CN101695584A - Injectable composite material capable of promoting bone regeneration and repair and preparation method thereof - Google Patents

Abstract

The injectable composite material for promoting bone regeneration and repair disclosed by the present invention is composed of sodium alginate, chitosan, multivariate trace elements synergistically doped with calcium phosphate porous microspheres, and bioactive glass nanoparticles as components through deionized water and cell culture. It is prepared by compounding and compounding liquid, and the mass percentage content of its components is: sodium alginate 0.10-0.50%; chitosan 0.01-0.20%; multivariate trace elements synergistically doped calcium phosphate porous microspheres 5-30%; biological activity Glass 0.05-0.50%; cell culture medium 25-55%; deionized water 30-45%. The preparation process of the invention is simple, and the prepared composite material has excellent injectability and rapid degradation characteristics, and the hydrogel network can enrich the calcium, phosphorus ions and trace elements released by the degradation of inorganic particles, and can promote the migration of osteoblast cells , growth, proliferation and differentiation, and has the effect of rapidly inducing bone regeneration and promoting bone repair for intraosseous micro-injury, fracture or bone defect.

Description

An injectable composite material for promoting bone regeneration repair and its preparation method

technical field

The invention relates to a hydrogel-bioactive inorganic microparticle injectable composite bone repair material, a preparation method and application, and belongs to the technical fields of biomedical materials and regenerative medicine.

Background technique

With the increasingly severe population expansion and the advent of the aging era, the treatment of bone damage caused by osteoporosis has become an important issue in various countries. The basic characteristics of osteoporosis are decreased bone density and significantly increased bone fragility, and the risk of intraosseous micro-injuries, fractures, and large-scale bone defects in the spine, femur, and wrist is greatly increased.

At present, there are no particularly effective drugs for the treatment of osteoporosis at home and abroad, and the main focus is on prevention. For a long time, the treatment of osteoporotic fractures and bone defects has been mainly based on internal fixation with metal or alloy materials, joint replacement, etc. Patients who are not suitable for replacement surgery are treated conservatively such as traction reduction. However, common problems such as delayed fracture union or nonunion and failure of internal fixation cause patients to stay in bed for a long time and lead to a large number of complications, so their disability and mortality rates have remained high.

In recent years, minimally invasive internal fixation surgery has gradually received clinical attention due to its advantages of small wounds and reduced blood loss. However, the bioactive design of internal fixation materials is still limited to surface modification of internal fixation and replacement metal materials to promote fracture fracture. The effect of surface healing is not obvious. Therefore, accelerating the development of new materials that can promote fracture healing and exploring new models of treatment for osteoporotic fractures and bone defects, shortening treatment time, and avoiding complications are effective ways to reduce mortality and completely cure osteoporotic fractures .

The promotion of osteoporotic fracture healing and defect repair puts forward very high requirements on the physicochemical and biological properties of biomaterials. On the one hand, the implant materials are required to have rapid degradability to meet the needs of new bone expansion; , it is required that the material has superior biological activity, can quickly induce bone regeneration, and promote bone healing at the fracture site; in addition, the technical requirements for delivering the implant material to the fracture surface and defect are relatively high, and the material is required to be highly rheological and able to pass through Injection and other methods allow the material to enter any narrow vacancy in the defect to form a uniform filling. At present, the bioactivity of conventional materials for bone defect filling and repair is poor, and the materials constructed with dense micro-nano particles still have problems such as bone regeneration and material degradation rates that are difficult to match, and calcium phosphate self-curing materials are injected into fractures and cause thrombosis. Clinically, pure calcium phosphate ceramics, self-curing materials, and bioglass large particle filling materials cannot meet the requirements of osteoporotic fracture and defect repair.

Porous octacalcium phosphate (Ca ₈ (HPO ₄ ) ₂ (PO ₄ ) ₄ ·5H ₂ O) is a metastable calcium phosphate salt that has gradually received widespread attention in recent years. Studies have shown that this calcium phosphate salt is The precursor material of bone and tooth tissue apatite has better degradability in physiological environment than tricalcium phosphate and hydroxyapatite. A large number of animal models and in vitro experimental studies in recent years have shown that octacalcium phosphate implant materials not only have superior biodegradability and biological activity than tricalcium phosphate and hydroxyapatite (O.Suzuki, et al. Curr.Med.Chem.2008, 15, 305-313), and has the potential to induce activity of promoting bone marrow mesenchymal stem cells to differentiate into osteoblasts (P.Habibovic, et al.J Mater Sci Mater Med.2004 15, 373 -80; T. Anada, et al. Tissue Eng. Part A. 2008, Jun, 965-978.). Doping silicon, strontium, zinc, magnesium and other trace elements in octacalcium phosphate is expected to improve the bioactivity, biodegradability and bone defect repair effect of the material. They play an irreplaceable role in regulating bone metabolism and enhancing bone strength. Biological efficacy.

