A multi-cooperative regulation composite bone bonding system and a preparation method and application thereof

Abstract

The application discloses a kind of multi-coordinated control composite bone bonding system and its preparation method and application.The composite bone bonding system includes powder component and liquid buffer component.The powder component contains phosphoserine, tetracalcium phosphate and other basic calcium phosphate salt;The mass content of phosphoserine in the powder component is 10%~50%, and the mass content of tetracalcium phosphate in the powder component is 10%~50%.The liquid buffer component is the mixed solution of citric acid and disodium hydrogen phosphate, and the pH value range is 4.4~9.4.By mixing powder component and liquid buffer component, the paste-like composite bone bonding system can be made.The application realizes the reaction control of acid-base neutralization by the material selection of powder component and the pH adjustment of liquid buffer component, reduces the solidification temperature rise, and inhibits local overheating, and the composite bone bonding system can be applied as bone repair biomaterial, dental repair biomaterial or oral implant.

Description

Technical Field

[0001] This invention belongs to the field of bone repair biomaterials. Specifically, it relates to a multi-synergistically regulated composite bone bonding system, its preparation method, and its applications. Background Technology

[0002] Calcium phosphate cement (CPC) is commonly used in clinical practice as a filling and repair material for problems such as bone defect repair, orthopedic instrument fixation, and fracture stabilization. However, although calcium phosphate cement (CPC) has certain bioactivity, its curing speed is too fast, the operation time is short, and the strength after curing is insufficient, making it difficult to meet complex clinical needs.

[0003] To improve the adhesion strength between calcium phosphate composite materials and bone surfaces, prior art 1 (CN102307941A) introduces a certain amount of a substance structurally similar to phosphoserine. This substance reacts with tetracalcium phosphate to generate a viscous gel-like substance, thus achieving bone bonding. However, in animal experiments, the adhesion performance of this bone adhesive is significantly reduced upon contact with blood, and its degradation rate in vivo does not match the osteogenic rate, affecting new bone formation. Furthermore, due to the large pH difference between phosphoserine and tetracalcium phosphate, the reaction temperature is very high during the acid-base neutralization reaction. The reaction temperature increases with the amount of bone adhesive used, which may not only damage the tissues surrounding the bone repair area but also trigger local inflammatory reactions or other side effects.

[0004] Both prior art 1 (CN102307941A) and prior art 2 (CN118697927A) mention that increasing the particle size of phosphoserine and tetracalcium phosphate, or increasing the proportion of phosphoserine, can reduce the rate of the neutralization reaction, thereby lowering the reaction temperature. However, increasing the particle size of the reactants or the proportion of phosphoserine may affect the viscous state length, putty state length, curing time, and final mechanical strength of the bone adhesive. Specifically, excessively large reactant particle sizes may lead to a lack of gelatinization, causing the material to directly agglomerate into granules and failing to form a viscous gel-like substance. Conversely, an excessively high proportion of phosphoserine will result in a decrease in the overall mechanical strength of the bone adhesive.

[0005] Therefore, there is a need for a bone adhesive that can adjust the curing time to cope with different fracture environments, control the reaction temperature, and exhibit significant adhesive strength and mechanical strength after curing. Summary of the Invention

[0006] To overcome the defects and shortcomings of existing technologies, such as insufficient mechanical strength, excessively high reaction temperature, uncontrollable short curing time, and side effects caused by excessive alkalinity, this invention provides a multi-synergistically regulated composite bone adhesive system, its preparation method, and its application. This bone adhesive reduces the reaction temperature of the gelatinization process through a multi-effect synergistic pH regulation mechanism, while improving the comprehensive mechanical properties of the bone adhesive.

[0007] In a first aspect, the present invention provides a multi-synergistically regulated composite bone bonding system, comprising a powder component and a liquid buffer component.

[0008] The powder component contains phosphoserine, tetracalcium phosphate, and other basic calcium phosphate salts; the phosphoserine content in the powder component is 10% to 50% by mass, and the tetracalcium phosphate content in the powder component is 10% to 50% by mass.

[0009] The pH range of the liquid buffer component is 4.4 to 9.4.

[0010] In some embodiments, the phosphoseserine content in the powder component is 20% to 40% by mass, and the tetracalcium phosphate powder component has a mass content of 10% to 30% by mass.

[0011] In some embodiments, the tetracalcium phosphate is prepared by a solid-state method and has a network structure.

