significantly lower than the three control groups (P < 0.05).

[0114] For the rat liver cross-incision model ( Figure 25 The blood loss in the control group was 1.5g, while the blood loss in the gauze group, gelatin sponge group, and OD+C / QGQL+A5 hydrogel group was significantly reduced (P<0.01). Compared with the OD+C / QGQL+A5 hydrogel group, the blood loss in the OD+C / QGQL+A15 and OD+C / QGQL+A30 hydrogel groups was further significantly reduced, at 0.15g and 0.06g, respectively. However, the blood loss in the OD+C / QGQL+A45 hydrogel group increased to 0.53g. Furthermore, the control group had the longest hemostasis time, at 4.4min. The hemostasis times in the gauze group, gelatin sponge group, and OD+C / QGQL+A5 hydrogel group were 2.1min, 2.1min, and 2.5min, respectively. However, the hemostasis time was reduced to 1.0 min in the OD+C / QGQL+A15 hydrogel group, while the hemostasis time was the shortest in the OD+C / QGQL+A30 hydrogel group, at 0.2 min. Compared with the OD+C / QGQL+A30 hydrogel, the hemostasis time was prolonged to 1.4 min in the OD+C / QGQL+A45 hydrogel group.

[0115] like Figure 26 As shown, in the rabbit liver volume defect bleeding model, the blank group showed the largest blood loss (25.7 g) and the longest hemostasis time (11.0 min). Inserting gelatin sponge into the liver defect reduced blood loss to 6.2 g and shortened the hemostasis time to 5.1 min (P < 0.05). Injecting OD+C / QGQL+A5 hydrogel precursor into the liver defect reduced blood loss and hemostasis time to 1.2 g and 3.5 min, respectively. Furthermore, injecting self-expanding and self-propelling OD+C / QGQL+A30 hydrogel precursor into the liver defect further reduced blood loss to 0.4 g and shortened the hemostasis time to 1.5 min.

[0116] Figure 27The hemostasis results of the rabbit liver volume defect model with coagulation disorder are shown. Compared with the normal coagulation function model (rabbit liver volume defect bleeding model with non-compressible bleeding), the blood loss in the control group increased to 42.7g (P<0.05). Although the hemostasis time was 7.7min, all rabbits in the coagulation disorder model control group died (80% died within 1 hour, 100% died after 24 hours), while rabbits in the normal coagulation function model control group were still alive after 24 hours. Therefore, the coagulation disorder model was successfully constructed, and this bleeding model was lethal. Compared with the control group, the blood loss and hemostasis time in the gelatin sponge group were significantly reduced, at 10.0g and 4.4min, respectively (P<0.05). After intralesional injection of OD+C / QGQL+A5 hydrogel precursor, the blood loss and hemostasis time were 3.2g and 2.6min, respectively, with better hemostasis effect than the gelatin sponge group (P<0.05). In particular, after applying OD+C / QGQL+A30 hydrogel to the wound, the blood loss was further reduced to 0.8g, and the hemostasis time was shortened to about 1.7min.

[0117] In cases where the bleeding site is unknown, the hydrogel precursor is injected into areas where wounds may exist. The hemostatic properties of the hydrogel are evaluated after 15 minutes. For a blind-view rabbit liver incision model (…),… Figure 28 The blank group showed the greatest blood loss, at 12g. Blood loss was reduced to 3.5g in the OD+C / QGQL+A5 hydrogel group and to 1g in the OD+C / QGQL+A30 hydrogel group (P<0.05).

[0118] For a blind-view rabbit kidney incision model ( Figure 29 The blood loss in the blank group was approximately 12g. The OD+C / QGQL+A5 hydrogel significantly reduced the blood loss to 3.9g. The OD+C / QGQL+A30 hydrogel group still showed the best hemostatic effect with a blood loss of 1.9g.

[0119] The hemostatic ability of OD+C / QGQL+A30 hydrogel in treating arterial bleeding was evaluated using a rat femoral artery bleeding model. Results are as follows: Figure 30 As shown, the blank group exhibited the highest blood loss at 5.8g, while the blood loss in the gauze and gelatin sponge groups was significantly reduced to 3.7g and 3.5g, respectively (P<0.001). The blood loss in the OD+C / QGQL+A5 hydrogel group was further reduced to 3.0g. In particular, the self-expanding and self-propelled OD+C / QGQL+A30 hydrogel group showed the lowest blood loss (2.2g).