Sodium alginate is a water-soluble polyelectrolyte polysaccharide with high negative charge density, which has good degradability and biocompatibility, and has been widely used in tissue engineering scaffolds and drug embedding materials. Chitosan is a natural polycationic polysaccharide, which is easy to degrade and the product is non-toxic. Its degradation can provide space for the growth of cells and tissues, thereby promoting the formation of new bone. The high water content hydrogel formed by the reconciliation of these two substances has excellent rheology and structural stability.

According to the current clinical application literature reports and the latest knowledge on the research progress of biomaterials, it is urgent to explore composite material systems composed of highly bioactive components and similar extracellular matrix, and to develop composite materials that can meet clinical requirements in terms of chemical composition and biological properties. It is a more ideal active material for rapid healing and complete repair of micro-injuries, fractures, and large-area bone defects in patients with osteoporosis. Such materials have a high-porosity gel-state extracellular matrix similar to bone tissue and inorganic minerals. Chemical components, especially the compounding of various trace elements, can actively regulate the proliferation and differentiation of osteoblast-related (stem) cells at the cellular and molecular levels, activate the rapid expression of genes related to bone regeneration, and achieve , Cells and tissues accept the active substances provided by ingestion or implantation to accurately regulate and respond, and a variety of trace elements can synergistically regulate the degradability of materials to achieve the best synergistic matching effect of bone defect regeneration and repair.

Contents of the invention

The object of the present invention is to provide a minimally invasive therapeutic injectable composite material which has a microstructure of extracellular matrix gel porous network and contains a variety of trace elements to significantly promote the rapid healing of osteoporotic fractures and the regeneration and repair of bone defects and its Preparation.

The injectable composite material for promoting bone regeneration and repair of the present invention is composed of sodium alginate, chitosan, multivariate trace elements synergistically doped with calcium phosphate porous microspheres, and bioactive glass nanoparticles as components through deionized water and cell culture. It is prepared by compounding liquid modulation, and the mass percentage of its components is:

Sodium alginate 0.10～0.50%;

Chitosan 0.01～0.20%;

Multivariate trace elements synergistically doped calcium phosphate porous microspheres 5-30%;

Bioactive glass 0.05～0.50%;

Cell culture fluid 25-55%;

Deionized water 30-45%, the sum of the above components is 100%.

The aforementioned calcium phosphate synergistically doped with multivariate trace elements is at least two synergistically doped octacalcium phosphate, hydroxyapatite, or a composite of the two of zinc, strontium, magnesium, and silicon, and the calcium phosphate porous microspheres are expressed in the form of oxides The mass percentage content of is:

CaO 40～55%

P ₂ O ₅ 38～44%

SiO ₂ 0～0.3%

SrO 0～5.5%

ZnO 0～3.5%

MgO 0～4.5%

H ₂ O 3-8%, the sum of the above components is 100%, and at least two substances of SiO ₂ , ZnO, MgO and SrO are not 0 at the same time.

The mole percentage content of the above-mentioned bioactive glass expressed in the form of oxide is:

CaO 32～50%

P ₂ O ₅ 0～12%

SiO ₂ 40～56%

B ₂ O ₃ 0～12%

_Na2O 3～8%

The particle size of the multi-component trace elements synergistically doped calcium phosphate porous microspheres is 5-600 μm; the particle size of the bioactive glass particles is 50-800 nm.