[0012] In some embodiments, the powder component further includes an acidic calcium phosphate salt selected from one of calcium hydrogen phosphate, calcium hydrogen phosphate monohydrate, calcium dihydrogen phosphate, and calcium chloride, or a mixture thereof in any proportion.

[0013] In some embodiments, the alkaline calcium phosphate salt is selected from one of α-tricalcium phosphate, β-tricalcium phosphate, hydroxyapatite, calcium silicate, octacalcium phosphate, or a mixture thereof in any proportion.

[0014] In some embodiments, the mass ratio of the alkaline calcium phosphate salt to the acidic calcium phosphate salt is 10%~65%:10%~60%, preferably 40%~65%:10%~30%.

[0015] In some embodiments, the liquid buffer component is a mixed solution of citric acid and disodium hydrogen phosphate.

[0016] In some embodiments, the volume-to-mass ratio of the liquid buffer component to the powder component is 0.2~0.5 ml / g.

[0017] In some embodiments, the composite bone bonding system further includes functional additives.

[0018] In some embodiments, the functional additive includes a first type of additive added to the powder component; the first type of additive is selected from growth factors, preferably collagen.

[0019] In some embodiments, the functional additive includes a second type of additive added to the liquid buffer component; the second type of additive is a material that can undergo a cross-linking reaction in the presence of calcium ions, preferably trehalose.

[0020] In a second aspect, the present invention provides a method for preparing a multi-synergistically regulated composite bone bonding system, comprising the following steps:

[0021] Step 1: Weigh out phosphoserine, tetracalcium phosphate and other basic calcium phosphate salts separately, mix them evenly to prepare a solid phase component, and put it into a disposable syringe for later use.

[0022] Step 2: Prepare a liquid buffer component with a pH range of 4.4 to 9.4 and put it into another disposable syringe for later use.

[0023] Step 3: Assemble the disposable syringes containing the solid and liquid components from Step 1 and Step 2, quickly flush them together, mix them evenly, and make a paste-like composite bone bonding system.

[0024] In a third aspect, the present invention provides the use of an implant adhesive or a composition comprising thereto in the preparation of a medicament for treating the following indications: bone tissue, dentistry, implants, soft tissue and wounds, congenital, disease and pathological indications, cosmetic and reconstructive indications;

[0025] Preferably, the disease is selected from: cancer (e.g., osteosarcoma), osteoporosis, rickets, osteogenesis imperfecta, fibrous dysplasia, Paget's disease, hearing loss, renal osteodystrophy, malignant bone tumors, bone infection, osteonecrosis or other genetic or developmental diseases;

[0026] Preferably, the bone tissue-related indications are selected from: bone degeneration, fracture, bone wear, bone corrosion, bone abrasion, internal bone fragmentation, or bone loss.

[0027] In a fourth aspect, the present invention provides a treatment method comprising administering an effective amount of the implant adhesive or a composition comprising the same to a subject in need, the treatment method being for treating the following indications: bone tissue, dental, implant, soft tissue and wound, congenital, disease and pathological indications, cosmetic and reconstructive indications;

[0028] Preferably, the disease is selected from: cancer (e.g., osteosarcoma), osteoporosis, rickets, osteogenesis imperfecta, fibrous dysplasia, Paget's disease, hearing loss, renal osteodystrophy, malignant bone tumors, bone infection, osteonecrosis or other genetic or developmental diseases;

[0029] Preferably, the bone tissue-related indications are selected from: bone degeneration, fracture, bone wear, bone corrosion, bone abrasion, internal bone fragmentation, or bone loss.

[0030] The present invention has the following beneficial effects:

[0031] (1) The system achieves multi-effect synergy through phosphoserine, tetracalcium phosphate and polybasic calcium phosphate in a liquid phase environment with adjustable acidity and alkalinity. Phosphoserine forms an interfacial barrier by complexing calcium ions and dynamically coating the particle surface, which slows down the dissolution mass transfer and exothermic rate. Polybasic calcium phosphate forms a gradient dissolution-precipitation kinetic sequence to achieve stepwise hydrolysis and dispersed exothermic reaction, avoiding the concentration of thermal peaks. The variable pH buffer neutralizes the acidity and alkalinity of hydrolysis by-products, stabilizes the phase balance and inhibits acid-base self-accelerating reaction. The three work together to achieve rate control, buffering and neutralization in one, reducing the solidification temperature rise from the source and inhibiting local overheating, making the reaction mild and controllable.

