Injectable composite hydrogel as well as preparation method and use method thereof

Abstract

The invention belongs to the field of hydrogel, and particularly relates to injectable composite hydrogel as well as a preparation method and a use method thereof. The injectable composite hydrogel provided by the invention comprises a component A and a component B, wherein the component A comprises a polyfunctional polymer, a thixotropic agent and an aqueous solvent, the polyfunctional polymer is one or more of gelatin, carboxymethyl chitosan and collagen, and the thixotropic agent is one or more of montmorillonite, bentonite, kaolinite, halloysite, magnesium aluminum silicate and magnesium lithium silicate; the component B comprises a multi-arm polyethylene glycol derivative and an aqueous solvent. The injectable composite hydrogel provided by the invention has good shear thinning performance and in-situ crosslinking performance, and has excellent injectability and embolism effect.

Description

Technical Field

[0001] The invention belongs to the field of hydrogels, and in particular relates to an injectable composite hydrogel and a preparation method and a use method thereof. Background Art

[0002] Embolization, also known as embolic therapy, refers to a technique that injects embolic material into the blood vessels of diseased organs in a controlled manner through a vein or intra-arterial catheter to block and interrupt blood supply in order to achieve the desired treatment purpose. Embolization is one of the three major techniques in interventional radiology. Compared with traditional open surgery, it has the advantages of being minimally invasive, safe, low-cost, less toxic and side effects, short recovery time, fewer complications, repeatable, and definite efficacy. It plays an important role in post-traumatic hemostasis, complications related to surgery or puncture, vascular lesions, elimination of diseased organs, palliative treatment of malignant tumors, preoperative embolization of tumors, and hemostasis treatment of massive tumor bleeding.

[0003] At present, there are a variety of injectable hydrogels used for vascular embolization, which usually have the characteristics of in situ cross-linking or shear thinning. In situ cross-linked gels are in liquid state before injection, and are responsive to stimuli such as heat, pH, and metal ions. After being injected into the blood vessels, they are in situ cross-linked and converted into a non-flowable gel state under the stimulation of the in vivo environment; two-component liquids can also be used, which are extruded through a double syringe and then form gels through physical and chemical cross-linking in situ. This type of gel has strict requirements on the cross-linking rate and operation time; if the cross-linking rate is too slow, there is a risk that the precursor solution will be diluted and washed away by the blood, which is easy to cause non-target embolism; if the cross-linking speed is too fast, gel may be formed prematurely during the injection process, introducing network defects, affecting the mechanical properties of the gel, and may even block the needle, catheter, and adhere to the blood vessel. Shear thinning gels are in a gel state before injection, and the viscosity decreases under a certain shear stress. They can be injected into the body. When the shear stress is removed, the viscosity and mechanical properties increase rapidly and return to the gel state, thereby achieving vascular embolism. This type of gel can effectively avoid problems such as blood dilution, catheter blockage, and blood vessel adhesion; however, its adhesion to vascular tissue is limited, and is restricted by its inherent properties. When the blood vessel is deformed or the pressure increases, the viscosity of the gel decreases under high shear stress, affecting the vascular embolization effect. Summary of the invention

[0004] In view of this, the object of the present invention is to provide an injectable composite hydrogel and a preparation method and a use method. The injectable composite hydrogel provided by the present invention has good shear thinning properties and in situ cross-linking properties, and has both excellent injectability and embolization effect.

[0005] The invention provides an injectable composite hydrogel, comprising a component A and a component B; wherein the components of the component A include a multifunctional polymer, a thixotropic agent and an aqueous solvent, the multifunctional polymer is one or more of gelatin, carboxymethyl chitosan and collagen, and the thixotropic agent is one or more of montmorillonite, bentonite, kaolinite, hectorite, halloysite, aluminum magnesium silicate and lithium magnesium silicate; the components of the component B include a multi-arm polyethylene glycol derivative and an aqueous solvent, and the multi-arm polyethylene glycol derivative is one or more of succinimide-terminated multi-arm polyethylene glycol, succinimide ester-terminated multi-arm polyethylene glycol, N-hydroxysuccinimide ester-terminated multi-arm polyethylene glycol, aldehyde-terminated multi-arm polyethylene glycol and benzaldehyde-terminated multi-arm polyethylene glycol.

