A biomimetic bone material with controllable solidification time, its preparation method and application

Abstract

This invention belongs to the field of bone repair biomaterials. It discloses a biomimetic bone material with controllable solidification time, comprising calcium phosphate salt, phosphate-based organic matter, and a biomimetic cancellation reactant. The biomimetic cancellation reactant comprises a cancellation reaction liquid phase and a cancellation reaction solid phase. The cancellation reaction liquid phase contains water, sodium citrate, and citric acid, while the cancellation reaction solid phase is sodium bicarbonate. This biomimetic bone material can effectively control the solidification time and degree of cancellation. Different ratios can be selected according to clinical surgical time requirements and the degree of bone cancellation at the clinical filling site, making it easy for clinical use.

Description

Technical Field

[0001] This invention belongs to the field of bone repair biomaterials, specifically relating to a biomimetic bone material with controllable solidification time, its preparation method, and its application. Background Technology

[0002] The treatment strategy for fractures and bone defects mainly involves reduction, fixation, and functional exercises. Clinically, fixation and filling of fractures and bone defects currently rely primarily on internal fixation and bone grafting materials, including autologous bone, allogeneic bone, and xenogeneic acellular bone, allowing for bone integration and repair through the body's self-regenerative capabilities. However, this surgical approach requires two follow-up surgeries: firstly, the internal fixation needs to be removed; secondly, the integration of the bone grafting material with the body's bone takes a considerable amount of time. Therefore, there is an urgent need to develop a novel biomedical material for immediate repair of bone tissue structures in clinical fracture and bone defect surgeries.

[0003] For immediate bone tissue repair, several solutions exist. Firstly, bone adhesives are considered an effective solution for repairing cortical bone, forming strong adhesion at the fracture ends, restoring the physiological position of the bone, and achieving bone support and stress strength. Patent application CN202310767115.2 invented an injectable adhesive that promotes fracture healing. This invention mimics the carboxyl groups on the side chains of marine barnacle biomaterials, which can absorb moisture from the interface to break the bond between the interface and the water layer, improving the bonding strength between the dynamic network and the interface, thereby enhancing the adhesive's adhesion performance. This results in good adhesion in solution, but due to significant differences in bone composition, issues exist regarding mechanical strength and biosafety. Patent application CN202211370224.2 invented a photocurable bone adhesive. This patent incorporates a photoinitiator into the bone adhesive, reducing the curing time. However, the curing process requires light initiation, reducing the ease of use of this adhesive. Secondly, artificial bone is another solution, which can achieve biomimicry of the structure of natural bone tissue, thereby promoting bone ingrowth and osseointegration. Patent application CN200910043405.2 discloses a method for manufacturing a biomimetic bone material with non-uniformly distributed pores. Using HA / Ti or HA / 316L composite powder as raw material, the raw material powder is separated into dense, transitional, and porous layers within a mold using a molybdenum sheet. Conventional pressing yields a compact, which is then vacuum-sintered to obtain the biomimetic bone. However, its composition and physical properties differ significantly from bone tissue, while achieving immediate integration with bone tissue. Patent application CN202210656568.3 discloses a biomimetic bone material based on icariin-functionalized polylactic acid and its preparation method, which also suffers from significant differences in composition compared to bone tissue.

[0004] Therefore, there is an urgent need to develop a biomimetic bone material with a composition close to bone and a controllable coagulation time that can achieve immediate bone repair. Summary of the Invention

[0005] In order to overcome the defects and shortcomings of the existing technology, the present invention provides a biomimetic bone material with controllable coagulation time, its preparation method and application.

[0006] Specifically, the present invention is achieved through the following technical solutions:

[0007] In a first aspect, the present invention provides a biomimetic bone material with controllable coagulation time, wherein the biomimetic bone material with controllable coagulation time is a biomimetic bone material obtained by mixing and reacting calcium phosphate salt, phosphate-based organic matter, and a biomimetic cancellation agent.

[0008] In some embodiments, the ratio of calcium phosphate salt, phosphate-based organic matter, and biomimetic loosening agent is 0.1 g-5 g : 0.05-3 g : 0.1-1 mL.

[0009] In some embodiments, the ratio of calcium phosphate salt, phosphate-based organic matter, and biomimetic loosening agent is 0.5 g-2 g : 0.2-1 g : 0.2-0.5 mL.

[0010] Preferably, the ratio of calcium phosphate salt, phosphate-based organic matter, and biomimetic loosening agent is 1 g: 0.5 g: 0.35 mL.