[0120] A porcine subclavian artery and vein complete transection model was used to simulate penetrating junction injuries, including those involving the axillary and subclavian arteries, which are closely associated with high mortality rates. Medical gauze and manual pressure were used as controls. Pigs undergoing complete arterial and venous transection experience significant blood loss within a short time (approximately 500-750 mL in 30 seconds) and will die within minutes without treatment. Therefore, no blank control was included in this experiment. Figure 31 As shown, the blood loss in the gauze group was 486 mL, and the hemostasis time was 26.8 min. However, the blood loss in the self-expanding, self-propelled OD+C / QGQL+A30 hydrogel group was only 11 mL, and the hemostasis time was 1.5 min, both significantly lower than the gauze group (P<0.05). Furthermore, the hydrogel application time was less than 17 s, while gauze filling required 42 s and an additional 3 min of pressure (P<0.001). The US military used a porcine subclavian artery and vein complete transection model to evaluate the hemostatic effect of Xstat. Xstat showed 75% hemostasis within 4 min and 100% hemostasis within 60 min. The post-treatment blood loss was 118±308 mL, and the application time was 25±5 s. Compared with Xstat, the self-expanding, self-propelled hydrogel has better hemostatic performance, can effectively treat severe arterial bleeding, improves the survival rate of pigs, and is biodegradable. The excellent hemostatic ability of this hydrogel comes from the synergistic effect of its self-expanding, self-propelling, and procoagulant properties. Therefore, this injectable, self-expanding, self-propelled hydrogel may be used for first aid in battlefield and traffic accident situations.

[0121] The in vivo biocompatibility of the hydrogel was evaluated using a subcutaneous implantation assay in rats. Figure 32 As shown, all three groups of samples exhibited a weak inflammatory response 7 days after subcutaneous implantation. Furthermore, the OD+C / QGQL+A30 hydrogel group showed an inflammatory response similar to the gelatin sponge group, but weaker than that of the OD+C / QQL+A30 group. 28 days after subcutaneous implantation in rats, the inflammatory response in all three groups decreased, and denser fibrous connective tissue was observed. However, the fibrous connective tissue in the OD+C / QGQL+A30 hydrogel group and the gelatin sponge group was thinner than that in the OD+C / QQL+A30 hydrogel group, and showed weaker inflammatory cell infiltration. These results indicate that the acute and chronic inflammatory responses after implantation in vivo were mild in all three groups. Furthermore, the introduction of GA attenuated the inflammatory response of the OD+C / QGQL+A30 hydrogel, indicating that this hemostatic hydrogel has good biocompatibility in vivo.

[0122] Example 7

[0123] By changing the gallic acid (polyphenol modified) in QCSG in Example 1 to 27.67 wt%, and keeping other conditions the same as in Example 1, an OD+C / QGQL+A hydrogel with high gallic acid content can be obtained.

[0124] Example 8

[0125] By changing the lauric acid (hydrophobic segment modified) in QCSL in Example 1 to 9.65 wt%, and keeping other conditions the same as in Example 1, an OD+C / QGQL+A hydrogel with high lauric acid content can be obtained.

[0126] Example 9

[0127] By changing the concentration of OD in Example 1 to 10wt%, while keeping other conditions the same as in Example 1, an OD+C / QGQL+A hydrogel with high OD content can be obtained.

[0128] Example 10

[0129] By changing the concentration of CaCO3 in Example 1 to 20 mg / mL, while keeping other conditions the same as in Example 1, an OD+C / QGQL+A hydrogel with high CaCO3 content can be obtained.

[0130] Example 11

[0131] By changing the concentration of QCSG in Example 1 to 7.5 wt%, while keeping other conditions the same as in Example 1, an OD+C / QGQL+A hydrogel with high QCSG content can be obtained.