The preparation method of the injectable composite material for promoting bone regeneration repair of the present invention comprises the following steps:

1) Add the inorganic salt containing SiO ₃ ^2- and PO ₄ ^3- into the aqueous solution of sodium polyaspartate or sodium polyacrylate at a molar ratio of 1:10, and control the concentration of sodium phosphate to 1-10%. The sodium mixed solution is maintained at 37-60°C, and the pH value of the mixed solution is adjusted to 4.8-7.0, and then a solution containing at least two ions of Ca ²⁺ , Sr ²⁺ , Zn ²⁺ and Mg ²⁺ is added dropwise to the In the sodium phosphate mixed solution, the ratio of the total number of moles of ions added dropwise to the total number of moles of SiO ₃ ^2- and PO ₄ ^3- is 8:6. After the addition is completed, maintain the temperature of the solution and continue to stir and age for 0 to 1000 minutes , and then filter the precipitated multi-element microelements synergistically doped calcium phosphate microspheres, and wash with deionized water and absolute ethanol in sequence, then filter, vacuum dry, and set aside;

2) Weigh an appropriate amount of calcium nitrate according to the molar ratio of the reaction product _CaO : _P2O5 : _{SiO2 : B2O3} : _Na2O : 32-50: 0-12: 40-56: 0-12: 3-8 , triethyl phosphate, ethyl orthosilicate, boric acid and sodium nitrate were added to ethanol in turn to fully react, aged at 60°C, and then calcined at 550-700°C to obtain bioactive glass nanopowder, called Disperse 0.05 to 0.15 g of bioactive glass nanoparticles into 2 to 6 g of cell culture medium to prepare a suspension, and set aside;

3) Weigh an appropriate amount of sodium alginate powder at room temperature, fully stir and dissolve it in an aqueous solution containing 500ppm Ca ²⁺ and 50ppm Sr ²⁺ , making it a sodium alginate hydrogel with a concentration of 5g/L, and set aside;

4) Weigh an appropriate amount of chitosan powder at room temperature and add it to a 5g/L acetic acid solution, stir it sufficiently to make it a chitosan solution with a concentration of 20g/L, and set aside;

5) Weigh 1-3g of multi-element microelements synergistically doped with calcium phosphate microspheres prepared according to step 1), and add them to 6g of sodium alginate hydrogel prepared according to step 3), stir evenly, and then add step 4) Slowly drop 0.5-1.0 g of the prepared chitosan solution into the hydrogel, stir evenly, then add the suspension prepared in step 2), and stir evenly to obtain the hydrogel-biologically active inorganic particle composite. Injection of bone repair material.

In the present invention, there are no strict restrictions on the types of soluble inorganic salts used for doping silicon, zinc, strontium and magnesium active elements. Generally, the inorganic salts containing Ca ²⁺ are Ca(CH ₃ COO) ₂ ·H ₂ O, One of Ca(NO ₃ ) ₂ and CaCl ₂ or any combination of the three; the inorganic salts containing PO ₄ ^3- are Na ₃ PO ₄ , Na ₂ HPO ₄ ·2H ₂ O and NaH ₂ PO ₄ ·12H ₂ O or any combination of the three; the inorganic salt containing SiO ₃ ^2- uses Na ₂ SiO ₃ ; the inorganic salt containing Sr ²⁺ uses one of SrCl ₂ and Sr(NO ₃ ) ₂ One or any combination of the two, the inorganic salt containing Zn ²⁺ adopts one of ZnCl ₂ and Zn(NO ₃ ) ₂ or any combination between the two; the inorganic salt containing Mg ²⁺ adopts MgCl ₂ and Mg(NO ₃ ) One of ₂ or any combination of the two.

The beneficial effects of the present invention are:

The injectable bone repair material of the present invention has a simple manufacturing process, and the ratio of each component is optimized to make it suitable for minimally invasive injection application, and at the same time, its good rheology makes it suitable for different shapes of fracture sections and filling of bone defect spaces. The organic-inorganic composite repair material prepared by this method not only has a high water content gel network similar to the extracellular hydrogel matrix, but also contains multiple trace element bioactive ions of strontium, zinc, magnesium and silicon. The acidity and alkalinity are regulated by the weak alkaline ions leached from the bioactive glass, satisfying the microenvironment for the migration, adhesion, growth, proliferation and differentiation of osteoblast cells; secondly, the highly hydrated hydrogel porous network structure is conducive to the transport of nutrients And the growth of new bone, especially the composite material formed by low content of sodium alginate, chitosan component and multiple trace elements doped calcium phosphate porous microspheres, high specific surface bioglass nanoparticles has rapid degradation characteristics , can provide space for rapid fracture healing and new bone ingrowth. In addition, the sodium alginate, chitosan bardo, and cationic groups in the hydrogel matrix network have adsorption effects on calcium phosphate microspheres and inorganic ions dissolved from bioglass, providing the most suitable environment for intracellular growth to promote cell proliferation and differentiation. Active ion dosage, thus optimizing the biological activity of new bone regeneration. The biodegradable injection-type inorganic micro-nano particle-hydrogel composite bone repair material of the present invention has the prospect of wide application in the regeneration and repair of various intraosseous micro-injuries, fractures and bone defects in osteoporosis human body.