[0011] In some embodiments, the calcium phosphate salt is one or more of tetracalcium phosphate, calcium phosphate, and hydroxyapatite.

[0012] Preferably, the calcium phosphate salt is tetracalcium phosphate.

[0013] In some embodiments, the phosphate-based organic compound is used to integrate calcium phosphate salts, including one or more combinations of phosphate amino acids, phosphonic acid carboxylic acids, and bisphosphonates.

[0014] Preferably, the phosphate-based organic compound is a phosphate amino acid.

[0015] More preferably, the phosphate-based organic compound is phosphoserine.

[0016] In some embodiments, the biomimetic fluffing agent is a mixture of a biomimetic fluffing liquid-phase reactant and a biomimetic fluffing solid-phase reactant.

[0017] The liquid-phase reactant contains sodium citrate and / or citric acid, and the liquid-phase reactant also contains water, while the solid-phase reactant is sodium bicarbonate.

[0018] Alternatively, the biomimetic fluffing agent may be sodium citrate.

[0019] Preferably, the molar ratio of sodium bicarbonate to citric acid is 3:1, and the reaction products are sodium citrate and carbon dioxide.

[0020] Preferably, the ratio of water, sodium citrate, and citric acid is 0.2-0.5 mL: 0-500 mg: 0-400 mg.

[0021] More preferably, the ratio of water, sodium citrate, and citric acid is 0.3-0.4 mL: 0-155 mg: 0-115 mg.

[0022] In a second aspect, the present invention provides a method for preparing biomimetic bone with controllable coagulation time as described in the first aspect above, comprising the following steps:

[0023] (1) Weigh out calcium phosphate, phosphate-based organic matter and sodium bicarbonate respectively, mix them evenly to prepare a solid phase component, and put it into a threaded disposable syringe for later use;

[0024] (2) Weigh out citric acid and sodium citrate solids respectively, add them to water to prepare a liquid phase component, and put it into another threaded disposable syringe for later use;

[0025] (3) After connecting the two threaded disposable syringes containing solid components and liquid components prepared in step (1) and step (1) respectively with disposable connectors, the solid components and liquid components are quickly and uniformly mixed to form a paste-like biomimetic bone fluid.

[0026] (4) Inject the paste-like biomimetic bone fluid prepared in step (3) into the site to be used for solidification.

[0027] In some embodiments, the threaded disposable syringe has a volume of 1-10 mL.

[0028] Preferably, a 5mL threaded disposable syringe is used.

[0029] In some embodiments, the curing time is 0-15 min. The curing time can be adjusted according to the total sodium citrate content.

[0030] Alternatively, in step (4), the contents of the two syringes can be mixed before being injected into one of the syringes.

[0031] In a third aspect, the present invention provides the application of biomimetic bone with controllable coagulation time as described in the first aspect above, or biomimetic bone with controllable coagulation time prepared by the preparation method described in the second aspect above.

[0032] Preferably, the present invention provides the application of a biomimetic bone material with controllable solidification time as described in the first aspect above, or a biomimetic bone material with controllable solidification time prepared by the preparation method described in the second aspect above, in the preparation of bone repair biomaterials.

[0033] In some embodiments, the paste-like biomimetic bone fluid is injected into the intended site using a disposable syringe and then solidified.

[0034] In some embodiments, the paste-like biomimetic bone material is used for bonding and filling fractures and bone defects. The biomimetic bone material of the present invention has certain compressive strength, tensile strength, and bonding properties, and can effectively control the curing time and degree of cancellation. Different ratios can be selected according to the clinical surgical time requirements and the degree of bone cancellation at the clinical filling site, making it easy to use in clinical practice.

[0035] In some embodiments, the biomimetic bone material has compressive strength, with an index range of 1.0-10.0 MPa.

[0036] In some embodiments, the biomimetic bone material has tensile strength, with an index range of 1.0-2.5 MPa.

[0037] In some embodiments, the biomimetic bone material has adhesive properties, with an index range of 0.2-1.0 MPa.

[0038] In some embodiments, the coagulation time of the biomimetic bone can be adjusted, ranging from 10s to 900s.

[0039] In some embodiments, the degree of cancellation of the biomimetic bone can be adjusted, with a trabecular distance of 45 μm-1000 μm, a bone area of ​​53%-95%, and a bone volume of 38%-96%.