[0006] Preferably, the content of the multifunctional polymer in the injectable composite hydrogel is 1 to 20 wt %.

[0007] Preferably, the content of the thixotropic agent in the injectable composite hydrogel is 1 to 20 wt%.

[0008] Preferably, the multi-arm polyethylene glycol derivative has 2 to 8 arms and a weight average molecular weight of 1,000 to 20,000.

[0009] Preferably, the content of the multi-arm polyethylene glycol derivative in the injectable composite hydrogel is 0.1-10 wt %.

[0010] Preferably, the aqueous solvent is purified water, water for injection, sodium chloride solution, phosphate buffer, borate buffer, triethanolamine buffer or sodium bicarbonate buffer.

[0011] Preferably, the volume ratio of component A to component B is (1-3):0.6.

[0012] The present invention provides a method for preparing the injectable composite hydrogel described in the above technical solution, comprising the following steps:

[0013] a) mixing a multifunctional polymer, a thixotropic agent and an aqueous solvent to obtain a component A of an injectable composite hydrogel;

[0014] b) mixing the multi-arm polyethylene glycol derivative and an aqueous solvent to obtain a component B of the injectable composite hydrogel;

[0015] There is no order between step a) and step b).

[0016] Preferably, step a) specifically comprises:

[0017] a1) mixing a multifunctional polymer with an aqueous solvent to obtain a multifunctional polymer solution;

[0018] a2) mixing the thixotropic agent with the remaining aqueous solvent to obtain a thixotropic agent gel;

[0019] There is no order of precedence between step a1) and step a2);

[0020] a3) mixing the multifunctional polymer solution with a thixotropic agent gel to obtain component A of an injectable composite hydrogel.

[0021] The present invention provides a method for using the injectable composite hydrogel described in the above technical solution, characterized in that it comprises the following steps:

[0022] Component A and component B are simultaneously injected and mixed into a gel through a double syringe;

[0023] Alternatively, component A and component B are premixed and then injected and gelled through a syringe.

[0024] Compared with the prior art, the present invention provides an injectable composite hydrogel and a preparation method and a use method. The injectable composite hydrogel provided by the present invention includes component A and component B; wherein the components of component A include a multifunctional polymer, a thixotropic agent and an aqueous solvent, the multifunctional polymer is one or more of gelatin, carboxymethyl chitosan and collagen, and the thixotropic agent is one or more of montmorillonite, bentonite, kaolinite, hectorite, halloysite, aluminum magnesium silicate and lithium magnesium silicate; the components of component B include a multi-arm polyethylene glycol derivative and an aqueous solvent, and the multi-arm polyethylene glycol derivative is one or more of succinimide-terminated multi-arm polyethylene glycol, succinimide ester-terminated multi-arm polyethylene glycol, N-hydroxysuccinimide ester-terminated multi-arm polyethylene glycol, aldehyde-terminated multi-arm polyethylene glycol and benzaldehyde-terminated multi-arm polyethylene glycol. The injectable composite hydrogel provided by the present invention has a specific type of multifunctional polymer, a thixotropic agent and a multi-arm polyethylene glycol derivative as main components, and has both shear thinning and in-situ cross-linking properties; wherein, the specific type of multifunctional polymer and the thixotropic agent component form a shear thinning gel through the action of electrostatics, hydrogen bonds, etc., so that the gel is semi-solid before being injected into the human body, and can be extruded through a syringe under moderate pressure to fill blood vessels of different shapes and sizes, and is not easily diluted or washed away by the blood flow; after injection, the specific type of multi-arm polyethylene glycol derivative component gradually cross-links with the specific type of multifunctional polymer to form a gel, and the mechanical properties are improved, so as to achieve the purpose of effective embolization of blood vessels. The injectable composite hydrogel provided by the present invention has a slow complete gelation speed, which significantly reduces the risk of clogging needles, catheters and sticky tubes; and the hydrogel has good mechanical properties, can withstand high shear stress, resist blood flow scouring, and effectively avoid potential non-target embolism; in addition, the hydrogel does not contain organic solvents and has a low toxicity risk. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying creative work.