Description of drawings

Fig. 1 is multivariate trace element cooperative doping calcium phosphate X-ray diffraction pattern of the present invention, among the figure (a) is the material containing Mg, Zn, Sr and Si trace element, aging 10 minutes; (b) is containing Mg, Materials containing trace elements of Zn and Sr, aged for 240 minutes; (c) materials containing trace elements of Mg and Zn, aged for 360 minutes; (d) materials containing trace elements of Mg and Zn, aged for 1000 minutes .

Fig. 2 is the scanning electron micrograph of the synergistic doping calcium phosphate calcium phosphate of multivariate trace element of the present invention, among the figure (a) is the material containing Mg, Zn, Sr and Si trace element, aging 10 minutes; (b) is containing Mg, Zn and Sr trace element material, aged for 240 minutes; (c) is a material containing Mg and Zn trace element material, aged for 360 minutes.

Fig. 3 is the scanning electron micrograph of composite material, among the figure (a) is the composite material photo containing Mg, Zn, Sr and Si doped microsphere; (b) is the composite material containing Mg, Zn and Sr doped microsphere Photo; (c) is a composite photo containing Mg, Zn, and Sr doped microspheres.

Fig. 4 is an X-ray photo of the composite material injected into the rat femoral bone marrow cavity model.

Fig. 5 is a bone density test diagram of the composite material injected into the rat femoral bone marrow cavity model.

Figure 6 is the two-dimensional and three-dimensional micro-CT photos of the composite material injected into the rat femoral bone marrow cavity model.

Fig. 7 is the HE staining optical photograph of the tissue specimen injected with the composite material into the rat femoral bone marrow cavity model.

Detailed ways

The present invention is further illustrated below in conjunction with examples, but these examples do not limit the scope of the present invention, and all technologies and materials prepared based on the above contents of the present invention all belong to the protection scope of the present invention. The purity of reagents used in the examples is not lower than the purity index of analytical reagents.

Example 1

1) Add the inorganic salt of Na ₂ SiO ₃ and Na ₃ PO ₄ containing SiO ₃ ^2- , PO ₄ ^3- to the aqueous solution of sodium polyaspartate at a molar ratio of 1:10, and control the concentration of sodium phosphate to 10% , keep the mixed solution at 37°C, and adjust the pH value of the solution to 7.0 with hydrochloric acid under continuous conditions, and form a uniform solution with continuous stirring, then add Ca ²⁺ , Sr ²⁺ , Zn ²⁺ and Mg ²⁺ ions The solution of Ca(CH ₃ COO) ₂ ·H ₂ O, SrCl ₂ , ZnCl ₂ and MgCl ₂ was added dropwise to the mixed solution of sodium phosphate, the total moles of Ca ²⁺ , Sr ²⁺ , Zn ²⁺ and Mg ²⁺ The total molar ratio of SiO ₃ ^2- and PO ₄ ^3- is 8:6. After the dropwise addition, maintain the solution temperature and continue to stir and age for 10 minutes. The balls were washed three times with deionized water and absolute ethanol, then filtered and dried in vacuum. Heterocalcium phosphate is octacalcium phosphate microspheres.

2) According to the reaction product CaO:P ₂ O ₅ :SiO ₂ :B ₂ O ₃ :Na ₂ O molar ratio 36:4:52:4:4, weigh appropriate amount of calcium nitrate, triethyl phosphate, ethyl orthosilicate Ester, boric acid and sodium nitrate were sequentially added into stirring ethanol for 2 hours, then aged at 60°C for 24 hours, and then calcined at 700°C for 1.5 hours to obtain bioactive glass nanopowder, and 0.15g of bioactive The glass nano-powder is dispersed in 2 g of cell culture medium DMEM to prepare a suspension, which is set aside;

3) Weigh an appropriate amount of sodium alginate powder at room temperature and fully stir and dissolve it in an aqueous solution containing 500ppm Ca ²⁺ and 50ppm Sr ²⁺ , making it a hydrogel with a concentration of 50g/L;