[0040] Beneficial effects of the present invention

[0041] (1) The biomimetic bone of the present invention forms biomimetic bone immediately through reaction, which is beneficial to the immediate integration of biomimetic bone and autologous bone during surgery.

[0042] (2) The biomimetic bone material of the present invention can effectively control the curing time by adjusting the sodium citrate ratio, which is beneficial to select according to the surgical implantation time requirements of different parts of the surgery and avoid curing too early or too late.

[0043] (3) The bionic bone of the present invention can effectively control the degree of cancellation by adjusting the ratio of bionic cancellation reactant to adapt to the mechanical strength and trabecular density of the surgical implantation site. Attached Figure Description

[0044] To make the objectives, technical solutions, and beneficial effects of this invention clearer, the following figures are provided for illustration:

[0045] Figure 1 This is a diagram of the bone surface observed under a scanning electron microscope in biomimetic bone.

[0046] Figure 2 This image shows the trabecular density of biomimetic bone reconstructed using Micro-CT.

[0047] Figure 3 Images of MC3T3 cells cultured with an extract of biomimetic bone and induced to form osteoblasts using an osteogenic induction solution, stained with an alkaline phosphatase staining kit.

[0048] Figure 4 This study investigated the effects of biomimetic bone extract on HUVEC cell culture and its promotion of angiogenesis.

[0049] Figure 5 This study examines the maintenance of bone continuity and bone integration under Micro-CT reconstruction after the use of biomimetic bone in a rabbit comminuted fracture model.

[0050] Figure 6 This image shows the bone integration under Micro-CT reconstruction after the use of biomimetic bone in a rabbit defect model. Detailed Implementation

[0051] The following detailed description, in conjunction with embodiments, illustrates a biomimetic bone material with controllable coagulation time, its preparation method, and its applications provided by the present invention. However, these descriptions should not be construed as limiting the scope of protection of the present invention.

[0052] Example 1

[0053] Weigh out 1.0 g of tetracalcium phosphate and 0.5 g of phosphoserine, mix them evenly to prepare a solid phase, and fill a 5 mL threaded disposable syringe for later use. Use 0.35 mL of water as the liquid phase and fill another 5 mL threaded disposable syringe for later use. Connect the two threaded disposable syringes containing the solid and liquid phases respectively using a disposable connector, and quickly and evenly mix them to prepare a paste-like biomimetic bone fluid.

[0054] Example 2

[0055] Weigh out 1.0 g of tetracalcium phosphate, 0.5 g of phosphoserine, and 76 mg of sodium bicarbonate. Mix them thoroughly to prepare the solid phase, and fill a 5 mL threaded disposable syringe for later use. Add 58 mg of citric acid to 0.35 mL of water to prepare the liquid phase, and fill another 5 mL threaded disposable syringe for later use. Connect the two threaded disposable syringes containing the solid and liquid phases respectively using a disposable connector, and quickly and evenly mix them to prepare a paste-like biomimetic bone fluid.

[0056] Example 3

[0057] Weigh out 1.0 g of tetracalcium phosphate, 0.5 g of phosphoserine, and 38 mg of sodium bicarbonate. Mix them thoroughly to prepare the solid phase, and fill a 5 mL threaded disposable syringe for later use. Add 39 mg of sodium citrate and 29 mg of citric acid to 0.35 mL of water to prepare the liquid phase, and fill another 5 mL threaded disposable syringe for later use. Connect the two threaded disposable syringes containing the solid and liquid phases respectively using a disposable connector, and quickly and evenly mix them to prepare a paste-like biomimetic bone fluid.

[0058] Example 4

[0059] Weigh out 1.0 g of tetracalcium phosphate and 0.5 g of phosphoserine, mix them evenly to prepare the solid phase, and fill a 5 mL threaded disposable syringe for later use. Add 78 mg of sodium citrate to 0.35 mL of water to prepare the liquid phase, and fill another 5 mL threaded disposable syringe for later use. Connect the two threaded disposable syringes containing the solid and liquid phases respectively using a disposable connector, and quickly and evenly mix them to prepare a paste-like biomimetic bone fluid.

[0060] Example 5

[0061] Weigh out 1.0 g of tetracalcium phosphate, 0.5 g of phosphoserine, and 151 mg of sodium bicarbonate. Mix them thoroughly to prepare the solid phase, and fill a 5 mL threaded disposable syringe for later use. Add 115 mg of sodium citrate to 0.35 mL of water to prepare the liquid phase, and fill another 5 mL threaded disposable syringe for later use. Connect the two threaded disposable syringes containing the solid and liquid phases respectively using a disposable connector, and quickly and evenly mix them to prepare a paste-like biomimetic bone fluid.