[0026] Figure 1 This is a photograph of the gel of Example 1 provided by the present invention being extruded through a syringe equipped with a 20G needle;

[0027] Figure 2 This is a photograph of the gel of Example 4 provided by the present invention being extruded through a syringe equipped with an 18G needle;

[0028] Figure 3 A curve diagram showing the shear viscosity of the gel of Comparative Example 1 provided by the present invention as a function of shear rate;

[0029] Figure 4 This is a diagram showing the structural recovery of the gel of Comparative Example 1 provided by the present invention when the shear stress is alternately tested at 10Pa and 200Pa;

[0030] Figure 5 The graph is a test result of the rheological properties of the gels of Example 1 and Comparative Example 1. DETAILED DESCRIPTION

[0031] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0032] The invention provides an injectable composite hydrogel, comprising a component A and a component B; wherein the components of the component A include a multifunctional polymer, a thixotropic agent and an aqueous solvent, and the components of the component B include a multi-arm polyethylene glycol derivative and an aqueous solvent.

[0033] In the injectable composite hydrogel provided by the present invention, the multifunctional polymer in the A component is one or more of gelatin, carboxymethyl chitosan and collagen; the content of the multifunctional polymer in the injectable composite hydrogel (the sum of the A component and the B component) is preferably 1 to 20 wt%, specifically 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt% or 20 wt%.

[0034] In the injectable composite hydrogel provided by the present invention, the thixotropic agent in the component A is one or more of montmorillonite, bentonite, kaolinite, hectorite, halloysite, aluminum magnesium silicate and lithium magnesium silicate; the content of the thixotropic agent in the injectable composite hydrogel (the sum of the components A and B) is preferably 1 to 20 wt%, specifically 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt% or 20 wt%.

[0035] In the injectable composite hydrogel provided by the present invention, the multi-arm polyethylene glycol derivative in the B component is one or more of succinimide-terminated multi-arm polyethylene glycol, succinimide ester-terminated multi-arm polyethylene glycol, N-hydroxysuccinimide (NHS) ester-terminated multi-arm polyethylene glycol, aldehyde-terminated multi-arm polyethylene glycol and benzaldehyde-terminated multi-arm polyethylene glycol; the number of arms of the multi-arm polyethylene glycol derivative is preferably 2 to 8, specifically 2, 3, 4, 5, 6, 7 or 8; the weight average molecular weight of the multi-arm polyethylene glycol derivative is preferably 1000 to 20000, specifically 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000 %, 11000, 12000, 13000, 14000, 15000, 16000, 17000, 18000, 19000 or 20000; the content of the multi-arm polyethylene glycol derivative in the injectable composite hydrogel (the sum of component A and component B) is preferably 0.1-10wt%, specifically 0.1wt%, 0.5wt%, 1wt%, 1.5wt%, 2wt%, 2.5wt%, 3wt%, 3.5wt%, 4wt%, 4.5wt%, 5wt%, 5.5wt%, 6wt%, 6.5wt%, 7wt%, 7.5wt%, 8wt%, 8.5wt%, 9wt%, 9.5wt% or 10wt%.

[0036] In the injectable composite hydrogel provided by the present invention, the aqueous solvents in the components A and B are independently selected from purified water, water for injection, sodium chloride solution, phosphate buffer, borate buffer, triethanolamine buffer or sodium bicarbonate buffer.