[0032] (2) Further, acidic calcium phosphate salts are introduced into the solid phase components. The acidic calcium phosphate salts and alkaline calcium phosphate salts undergo an acid-base neutralization reaction under aqueous conditions to generate hydroxyapatite, which improves the bioactivity of the bone adhesive, effectively stimulates and induces osteoblast gene expression, and promotes osteoblast differentiation. The generated hydroxyapatite enhances the mechanical strength of the bone adhesive on the one hand, and promotes the dissolution of calcium phosphate salts and the continuous deposition of hydroxyapatite on the other hand, thus achieving self-curing of the bone adhesive.

[0033] (3) The system uses stepwise hydrolysis, interface coating and pH neutralization to reduce the curing temperature rise, avoid thermal damage to soft tissue caused by high temperature and improve safety; through the complexation regulation of calcium salt ratio and phosphoserine, the curing time is stabilized within the clinically operable window to meet the needs of intraoperative shaping, positioning and rapid fixation; at the same time, a uniform and dense hydroxyapatite-based adhesive structure is formed under mild reaction conditions, taking into account the initial adhesive strength, anti-collapse and later osteoconductivity, to achieve stable fixation and osseointegration compatibility. This comprehensive balance of temperature control safety, controllable operation and mechanical adaptation effectively solves the pain points of traditional bone cement such as excessive heat release, difficulty in controlling the curing rhythm or difficulty in balancing mechanical and biocompatibility, and is more suitable for clinical scenarios such as fracture repair, bone defect filling and prosthesis fixation, and has important application value.

[0034] (4) By adjusting the pH value of the liquid buffer component and matching the selected functional additives, bone adhesives with different performance combinations can be customized, including rapid solidification and high early strength, high compressive strength and controllable degradation rate, excellent injection operability and anti-collapse properties, and bioactivity that promotes cell adhesion and osteogenic differentiation. Attached Figure Description

[0035] Figure 1 The image shows the surface condition of the composite bone bonding system prepared in Example 1 as observed under a scanning electron microscope.

[0036] Figure 2 The image shows a magnified view of the surface of the composite bone bonding system prepared in Example 1 under a scanning electron microscope.

[0037] Figure 3 The diagram shows the process of testing the compressive strength of the composite bone bonding system prepared in Example 1.

[0038] Figure 4 The diagram shows the tensile strength testing process of the composite bone bonding system prepared in Example 1.

[0039] Figure 5 The diagram shows the process of testing the adhesion strength of the composite bone bonding system prepared in Example 1.

[0040] Figure 6 The highest temperature released by the composite bone bonding system prepared for the examples and comparative examples is shown in the figure. Detailed Implementation

[0041] The present invention will be further explained and described below with reference to the accompanying drawings, but these should not be construed as limiting the scope of protection of the present invention.

[0042] Example 1

[0043] This embodiment provides a multi-synergistically regulated composite bone adhesion system, the preparation method of which is as follows:

[0044] Weigh out 0.9g of phosphoserine, 0.36g of tetracalcium phosphate, 1.422g of α-tricalcium phosphate, 18mg of hydroxyapatite, 0.24g of dicalcium phosphate, and 60mg of dihydrogen phosphate. Mix them thoroughly to prepare a solid phase, which is then placed into a 5mL threaded disposable syringe for later use. Prepare a liquid phase using 0.9mL of citrate-disodium hydrogen phosphate buffer solution (pH 7.4), which is placed into another 5mL threaded disposable syringe for later use. Connect the two syringes with a disposable connector and mix them quickly and evenly to obtain a paste-like composite bone adhesive.

[0045] Figure 1 , 2The images show the surface condition and a magnified view of the composite bone bonding system prepared in Example 1 under a scanning electron microscope. As can be seen from the images, the surface of the material is not flat and dense, but exhibits a unique micro / nano-scale rough morphology. This structure increases the specific surface area of ​​the material, which is beneficial for protein adsorption and cell pseudopodia adhesion.

[0046] Example 2

[0047] This embodiment provides a multi-synergistically regulated composite bone adhesion system. 1.5g of phosphoserine, 1.5g of tetracalcium phosphate, 0.8g of α-tricalcium phosphate, and 20mg of hydroxyapatite were weighed and uniformly mixed to prepare the solid phase. 0.76mL of citrate-disodium hydrogen phosphate buffer solution with pH 4.4 was used as the liquid phase.