[0062] Example 6

[0063] Weigh out 1.0 g of tetracalcium phosphate, 0.5 g of phosphoserine, and 76 mg of sodium bicarbonate. Mix them thoroughly to prepare the solid phase, and fill a 5 mL threaded disposable syringe for later use. Add 78 mg of sodium citrate and 58 mg of citric acid to 0.35 mL of water to prepare the liquid phase, and fill another 5 mL threaded disposable syringe for later use. Connect the two threaded disposable syringes containing the solid and liquid phases respectively using a disposable connector, and quickly and evenly mix them to prepare a paste-like biomimetic bone fluid.

[0064] Example 7

[0065] Weigh out 1.0 g of tetracalcium phosphate and 0.5 g of phosphoserine, mix them evenly to prepare the solid phase, and fill a 5 mL threaded disposable syringe for later use. Add 155 mg of sodium citrate to 0.35 mL of water to prepare the liquid phase, and fill another 5 mL threaded disposable syringe for later use. Connect the two threaded disposable syringes containing the solid and liquid phases respectively using a disposable connector, and quickly and evenly mix them to prepare a paste-like biomimetic bone fluid.

[0066] Example 8

[0067] Weigh out 1.0 g of hydroxyapatite, 0.5 g of phosphoserine, and 38 mg of sodium bicarbonate. Mix them thoroughly to prepare the solid phase, and fill a 5 mL threaded disposable syringe for later use. Add 39 mg of sodium citrate and 29 mg of citric acid to 0.35 mL of water to prepare the liquid phase, and fill another 5 mL threaded disposable syringe for later use. Connect the two threaded disposable syringes containing the solid and liquid phases respectively using a disposable connector, and quickly and evenly mix them to prepare a paste-like biomimetic bone fluid.

[0068] Example 9

[0069] Weigh out 1.0 g of tetracalcium phosphate, 0.5 g of phosphotyrosine, and 38 mg of sodium bicarbonate. Mix them thoroughly to prepare the solid phase, and fill a 5 mL threaded disposable syringe for later use. Add 39 mg of sodium citrate and 29 mg of citric acid to 0.35 mL of water to prepare the liquid phase, and fill another 5 mL threaded disposable syringe for later use. Connect the two threaded disposable syringes containing the solid and liquid phases respectively using a disposable connector, and quickly and evenly mix them to prepare a paste-like biomimetic bone fluid.

[0070] Example 10

[0071] Weigh out 1.0 g of tetracalcium phosphate, 0.5 g of 3-phosphonopropionic acid, and 38 mg of sodium bicarbonate. Mix them thoroughly to prepare the solid phase, and fill a 5 mL threaded disposable syringe for later use. Add 39 mg of sodium citrate and 29 mg of citric acid to 0.35 mL of water to prepare the liquid phase, and fill another 5 mL threaded disposable syringe for later use. Connect the two threaded disposable syringes containing the solid and liquid phases respectively using a disposable connector, and quickly and evenly mix them to prepare a paste-like biomimetic bone fluid.

[0072] The biomimetic bone materials obtained in Examples 1-10 were subjected to curing time, compressive strength, tensile strength, and adhesion strength tests, respectively.

[0073] Example 1: Curing time, compressive strength, tensile strength, and adhesive strength tests

[0074] 1. The paste-like biomimetic bone fluid obtained in Examples 1-10 was squeezed into a mold with a diameter of 6 mm for curing. The curing time was timed. After curing, the obtained biomimetic bone was taken out and subjected to a compressive strength test.

[0075] 2. The paste-like biomimetic bone fluid obtained in Examples 1-10 was evenly applied to both ends of the broken pig femur. After the bonding process began, a pressure of 10N was applied to the top of the metal column. After curing, the test object was placed in the fixture, and the tensile strength was measured. The applied force was perpendicular to the surface of the bonded pig bone at a 90° angle. A universal joint or metal wire was used to connect the testing machine and the bonded pig bone. The tensile strength of the bonded pig femur was tested at a speed of 20mm / min.