[0037] In the injectable composite hydrogel provided by the present invention, the volume ratio of component A to component B is preferably (1-3):0.6, specifically 1:0.6, 1.1:0.6, 1.2:0.6, 1.3:0.6, 1.4:0.6, 1.5:0.6, 1.6:0.6, 1.7:0.6, 1.8:0.6, 1.9:0.6, 2:0.6, 2.1:0.6, 2.2:0.6, 2.3:0.6, 2.4:0.6, 2.5:0.6, 2.6:0.6, 2.7:0.6, 2.8:0.6, 2.9:0.6 or 3:0.6.

[0038] The present invention provides a method for preparing the injectable composite hydrogel described in the above technical solution, comprising the following steps:

[0039] a) mixing a multifunctional polymer, a thixotropic agent and an aqueous solvent to obtain a component A of an injectable composite hydrogel;

[0040] b) mixing the multi-arm polyethylene glycol derivative and an aqueous solvent to obtain a component B of the injectable composite hydrogel;

[0041] There is no order between step a) and step b).

[0042] In the preparation method provided by the present invention, step a) preferably includes the following process:

[0043] a1) mixing a multifunctional polymer with an aqueous solvent to obtain a multifunctional polymer solution;

[0044] a2) mixing the thixotropic agent with the remaining aqueous solvent to obtain a thixotropic agent gel;

[0045] There is no order of precedence between step a1) and step a2);

[0046] a3) mixing the multifunctional polymer solution with a thixotropic agent gel to obtain component A of an injectable composite hydrogel.

[0047] In the specific process of the above step a) provided by the present invention, in process a1), the mixing temperature is preferably 20-80°C, specifically 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C or 80°C.

[0048] In the preparation method provided by the present invention, after obtaining component A and component B, they are preferably sterilized by irradiation.

[0049] The present invention also provides a method for using the injectable composite hydrogel described in the above technical solution, comprising the following steps:

[0050] Component A and component B are simultaneously injected and mixed into a gel through a double syringe;

[0051] Alternatively, component A and component B are premixed and then injected and gelled through a syringe.

[0052] The technical solution provided by the present invention uses a specific type of multifunctional polymer, a thixotropic agent and a multi-arm polyethylene glycol derivative as the main components of the hydrogel, and has the following advantages:

[0053] (1) It has both shear-thinning and in-situ gel properties. Before being injected into the human body, the gel is in a semi-gel state and can be squeezed out through a syringe under moderate pressure to fill blood vessels of different shapes and sizes. It is not easily diluted or washed away by the blood flow. After injection, it gradually cross-links to form an in-situ gel, which improves the mechanical properties and achieves the purpose of effective embolization of blood vessels.

[0054] (2) The gel completely gels slowly, significantly reducing the risk of clogging needles, catheters, and sticky tubes; it has good mechanical properties, can withstand high shear stress and blood flow erosion, and effectively avoids potential non-target embolism; it does not contain organic solvents and has a low toxicity risk.

[0055] For the purpose of greater clarity, the present invention is described in detail with reference to the following examples and comparative examples.

[0056] Example 1

[0057] 1) Dissolve 0.06 g of gelatin (type A pig skin gelatin, Xintian Gelatin Co., Ltd.) in 0.4 mL of water for injection and stir at 30-50°C to dissolve;

[0058] 2) Dissolve 0.06 g of lithium magnesium silicate in 1 mL of water for injection and stir rapidly until a colorless, transparent gel is formed;

[0059] 3) pouring the hot gelatin aqueous solution into the lithium magnesium silicate gel, and stirring rapidly until uniform, to obtain a gel A having shear thinning properties;

[0060] 4) 0.03 g of NHS ester-terminated eight-arm polyethylene glycol (weight average molecular weight 15000 Da, Xiamen Sinobond Biotechnology Co., Ltd.) was dissolved in 0.6 mL of phosphate buffer (pH = 7.4) to obtain a polymer aqueous solution B containing reactive end groups;

[0061] 5) After the above components A and B are filled, they are sterilized by irradiation to obtain the injectable composite hydrogel of the present invention.