[0132] Example 12

[0133] By changing the concentration of QCSL in Example 1 to 7.5 wt%, while keeping other conditions the same as in Example 1, an OD+C / QGQL+A hydrogel with high QCSL content can be obtained.

[0134] Example 13

[0135] By replacing QCSL and QCSG in Example 1 with gelatin, and keeping other conditions the same as in Example 1, a self-expanding and self-propelling hydrogel cross-linked with gelatin and OD can be obtained.

[0136] Example 14

[0137] By replacing QCSL and QCSG in Example 1 with aminated gelatin, and keeping other conditions the same as in Example 1, a self-expanding and self-propelling hydrogel cross-linked with aminated gelatin and OD can be obtained.

[0138] Example 15

[0139] By replacing QCSL and QCSG in Example 1 with aminated sodium alginate, and keeping other conditions the same as in Example 1, a self-expanding and self-propelling hydrogel cross-linked with aminated sodium alginate and OD can be obtained.

[0140] Example 16

[0141] By replacing QCSL and QCSG in Example 1 with amino-modified hyaluronic acid, and keeping other conditions the same as in Example 1, a self-expanding and self-propelling hydrogel cross-linked with amino-modified hyaluronic acid and OD can be obtained.

[0142] Example 17

[0143] By replacing QCSL and QCSG in Example 1 with aminated poly(ethylene glycol-glycerol-sebacic acid), and keeping other conditions the same as in Example 1, a self-expanding and self-propelling hydrogel crosslinked with aminated poly(ethylene glycol-glycerol-sebacic acid) and OD can be obtained.

[0144] Example 18

[0145] By replacing OD in Example 1 with oxidized hyaluronic acid, and keeping other conditions the same as in Example 1, a self-expanding and self-propelling hydrogel crosslinked with oxidized hyaluronic acid, QCSL and QCSG, can be obtained.

[0146] Example 19

[0147] By replacing OD in Example 1 with sodium oxidized alginate, and keeping other conditions the same as in Example 1, a self-expanding and self-propelling hydrogel crosslinked with sodium oxidized alginate and QCSL and QCSG can be obtained.

[0148] Example 20

[0149] By replacing OD in Example 1 with pullulan oxidase, and keeping other conditions the same as in Example 1, a self-expanding and self-propelling hydrogel crosslinked with QCSL and QCSG and pullulan oxidase can be obtained.

[0150] Example 21

[0151] By replacing OD in Example 1 with aldehyde-based poly(ethylene glycol-glycerol-sebacic acid), and keeping other conditions the same as in Example 1, a self-expanding and self-propelling hydrogel crosslinked with aldehyde-based poly(ethylene glycol-glycerol-sebacic acid) can be obtained.

[0152] Example 22

[0153] By replacing the acetic acid in Example 1 with protonated tranexamic acid, and keeping other conditions the same as in Example 1, a self-expanding and self-propelled hydrogel in which protonated tranexamic acid and calcium carbonate produce carbon dioxide can be obtained.

[0154] Example 23

[0155] By replacing the acetic acid in Example 1 with dilute hydrochloric acid, and keeping other conditions the same as in Example 1, a self-expanding and self-propelling hydrogel in which dilute salt and calcium carbonate produce carbonic acid can be obtained.

[0156] Example 24

[0157] By replacing acetic acid with phosphoric acid in Example 1, and keeping other conditions the same as in Example 1, a self-expanding and self-propelled hydrogel in which phosphoric acid and calcium carbonate produce carbon dioxide can be obtained.

[0158] Example 25

[0159] By replacing calcium carbonate in Example 1 with sodium bicarbonate, and keeping other conditions the same as in Example 1, a self-expanding and self-propelled hydrogel in which acetic acid and sodium bicarbonate produce carbon dioxide can be obtained.

[0160] Example 26

[0161] By replacing calcium carbonate with sodium carbonate in Example 1, and keeping other conditions the same as in Example 1, a self-expanding and self-propelled hydrogel in which acetic acid and sodium carbonate produce carbon dioxide can be obtained.

[0162] Example 27

[0163] By replacing acetic acid with hydrogen peroxide and calcium carbonate with catalase in Example 1, and keeping other conditions the same as in Example 1, a self-expanding and self-propelled hydrogel that generates oxygen from hydrogen peroxide and catalase can be obtained.