[0076] 3. Apply the paste-like biomimetic bone fluid obtained in Examples 1-10 to a smooth pig bone piece, apply a force of 10N to press it to solidify, place it at 37 degrees Celsius for 30 minutes after solidification, place the test object in a fixture, and measure the adhesion strength. The applied force is parallel to the pig bone piece to be bonded, and the adhesion strength of the bonded pig bone piece is tested at a speed of 20mm / min.

[0077] The test results are shown in Table 1.

[0078] Table 1

[0079]

[0080]

[0081] The table shows that as the total sodium citrate content increases, the curing time increases accordingly. Meanwhile, as the proportion of citric acid increases, the compressive and tensile strength of the biomimetic bone decreases, while the adhesion strength shows no significant trend.

[0082] Example 2: Bone Parameter Testing

[0083] 1. The biomimetic bone obtained in Examples 1-7 was observed using a scanning electron microscope to determine the size and number of pores, and the trabecular distance and percentage of bone area were statistically analyzed.

[0084] 2. The biomimetic bone obtained in Examples 1-7 was scanned using Micro-CT and reconstructed in 3D to calculate the percentage of bone volume.

[0085] Test results are available Figure 1 , Figure 2 And Table 2.

[0086] Table 2

[0087]

[0088] The table shows that as the proportion of citric acid increases, the distance between bone trabeculae increases, the percentage of bone area decreases, and the percentage of bone volume decreases, indicating that the degree of cancellation of biomimetic bone can be controlled by adjusting the proportion of citric acid.

[0089] Example 3: Osteogenesis test, angiogenesis test, and osseointegration test

[0090] 3.1 Osteogenesis Test

[0091] The biomimetic bone extract was used for osteogenic differentiation experiments. The specific procedure was as follows: MC3T3 cells (from ATCC) were seeded into 96-well plates, with 5,000 cells per well. The extract obtained in Example 4 (experimental group) or ordinary α-MEM medium (control group) was added to different wells, along with an equal volume of osteogenic induction solution (10 mmol / L sodium β-glycerophosphate, 0.05 mmol / L vitamin C, and 100 mmol / L dexamethasone) to each well. The cells were cultured for 7 days, with the medium changed every two days. After 7 days, the cells were fixed with 4% paraformaldehyde for 10 minutes, and ALP staining was performed using an alkaline phosphatase (ALP) staining kit. The effect on osteogenic differentiation induction was determined based on the ALP staining area. The osteogenic differentiation results are shown below. Figure 3 As shown in the figure, the biomimetic bone extract group exhibited significantly higher ALP staining compared to the blank control group, indicating an effective osteogenic promoting effect.

[0092] 3.2 Angiogenesis Test

[0093] 50 μL of matrix gel was pre-coated at 4°C to the bottom of a 96-well plate to minimize air bubble formation, and incubated overnight at 4°C to ensure even distribution. The overnight 96-well plate was then placed in a 37°C incubator to allow the matrix gel to harden. HUVEC cells (from ATCC) were digested and resuspended in standard DMEM medium (control group) and the extract from Example 4 (experimental group), respectively. The resuspended cells were seeded in 96-well plates covered with matrix gel at a density of 30,000 cells / well. After 6 hours of culture, cell ring formation was observed under a microscope. The results of the angiogenesis test are shown below. Figure 4 As shown in the figure, the biomimetic bone extract group exhibited significantly more vascular ring formation compared to the blank control group, demonstrating an effective angiogenesis-promoting effect.

[0094] 3.3 Osteoporosis Integration Test

[0095] A comminuted fracture model of the rabbit femur was created: After anesthetizing the rabbits, the skin of the leg was prepared, disinfected, and incised to expose the femur layer by layer. A rectangular bone defect model was created using a wire saw. The bone fragments were then crushed into four pieces. During the surgery, the experimental group used the biomimetic bone graft described in Example 4 to bond the cortical bone fragments, while the control group did not undergo bonding. Four weeks later, a Micro-CT scan was performed, and bone reconstruction was conducted to observe whether the biomimetic bone graft effectively bonded and integrated the cortical bone tissue. The Micro-CT reconstruction results are shown below. Figure 5 As shown in the figure, compared with the control group, the femoral cortical bone in the biomimetic bone group showed good adhesion and integration, with continuous cortical bone. The biomimetic bone and cortical bone were integrated, demonstrating good compact bone integration.