[0062] Example 2

[0063] 1) Dissolve 0.06 g of gelatin in 0.4 mL of water for injection and stir at 30-50°C to dissolve;

[0064] 2) Dissolve 0.06 g of lithium magnesium silicate in 1 mL of water for injection and stir rapidly until a colorless, transparent gel is formed;

[0065] 3) pouring the hot gelatin aqueous solution into the lithium magnesium silicate gel, and stirring rapidly until uniform, to obtain a gel A having shear thinning properties;

[0066] 4) dissolving 0.06 g of NHS ester-terminated eight-arm polyethylene glycol in 0.6 mL of phosphate buffer (pH=7.4) to obtain a polymer aqueous solution B containing reactive end groups;

[0067] 5) After the above components A and B are filled, they are sterilized by irradiation to obtain the injectable composite hydrogel of the present invention.

[0068] Example 3

[0069] 1) Dissolve 0.08 g of carboxymethyl chitosan (Zhejiang Jinke Pharmaceutical Co., Ltd.) in 0.8 mL of water for injection and stir at room temperature to dissolve;

[0070] 2) Dissolve 0.08 g of lithium magnesium silicate in 0.8 mL of water for injection and stir rapidly until a colorless, transparent gel is formed;

[0071] 3) pouring the carboxymethyl chitosan aqueous solution into the lithium magnesium silicate gel and rapidly stirring until uniform, thereby obtaining a gel A having shear thinning properties;

[0072] 4) dissolving 0.08 g of NHS ester-terminated four-arm polyethylene glycol (weight average molecular weight 10,000 Da, Xiamen Sinobond Biotechnology Co., Ltd.) in 0.4 mL of phosphate buffer (pH = 7.4) to obtain a polymer aqueous solution B containing reactive end groups;

[0073] 5) After the above components A and B are filled, they are sterilized by irradiation to obtain the injectable composite hydrogel of the present invention.

[0074] Example 4

[0075] 1) Dissolve 0.04 g of gelatin in 0.4 mL of water for injection and stir at 30-50°C to dissolve;

[0076] 2) Dissolve 0.08 g of lithium magnesium silicate in 1 mL of water for injection and stir rapidly until a colorless, transparent gel is formed;

[0077] 3) pouring the hot gelatin aqueous solution into the lithium magnesium silicate gel, and stirring rapidly until uniform, to obtain a gel A having shear thinning properties;

[0078] 4) dissolving 0.04 g of benzaldehyde-terminated four-arm polyethylene glycol (weight average molecular weight 10,000 Da, Xiamen Sinobond Biotechnology Co., Ltd.) in 0.6 mL of phosphate buffer (pH = 7.4) to obtain a polymer aqueous solution B containing reactive end groups;

[0079] 5) After the above components A and B are filled, they are sterilized by irradiation to obtain the injectable composite hydrogel of the present invention.

[0080] Comparative Example 1

[0081] 1) Dissolve 0.06 g of gelatin in 1 mL of water for injection and stir at 30-50°C to dissolve;

[0082] 2) Dissolve 0.06 g of lithium magnesium silicate in 1 mL of water for injection and stir rapidly until a colorless, transparent gel is formed;

[0083] 3) Pour the hot gelatin aqueous solution into the lithium magnesium silicate gel, stir rapidly until uniform, and sterilize by irradiation after filling to obtain a gel with shear thinning properties.

[0084] Comparative Example 2

[0085] 1) Dissolve 0.08 g of carboxymethyl chitosan in 1 mL of water for injection and stir at room temperature to dissolve;

[0086] 2) Dissolve 0.08 g of lithium magnesium silicate in 1 mL of water for injection and stir rapidly until a colorless, transparent gel is formed;

[0087] 3) Pour the carboxymethyl chitosan aqueous solution into the lithium magnesium silicate gel and stir rapidly until it is uniform to obtain a gel with shear thinning properties.