[0164] Example 28

[0165] By replacing acetic acid with hydrogen peroxide and calcium carbonate with manganese dioxide in Example 1, and keeping other conditions the same as in Example 1, a self-expanding and self-propelled hydrogel that generates oxygen from hydrogen peroxide and manganese dioxide can be obtained.

[0166] Example 29

[0167] By replacing acetic acid with hydrogen peroxide and calcium carbonate with cerium dioxide in Example 1, and keeping other conditions the same as in Example 1, a self-expanding and self-propelled hydrogel that generates oxygen from hydrogen peroxide and cerium dioxide can be obtained.

[0168] Example 30

[0169] In this example, the concentration of acetic acid added was 1 μL / mL, and the rest was the same as in Example 1.

[0170] Example 31

[0171] In this example, the concentration of acetic acid added was 200 μL / mL, and the rest was the same as in Example 1.

[0172] Example 32

[0173] In this embodiment, the concentration of CaCO3 particles added is 1 mg / mL, and the rest is the same as in Example 1.

[0174] Example 33

[0175] In this embodiment, the concentration of CaCO3 particles added is 20 mg / mL, and the rest is the same as in Example 1.

[0176] Example 34

[0177] In this embodiment, the concentration of CaCO3 particles added is 40 mg / mL, and the rest is the same as in Example 1.

[0178] Example 35

[0179] In this embodiment, the concentration of CaCO3 particles added is 60 mg / mL, and the rest is the same as in Example 1.

[0180] Example 36

[0181] In this embodiment, the concentration of CaCO3 particles added is 100 mg / mL, and the rest is the same as in Example 1.

[0182] Example 37

[0183] In this embodiment, the concentrations of QCSG and QCSL added are both 10%, and the rest is the same as in Example 1.

[0184] Example 38

[0185] In this embodiment, the concentrations of QCSG and QCSL added are 20%, and the rest are the same as in Example 1.

[0186] Example 39

[0187] In this example, the concentrations of QCSG and QCSL added are 0.5 mg / mL, and the rest is the same as in Example 1.

[0188] Example 40

[0189] In this embodiment, the concentration of Odex added is 40%, and the rest is the same as in Example 1.

[0190] Example 41

[0191] In this embodiment, the concentration of Odex added is 0.5%, and the rest is the same as in Example 1.

[0192] Example 42

[0193] In this embodiment, the concentration of Odex added is 20%, and the rest is the same as in Example 1.

[0194] As can be seen from the above embodiments, the present invention can prepare different self-expanding and self-propelling hydrogel dressings by adjusting the amount of QCSG, QCSL, OD, CaCO3 or acetic acid. It can also prepare different self-expanding and self-propelling hydrogel dressings by replacing QCSG and QCSL with other aminated polymers, and can also prepare different self-expanding and self-propelling hydrogel dressings by replacing OD with other aldehyde-modified polymers.

[0195] The hydrogel dressing prepared by this invention is injectable and self-expanding, enabling it to be injected into narrow, deep wounds and rapidly expand to seal the wound, addressing deep, non-compressible bleeding. Furthermore, the prepared hydrogel dressing is self-propelled, effectively controlling bleeding in blind areas. Moreover, the prepared hydrogel dressing has multiple procoagulant advantages, effectively controlling bleeding from coagulation disorders and arterial bleeding. Finally, the prepared hydrogel dressing is biodegradable, avoiding the need for secondary surgery to remove residual material.