4) Weigh an appropriate amount of chitosan powder at room temperature and add it to a 5g/L acetic acid solution, stir it sufficiently to make it a chitosan solution with a concentration of 20g/L, and set aside;

5) Weigh 3g of multivariate trace elements prepared in step 1) to synergistically dope calcium phosphate microspheres, and add 6g of sodium alginate hydrogel prepared in step 3), and after fully stirring, mix the chitosan prepared in step 4) Slowly drop 1.0 g of the sugar solution into the hydrogel and stir evenly; then add the suspension prepared in step 2) and stir evenly to obtain the hydrogel-bioactive inorganic particle composite injectable material. The pH value of the composite material was measured to be 7.6. The SEM photo of the cross-sectional structure of the composite material prepared in this example is shown in Figure 3(a), and the microsphere particles are evenly distributed in the hydrogel network.

Example 2

The preparation method is the same as that in Example 1, the difference is that: step 1) adding the Na ₂ HPO ₄ ·2H ₂ O inorganic salt containing PO ₄ ^3- into the aqueous solution of sodium polyacrylate at a molar ratio of 1:10, and controlling the concentration of sodium phosphate to 10%, the mixed solution was maintained at 60°C, and the pH value of the solution was adjusted to 4.8 with hydrochloric acid under continuous conditions, and a uniform solution was formed by continuous stirring, and then Ca ²⁺ , Sr ²⁺ , Zn ²⁺ and Mg ^{2 +} ions of CaCl ₂ , SrCl ₂ , ZnCl ₂ and MgCl ₂ are added dropwise to the sodium phosphate mixed solution, the total moles of Ca ²⁺ , Sr ²⁺ , Zn ²⁺ and Mg ²⁺ and the moles of PO ₄ ^3- The ratio was 8:6. After the dropwise addition, the temperature of the solution was maintained and the solution was continuously stirred and aged for 240 minutes. The octacalcium phosphate microsphere particles were partially transformed, and the composite microspheres of hydroxyapatite and octacalcium phosphate with a slower degradation rate were obtained. Wash with deionized water and absolute ethanol three times successively, then filter and dry in vacuum. The X-ray diffraction patterns and morphology scanning electron micrographs of the microsphere particles are shown in Fig. 1(b) and Fig. 2(b) respectively.

The morphology photo of the composite material prepared in this example is shown in Figure 3(b), and the microspheres are evenly distributed in the hydrogel network.

Example 3

The preparation method is the same as in Example 1, the difference is that: Step 1) Add Na ₃ PO ₄ containing PO ₄ ^3- in a molar ratio of 1:10 into the aqueous solution of sodium polyacrylate, control the concentration of sodium phosphate to 10%, and mix the The solution is maintained at 40°C, and the pH value of the solution is adjusted to 6.8 with hydrochloric acid under continuous conditions, and a uniform solution is formed by continuous stirring, and then CaCl ₂ , Zn(NO3) containing Ca ²⁺ , Zn ²⁺ and Mg ²⁺ ions ₂ and MgCl ₂ solution are added dropwise to the sodium phosphate mixed solution, the ratio of the total moles of Ca ²⁺ , Zn ²⁺ and Mg ²⁺ to the moles of PO ₄ ^3- is 8:6, and the temperature of the solution is maintained after the addition is completed. And continuously stirred and aged for 360 minutes, the octacalcium phosphate microsphere particles were transformed, and the hydroxyapatite microspheres with a slower degradation rate were obtained, which were washed three times with deionized water and absolute ethanol, then filtered, and vacuum-dried. The X-ray diffraction patterns and morphology scanning electron micrographs of the microsphere particles are shown in Figure 1(c) and Figure 2(c), respectively.

The morphology photo of the composite material prepared in this example is shown in Figure 3(c), and the microspheres are evenly distributed in the hydrogel network.