[0088] Comparative Example 3

[0089] 1) Dissolve 0.06 g polyethyleneimine (number average molecular weight 2000 Da) in 1 mL water for injection at room temperature;

[0090] 2) Dissolve 0.06 g of lithium magnesium silicate in 1 mL of water for injection and stir rapidly until a colorless, transparent gel is formed;

[0091] 3) Pour the polyethyleneimine aqueous solution into the lithium magnesium silicate gel, stir rapidly until uniform, and sterilize by irradiation after filling.

[0092] Comparative Example 4

[0093] 1) Dissolve 0.06 g of trilysine in 1 mL of water for injection at room temperature;

[0094] 2) Dissolve 0.06 g of lithium magnesium silicate in 1 mL of water for injection and stir rapidly until a colorless, transparent gel is formed;

[0095] 3) Pour the trilysine aqueous solution into the lithium magnesium silicate gel, stir rapidly until uniform, and sterilize by irradiation after filling.

[0096] Performance Evaluation

[0097] (1) Gel formation performance

[0098] The samples described in Comparative Examples 1, 2, 3 and 4 were placed in 20 mL glass bottles, and the glass bottles were inverted to observe the gel formation. The results are shown in Table 1. Gelatin and carboxymethyl chitosan containing both amino and carboxyl groups can form gels with thixotropic agents; while trilysine and polyethyleneimine containing only amino groups cannot form gels with thixotropic agents, and will also affect the performance of thixotropic agents in forming gels through electrostatic action, resulting in a decrease in the viscosity of the thixotropic agent and the formation of a flowable liquid.

[0099] Table 1 Summary of gel formation properties

[0100] Whether gel is formed Sample status Comparative Example 1 yes Non-flowing gel Comparative Example 2 yes Non-flowing gel Comparative Example 3 no Flowable viscous liquid Comparative Example 4 no Flowable viscous liquid

[0101] (2) Gel injectability

[0102] Figure 1 This is a photo of the gel described in Example 1 squeezed out through a syringe equipped with a 20G needle. Figure 2 This is a photograph of the gel described in Example 4 extruded through a syringe equipped with an 18G needle.

[0103] Figure 3 The shear viscosity of comparative example 1 changes with the shear rate. As the shear rate increases, the viscosity of the sample gradually decreases, indicating that the system has shear thinning properties and can be extruded through a syringe. Figure 4 This is the structural recovery of comparative example 1 when the shear stress is alternately tested at 10Pa and 200Pa, indicating that the system has excellent structural recovery ability and stability, and can quickly restore mechanical properties after extrusion.

[0104] The above results show that the gel of the present invention has shear thinning properties and can be extruded in a semi-gel state through needles of different diameters. Compared with the in-situ cross-linked gel whose precursor is a liquid, the gel of the present invention has a higher viscosity after injection and is not easily diluted or washed away by the blood flow.

[0105] (3) Gel extrusion force measurement

[0106] For Example 1, Example 2, Example 3, Example 4 and Comparative Example 1, after the A and B components were mixed, the extrusion force of the gel when it was pushed out through a 2 mL syringe was recorded, wherein the syringe was equipped with an 18G needle with a length of 100 mm, and the injection speed was 2 mL / min. The results are shown in Table 2. The extrusion force required for the hydrogel of the present invention is 28 to 39 N, and the extrusion force can be controlled by adjusting the thixotropic agent content, which is convenient for injection.

[0107] (4) Determination of gel time

[0108] For Example 1, Example 2, Example 3, Example 4, and Comparative Example 1, during the preparation of the hydrogel, the gelation time was recorded, wherein the time required for the system to transform from a semi-gel state with shear thinning properties to a non-flowable gel state was defined as the gelation time of the system. The results are shown in Table 2. After being extruded in a semi-gel state, the hydrogel of the present invention can be completely transformed into a gel state within 180 to 220 seconds, reflecting the property of in-situ cross-linking; the gelation time can be controlled by adjusting the type and proportion of the multifunctional polymer and the content of the polyethylene glycol derivative.