[0048] Example 3

[0049] This embodiment provides a multi-synergistically regulated composite bone adhesion system. 0.3g of phosphoserine, 0.3g of tetracalcium phosphate, 1.2g of α-tricalcium phosphate, 15mg of hydroxyapatite, 0.6g of calcium hydrogen phosphate monohydrate, and 0.3g of calcium dihydrogen phosphate were weighed and uniformly mixed to prepare the solid phase. 1.2mL of citrate-disodium hydrogen phosphate buffer solution with a pH of 9.4 was used as the liquid phase.

[0050] Example 4

[0051] This embodiment provides a multi-synergistically regulated composite bone adhesion system. The solid phase consists of 0.9 g of phosphoserine, 0.36 g of tetracalcium phosphate, 1.422 g of β-tricalcium phosphate, 18 mg of hydroxyapatite, 0.24 g of dicalcium phosphate, and 60 mg of dihydrogen phosphate. The liquid phase consists of 0.9 mL of citrate-disodium hydrogen phosphate buffer solution at pH 7.4.

[0052] Example 5

[0053] This embodiment provides a multi-synergistically regulated composite bone adhesion system. The solid phase component is prepared by weighing 0.9g of phosphoserine, 0.36g of tetracalcium phosphate, 1.222g of α-tricalcium phosphate, 18mg of hydroxyapatite, 200mg of calcium silicate, 0.24g of dicalcium phosphate, and 60mg of dihydrogen phosphate. The liquid phase component is prepared using 0.9mL of citrate-disodium hydrogen phosphate buffer solution with a pH of 7.4.

[0054] Example 6

[0055] This embodiment provides a multi-synergistically regulated composite bone adhesion system. The solid phase component is prepared by weighing 0.9g of phosphoserine, 0.36g of tetracalcium phosphate, 1.222g of α-tricalcium phosphate, 18mg of hydroxyapatite, 200mg of octacalcium phosphate, 0.24g of dicalcium phosphate, and 60mg of dihydrogen phosphate. The liquid phase component is prepared using 0.9mL of citrate-disodium hydrogen phosphate buffer solution with a pH of 7.4.

[0056] Example 7

[0057] This embodiment provides a multi-synergistically regulated composite bone adhesion system. The solid phase component is prepared by weighing 0.9g of phosphoserine, 0.36g of tetracalcium phosphate, 1.422g of α-tricalcium phosphate, 18mg of hydroxyapatite, 0.24g of dicalcium phosphate, 60mg of dihydrogen phosphate, and 30mg of calcium chloride. The liquid phase component is prepared using 0.9mL of citrate-disodium hydrogen phosphate buffer solution with a pH of 7.4.

[0058] Example 8

[0059] This embodiment provides a multi-synergistically regulated composite bone adhesion system. The solid phase component is prepared by weighing 0.9g of phosphoserine, 0.36g of tetracalcium phosphate, 1.422g of α-tricalcium phosphate, 18mg of hydroxyapatite, 0.24g of calcium hydrogen phosphate monohydrate, 60mg of calcium dihydrogen phosphate, and 1mg of collagen. The liquid phase component is prepared using 0.9mL of citrate-disodium hydrogen phosphate buffer solution at pH 7.4.

[0060] Example 9

[0061] This embodiment provides a multi-synergistically regulated composite bone adhesion system. 0.9g of phosphoserine, 0.525g of tetracalcium phosphate, 0.5145g of α-tricalcium phosphate, 10.5mg of hydroxyapatite, 0.525g of dicalcium phosphate, and 0.525g of dihydrogen phosphate were weighed and prepared as the solid phase. 0.9mL of citrate-disodium hydrogen phosphate buffer solution with a pH of 7.4 was used as the liquid phase.

[0062] Example 10

[0063] This embodiment provides a multi-synergistically regulated composite bone adhesion system. A solid phase component was prepared by weighing 0.9g of phosphoserine, 0.36g of tetracalcium phosphate, 1.833g of α-tricalcium phosphate, 18mg of hydroxyapatite, and 0.24g of dicalcium phosphate. A 1.0mL citrate-disodium hydrogen phosphate buffer solution with a pH of 7.4 was used as the liquid phase component.