[0196] In summary, this invention has prepared a series of injectable, self-expanding, and self-propelled hydrogels based on CaCO3 foaming and Schiff base crosslinking for rapid control of arterial bleeding and intraperitoneal bleeding under blind-field conditions. The optimized hydrogel can rapidly expand (within 30 seconds) to three times its own volume and exhibits excellent self-propelling properties. In surface bleeding models such as rat liver circular slice models and rat liver cruciate incision models, the blood loss and hemostasis time of this hydrogel are lower than those of gelatin sponges (blood loss is almost 0g, and hemostasis time is shortened by more than 86%), mainly because the hydrogel can quickly seal the wound and its components can promote coagulation. For rabbit liver volume defect bleeding models that cannot be pressed and rabbit liver volume defect models with coagulation disorders, the self-expanding and self-propelling properties of the hydrogel also significantly reduce blood loss and hemostasis time compared to gelatin sponges (blood loss is reduced by more than 92%, and hemostasis time is shortened by more than 61%). Furthermore, in blind-view rabbit liver and kidney incision models, the self-expanding and self-propelling hydrogel effectively covered areas where wounds might exist, demonstrating excellent hemostasis (blood loss was reduced by more than 88% compared to the control group). The optimized hydrogel showed superior hemostasis in a rat femoral artery hemorrhage model compared to gauze and gelatin sponge (blood loss was reduced by 37% compared to the gelatin sponge group). In particular, the hydrogel effectively controlled complete transection bleeding of the porcine subclavian artery and vein, reducing blood loss by 97% and shortening hemostasis time by 95% compared to the medical gauze group with 3 minutes of pressure. Moreover, the hydrogel degraded by more than 50% within 7 days in PBS (pH=7.4). All results indicate that injectable self-expanding and self-propelling hydrogels have great potential for controlling arterial bleeding and blind-view intraperitoneal hemorrhage.

[0197] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A device for forming a self-swelling, self-propelling hydrogel haemostatic dressing, characterised in that, The application relates to a method for preparing a water-soluble hydrogel, comprising the following steps: a first carrying device is loaded with a mixed solution of a functionally modified amino polymer and a first reactant, wherein the first reactant is an acid or hydrogen peroxide; a second carrying device is loaded with a mixed dispersion of a functionally modified aldehyde polymer and a second reactant, wherein the second reactant is a carbonic compound, a catalase or a nano-particle with catalase activity; the acid is any one of acetic acid, protonated tranexamic acid, dilute hydrochloric acid or phosphoric acid; the carbonic compound is a carbonate or a bicarbonate; the nano-particle with catalase activity is a manganese dioxide particle or a cerium dioxide particle; the functionally modified amino polymer is a quaternary ammonium salt modification, a hydrophobic chain segment modification or a polyphenol group modification; the functionally modified aldehyde polymer is a quaternary ammonium salt modification, a hydrophobic chain segment modification or a polyphenol group modification; the aldehyde polymer is oxidized dextran, oxidized hyaluronic acid, oxidized sodium alginate, oxidized pullulan or an aldehyde polymer of poly (ethylene glycol-glycerol-sebacic acid); the amino polymer is chitosan, gelatin, amino gelatin, amino sodium alginate, amino hyaluronic acid or an amino polymer of poly (ethylene glycol-glycerol-sebacic acid); a mixing device is used to mix the substances output by the first carrying device and the substances output by the second carrying device and then deliver the mixed substances to a target area; after the two substances are mixed, the functionally modified amino polymer and the functionally modified aldehyde polymer react to generate a hydrogel, and the first reactant and the second reactant react to generate gas; the hydrogel self-expands during the reaction, and the gas propels the hydrogel to fill the target area; the mass fraction of the functionally modified amino polymer in the mixed solution of the first carrying device is 0.5% to 20%, and the concentration of the first reactant is 1 to 200 muL / mL; the mass fraction of the functionally modified aldehyde polymer in the mixed solution of the second carrying device is 0.5% to 40%, and the concentration of the second reactant is 1 to 100 mg / mL; the first carrying device and the second carrying device are both needle tubes, and the mixing device is a spiral needle head; the acid is acetic acid, and the carbonic compound is calcium carbonate. ​ ​ ​ ​ ​ ​ ​ ​ 2. A device for forming a self swelling self propelling hydrogel haemostatic dressing according to claim 1 characterised in that, ​ 3. A device for forming a self-swelling, self-propelling hydrogel haemostatic dressing according to claim 1, wherein, ​ 4. A device for forming a self swelling self propelling hydrogel haemostatic dressing according to claim 1 characterised in that, ​ 5. A device for forming a self-swelling, self-propelling hydrogel haemostatic dressing according to claim 1, wherein, ​

Images