[0109] Table 2 Summary of gel extrusion force and gel time

[0110] Extrusion force / N Gel time / s Example 1 36 180 Example 2 39 120 Example 3 28 220 Example 4 31 190 Comparative Example 1 37 -- Comparative Example 2 29 --

[0111] (5) Determination of rheological properties

[0112] For Example 1, the gel was allowed to stand for 10 minutes after extrusion, and the storage modulus and loss modulus of the gel were tested as a function of shear stress, and compared with those of Comparative Example 1. Figure 5 The stress scanning results shown indicate that when the shear stress is less than 1200Pa, the storage modulus and loss modulus of the gel described in Example 1 do not change, and the gel structure is stable; when the shear stress is greater than 1200Pa, the loss modulus is higher than the storage modulus, and the gel structure is destroyed; while the shear stress that the gel described in Comparative Example 1 can withstand is only 170Pa; indicating that the gel described in the present invention can withstand greater shear stress and has greater resistance to blood flow scouring under the same conditions.

[0113] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. An injectable composite hydrogel, characterized in that: It comprises component A and component B; wherein the components of component A comprise a multifunctional polymer, a thixotropic agent and an aqueous solvent, the multifunctional polymer is one or more of gelatin, carboxymethyl chitosan and collagen, and the thixotropic agent is one or more of montmorillonite, bentonite, kaolinite, hectorite, halloysite, aluminum magnesium silicate and lithium magnesium silicate; the components of component B comprise a multi-arm polyethylene glycol derivative and an aqueous solvent, and the multi-arm polyethylene glycol derivative is one or more of succinimide-terminated multi-arm polyethylene glycol, succinimide ester-terminated multi-arm polyethylene glycol, N-hydroxysuccinimide ester-terminated multi-arm polyethylene glycol, aldehyde-terminated multi-arm polyethylene glycol and benzaldehyde-terminated multi-arm polyethylene glycol.

2. The injectable composite hydrogel according to claim 1, characterized in that: The content of the multifunctional polymer in the injectable composite hydrogel is 1 to 20 wt %.

3. The injectable composite hydrogel according to claim 1, characterized in that: The content of the thixotropic agent in the injectable composite hydrogel is 1-20wt%.

4. The injectable composite hydrogel according to claim 1, characterized in that: The number of arms of the multi-arm polyethylene glycol derivative is 2 to 8, and the weight average molecular weight is 1,000 to 20,000.

5. The injectable composite hydrogel according to claim 1, characterized in that: The content of the multi-arm polyethylene glycol derivative in the injectable composite hydrogel is 0.1-10 wt %.

6. The injectable composite hydrogel according to claim 1, characterized in that: The aqueous solvent is purified water, water for injection, sodium chloride solution, phosphate buffer, borate buffer, triethanolamine buffer or sodium bicarbonate buffer.

7. The injectable composite hydrogel according to claim 1, characterized in that: The volume ratio of the component A to the component B is (1-3):0.

6.

8. A method for preparing the injectable composite hydrogel according to any one of claims 1 to 7, characterized in that: The following steps are involved: a) mixing a multifunctional polymer, a thixotropic agent and an aqueous solvent to obtain a component A of an injectable composite hydrogel; b) mixing the multi-arm polyethylene glycol derivative and an aqueous solvent to obtain a component B of the injectable composite hydrogel; There is no order between step a) and step b).

9. The injectable composite hydrogel according to claim 8, characterized in that: Step a) specifically includes: a1) mixing a multifunctional polymer with an aqueous solvent to obtain a multifunctional polymer solution; a2) mixing the thixotropic agent with the remaining aqueous solvent to obtain a thixotropic agent gel; There is no order of precedence between step a1) and step a2); a3) mixing the multifunctional polymer solution with a thixotropic agent gel to obtain component A of an injectable composite hydrogel.

10. A method for using the injectable composite hydrogel according to any one of claims 1 to 7, characterized in that: The following steps are involved: Component A and component B are simultaneously injected and mixed into a gel through a double syringe; Alternatively, component A and component B are premixed and then injected and gelled through a syringe.

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