[0064] Comparative Example 1

[0065] This comparative example provides a composite bone bonding system with excessively high acidic calcium phosphate content. 0.9 g of phosphoserine, 0.24 g of tetracalcium phosphate, 57 mg of α-tricalcium phosphate, 3 mg of hydroxyapatite, 0.36 g of dicalcium phosphate, and 1.44 g of dihydrogen phosphate were weighed and prepared as the solid phase. 0.9 mL of citrate-disodium hydrogen phosphate buffer solution with a pH of 7.4 was used as the liquid phase.

[0066] Comparative Example 2

[0067] This comparative example provides a composite bone bonding system with a strongly acidic liquid phase component. Based on Example 1, it uses 0.9 mL of citrate-disodium hydrogen phosphate buffer solution with a pH of 2.4 as the liquid phase component.

[0068] Comparative Example 3

[0069] This comparative example provides a composite bone bonding system with a strongly alkaline liquid phase component. Based on Example 1, 0.9 mL of citrate-disodium hydrogen phosphate buffer solution with a pH of 10.4 is used as the liquid phase component.

[0070] Comparative Example 4

[0071] This comparative example provides a composite bone bonding system with excessively low phosphoserine content. Specifically, 0.15g of phosphoserine, 0.36g of tetracalcium phosphate, 1.422g of α-tricalcium phosphate, 18mg of hydroxyapatite, 0.84g of dicalcium phosphate, and 0.21g of dihydrogen phosphate were weighed as the solid phase component. 0.9mL of citrate-disodium hydrogen phosphate buffer solution with pH 7.4 was used as the liquid phase component.

[0072] Comparative Example 5

[0073] This comparative example provides a composite bone bonding system with insufficient liquid phase components. Based on Example 1, it uses 0.5 mL of citrate-disodium hydrogen phosphate buffer solution with a pH of 7.4 as the liquid phase component.

[0074] Test Example 1

[0075] This test example examines the compressive strength, tensile strength, and adhesive strength of the composite bone bonding systems prepared in the above embodiments and comparative examples:

[0076] 1. For example Figure 3 As shown, the paste-like bone adhesives obtained in Examples 1-10 and Comparative Examples 1-5 were extruded into a mold with a diameter of 25 mm for curing. The curing time was timed, and after curing, the bone adhesives were taken out and subjected to a compressive strength test.

[0077] 2. For example Figure 4As shown, the paste-like bone adhesives obtained in Examples 1-10 and Comparative Examples 1-5 were 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 adhesive was left to stand for 60 minutes and then placed in a fixture to measure the tensile strength. The applied force was perpendicular to the surface of the bonded pig femur at a 90° angle. A universal joint or metal wire was used to connect the testing machine and the bonded pig femur. The tensile strength of the bonded pig femur was tested at a speed of 20mm / min.

[0078] 3. For example Figure 5 As shown, the paste-like bone adhesives obtained in Examples 1-10 and Comparative Examples 1-5 were applied to smooth pig bone pieces, and a force of 10N was applied to press them to cure them. After curing, they were left to stand for 60 minutes, and then placed in a fixture to measure the adhesion strength. The applied force was parallel to the pig bone pieces to be bonded, and the shear strength of the bonded pig bone pieces was tested at a speed of 20mm / min.

[0079] 4. Place the powders from Examples 1-10 and Comparative Examples 1-5 into a time-measuring mold, add the corresponding buffer solution and stir. Start timing. After stirring until it becomes a paste, use a Gilmore instrument to test the curing of the bone adhesive system. Stop timing after curing. The total time is the bone adhesive curing time.

[0080] The test results are shown in Table 1:

[0081] Table 1

[0082]

[0083] Table 1 shows that all the solutions proposed in this invention successfully solidified and exhibited stable mechanical properties, with solidification times meeting clinical requirements. However, Comparative Examples 1 and 2 failed to solidify due to an imbalance in the calcium-to-phosphorus ratio or a strongly acidic liquid phase. Comparative Examples 3 and 4, with their overly alkaline liquid phases or excessively low phosphoserine content, while successfully solidifying, lacked a paste-like stage and had excessively short solidification times, making them unsuitable for use as bone adhesives. Comparative Example 5, with a liquid-to-solid volumetric ratio of 0.18 ml / g, below the lower limit of 0.2 ml / g, resulted in an overly viscous adhesive with uneven mixing, preventing normal clinical application.

[0084] Therefore, this invention improves the compressive strength, tensile strength, and adhesive strength of the composite bone bonding system by adjusting the solid phase ratio and the pH of the liquid phase, and controls the solidification time within a reasonable range.