[0096] 3.4 Cancellous bone integration test

[0097] A circular bone defect model was created in the rabbit femoral condyle: After anesthetizing the rabbit, the skin of the leg was prepared, disinfected, and incised to expose the femoral condyle layer by layer. A circular bone defect was created by punching holes using a puncher, and the biomimetic bone material from Example 4 was implanted into the defect site. Four weeks later, a Micro-CT scan was performed, and bone reconstruction was conducted to observe whether the biomimetic bone material integrated with the bone tissue. The Micro-CT reconstruction results are shown below. Figure 6 As shown in the image, the biomimetic bone is completely integrated with the cancellous bone of the femoral condyle defect, with no boundary appearing, demonstrating a good cancellous bone integration effect.

[0098] The above description is only a preferred embodiment of the present invention. It should be noted that although the present invention has been described in detail through the above preferred embodiments, those skilled in the art should understand that several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be considered as the scope of protection of the present invention and do not depart from the scope defined by the claims of the present invention.

Claims

1. A biomimetic bone material with controllable solidification time, characterized in that: The biomimetic bone material comprises calcium phosphate salt, phosphate-based organic matter, and a biomimetic cancellation agent.

2. The biomimetic bone material according to claim 1, characterized in that: The biomimetic bone material is composed of calcium phosphate salt, phosphate-based organic matter, and a biomimetic cancellation agent.

3. The biomimetic bone material according to claim 1, characterized in that: The ratio of calcium phosphate salt, phosphate-based organic matter, and biomimetic loosening agent is 0.1 g-5 g: 0.05-3 g: 0.1-1 mL; preferably, the ratio is 0.5 g-2 g: 0.2-1 g: 0.2-0.5 mL; more preferably, the ratio is 1 g: 0.5 g: 0.35 mL.

4. The biomimetic bone material according to claim 1, characterized in that: The calcium phosphate salt is one or more of tetracalcium phosphate, calcium phosphate, and hydroxyapatite. Preferably, the calcium phosphate salt is tetracalcium phosphate. The phosphate-based organic compound used to integrate the calcium phosphate salt includes one or more of phosphate amino acids, phosphonic acid carboxylic acids, and bisphosphonates. Preferably, the phosphate-based organic compound is a phosphate amino acid. More preferably, the phosphate-based organic compound is phosphoserine.

5. The biomimetic bone material according to claim 1, characterized in that: The biomimetic fluffing agent is composed of a mixture of a biomimetic fluffing liquid phase agent and a biomimetic fluffing solid phase agent; The liquid-phase reactant comprises sodium citrate and / or citric acid, and the liquid-phase reactant also comprises water; the solid-phase reactant is sodium bicarbonate. Alternatively, the biomimetic fluffing agent may be sodium citrate.

6. The biomimetic bone material according to claim 5, characterized in that: The molar ratio of sodium bicarbonate to citric acid is 3:1, and the reaction products are sodium citrate and carbon dioxide. Preferably, the ratio of water, sodium citrate, and citric acid is 0.2-0.5 mL: 0-500 mg: 0-400 mg; more preferably, the ratio of water, sodium citrate, and citric acid is 0.3-0.4 mL: 0-155 mg: 0-115 mg.

7. A method for preparing biomimetic bone with controllable solidification time according to any one of claims 1 to 6, comprising the following steps: (1) Weigh out calcium phosphate salt and phosphate-based organic matter separately, mix them evenly to prepare a solid phase component, and put it into a threaded disposable syringe for later use; (2) Weigh out sodium citrate solid, add it to water to prepare a liquid phase component, and put it into another threaded disposable syringe for later use; (3) After connecting the two threaded disposable syringes containing solid components and liquid components prepared in step (1) and step (1) respectively with disposable connectors, the solid components and liquid components are quickly and uniformly mixed to form a paste-like biomimetic bone fluid. (4) Inject the paste-like biomimetic bone fluid prepared in step (3) into the site to be used for solidification.

8. The application of the biomimetic bone material with controllable solidification time according to any one of claims 1 to 6, or the biomimetic bone material with controllable solidification time prepared by the preparation method according to claim 7, in the preparation of bone repair biomaterials.

9. The application according to claim 8, characterized in that: the biomimetic bone is used for bonding and filling fractures and bone defects.

10. The application according to claim 8, characterized in that: The biomimetic bone material has compressive strength, ranging from 1.0 to 10.0 MPa; tensile strength, ranging from 1.0 to 2.5 MPa; adhesive properties, ranging from 0.2 to 1.0 MPa; and adjustable coagulation time, ranging from 10 to 900 seconds.

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