[0085] Test Example 2

[0086] This test example examines the temperature parameters of the composite bone bonding systems obtained in Examples 1-10 and Comparative Examples 1-5:

[0087] The composite bone bonding systems prepared in Examples 1-10 and Comparative Examples 1-5 were observed using thermocouples and are denoted as 1-10 and Comparative Examples 1-5, respectively. The results are as follows: Figure 6 As shown, the average temperature of the composite bone bonding systems prepared in Examples 1-10 was 37.86℃, with the highest temperature not exceeding 40℃ and the lowest reaching 35.5℃. The lower temperature avoids damage to the surrounding tissues in the bone repair area due to excessive heat, preventing local inflammatory reactions or other side effects. In Comparative Example 1, the proportion of acidic calcium phosphate was high, and in Comparative Example 2, the buffer solution pH was strongly acidic, making the entire system acidic. The temperature was further reduced to 24.5℃, but due to the excessive acidity, the solid-liquid mixture did not react or the reaction was minimal, failing to solidify and thus unsuitable as a bone repair material. In Comparative Example 3, the buffer solution pH was strongly alkaline, making the entire system strongly alkaline. In Comparative Example 4, the phosphoserine content was low, while the alkaline calcium phosphate content was too high. After the reaction began, the phosphoserine was rapidly consumed, releasing a large amount of heat, reaching a temperature of 68.7℃. Furthermore, Comparative Examples 3 and 4 solidified within approximately 30 seconds after solid-liquid mixing, resulting in a very short operating window, unsuitable for clinical use. In Comparative Example 5, the liquid-to-solid volume ratio was below the lower limit, resulting in an overly thick adhesive, uneven mixing, and excessive temperature fluctuations, making it impossible to perform temperature measurements normally.

[0088] Summary Table 1 and Figure 6 The results show that the composite bone bonding system proposed in this application has moderate temperature and coagulation time, which can meet the needs of clinical operation. At the same time, the comprehensive mechanical properties have been significantly improved, solving the problems of existing technologies that cannot generate viscous gel-like substances or have insufficient comprehensive mechanical strength after coagulation in order to reduce the temperature.

[0089] 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 multi-synergistically regulated composite bone bonding system, comprising a powder component and a liquid buffer component, characterized in that: The volume-to-mass ratio of the liquid buffer component to the powder component is 0.2~0.5 ml / g; The powder component comprises phosphoserine, acidic calcium phosphate, tetracalcium phosphate, and other basic calcium phosphate; the phosphoserine content in the powder component is 20% to 40% by mass, and the tetracalcium phosphate content in the powder component is 10% to 30% by mass. The liquid buffer component is a mixed solution of citric acid and disodium hydrogen phosphate, with a pH range of 4.4 to 9.

4.

2. The multi-synergistic regulation composite bone adhesion system as described in claim 1, characterized in that: The alkaline calcium phosphate salt is selected from one of α-tricalcium phosphate, β-tricalcium phosphate, hydroxyapatite, octacalcium phosphate, or any mixture thereof in any proportion.

3. The multi-synergistic control composite bone adhesion system as described in claim 1, characterized in that: The acidic calcium phosphate salt is selected from one of calcium hydrogen phosphate, calcium hydrogen phosphate monohydrate, calcium dihydrogen phosphate, or a mixture thereof in any proportion.

4. The multi-synergistic regulation composite bone adhesion system as described in claim 1, characterized in that: The mass ratio of the alkaline calcium phosphate salt to the acidic calcium phosphate salt is 10%~65%:10%~60%.

5. The multi-synergistic regulation composite bone adhesion system as described in claim 1, characterized in that: The composite bone bonding system also includes growth factors added to the powder components.

6. A method for preparing a multi-synergistically regulated composite bone bonding system, characterized in that: To prepare the composite bone bonding system as described in any one of claims 1 to 5, the powder component and the liquid buffer component are respectively loaded into two syringes, connected by connectors and quickly flushed to mix the powder component and the liquid buffer component evenly, thus forming the composite bone bonding system.

7. Use of a composite bone bonding system as described in any one of claims 1 to 5 or a composite bone bonding system prepared by the method described in claim 6 in the preparation of a medicament for the treatment of the following indications: bone tissue, dentistry, implants, soft tissue and wounds, cosmetic and reconstructive indications.

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