Example 4

With embodiment 1 preparation method, difference is:

The aging time in step 1) is controlled to be 1000 minutes, and multivariate trace elements are synergistically doped with hydroxyapatite microspheres, and the X-ray diffraction pattern of the microsphere particles is shown in Figure 1(d);

Step 2) Weigh the appropriate amount of calcium nitrate, triethyl phosphate, orthosilicic acid according to the reaction product CaO:P ₂ O ₅ :SiO ₂ : _{B 2} O ₃ :Na ₂ O molar ratio 38:6:52:0:4 Ethyl ester and sodium nitrate were sequentially added to ethanol under stirring to react for 2 hours, then aged at 60°C for 48 hours, and then calcined at 600°C for 1.5 hours to obtain bioactive glass nanopowder, and 0.10 g of bioactive glass The nanopowder is dispersed into 2g of cell culture medium DMEM to prepare a suspension;

Then, weigh 3g of microspheres prepared by step 1), and add 6g of the sodium alginate hydrogel prepared in step 3), after fully stirring, slowly drop 1.0g of chitosan solution prepared in step 4) into the hydrogel, fully stirred evenly; then add the suspension prepared in step 2) into the composite hydrogel, and stir evenly to obtain the hydrogel-biologically active inorganic particle composite material. The pH value of the composite material was measured to be 7.2.

Example 5

The composite material prepared in Example 1 was used to test the bone regeneration efficiency and material degradability of the femoral marrow cavity of rats with osteoporosis. The specific methods and results were as follows: the samples were sterilized by γ-ray radiation, and 30 12-week-old SD females were sterilized. Among them, 15 rats had their ovaries removed, which was the OVXed experimental group; the remaining 15 rats had only a small amount of adipose tissue removed from the ovaries, and they were the Sham sham operation control group. When 30 rats were kept clean and kept until 24 weeks old, the bone mineral density of the femur in the experimental group and the control group were 0.11±0.03 and 0.19±0.02 respectively, and there was a statistically significant difference, indicating that the rats in the experimental group had suffered from osteoporosis. The material samples were sterilized by γ-ray radiation, and 1.5 g of sterile samples were injected into the femoral cavities of the two hind legs of the two groups of rats under aseptic and anesthesia conditions, and then the injection needle holes were sealed with bone wax, and the cortex was sutured. After continuing to feed for 1 to 8 weeks, the rats were sacrificed according to the method of overdose anesthesia injection, and the complete femur was taken for X-ray, bone density, micro-CT two-dimensional and three-dimensional slice structure reconstruction and histological HE staining, respectively, as shown in Figure 4 ~7 shown. New bone mineralization was found in the femur of the experimental group at the 8th week (see Figure 4); the bone density of the femur in the experimental group increased rapidly with time, and there was no significant difference from the control group at the 8th week (see Figure 5); although the experimental group The porous bone degeneration was obvious in the group, but the mineralization of the injected material was obvious, and the material in the control group did not mineralize into bone due to rapid degradation (see Figure 6). There are still residual fragments in the degradation and disintegration of the microsphere particle material, and the material is degraded after 8 days in the control group, and there is no new bone (see Figure 7).

Claims (7)

1. An injectable composite material for promoting bone regeneration and repairing, characterized in that it is composed of sodium alginate, chitosan, multivariate trace elements synergistically doped with calcium phosphate porous microspheres, and bioactive glass nanoparticles as constituents. Ionized water and cell culture fluid are compounded and prepared, and the mass percentage of its components is: Sodium alginate 0.10～0.50%; Chitosan 0.01～0.20%; Multivariate trace elements synergistically doped calcium phosphate porous microspheres 5-30%; Bioactive glass 0.05～0.50%; Cell culture fluid 25-55%; Deionized water 30-45%, the sum of the above components is 100%. 2. The injectable composite material according to claim 1, characterized in that said multi-component trace element synergistically doped calcium phosphate is at least two synergistically doped octacalcium phosphate, hydroxyapatite, zinc, strontium, magnesium and silicon Stone or a composite of the two, the mass percentage content of calcium phosphate porous microspheres expressed in the form of oxides is: CaO 40～55% P ₂ O ₅ 38～44% SiO ₂ 0～0.3% SrO 0～5.5% ZnO 0～3.5% MgO 0～4.5% H ₂ O 3-8%, the sum of the above components is 100%, and at least two substances of SiO ₂ , ZnO, MgO and SrO are not 0 at the same time. 3. The injectable composite material according to claim 1, characterized in that the molar percentage content of said bioactive glass expressed in oxide form is: CaO 32～50% P ₂ O ₅ 0～12% SiO ₂ 40～56% B ₂ O ₃ 0～12% _Na2O 3～8% 4. The injectable composite material according to claim 1 or 2, characterized in that the particle size of the calcium phosphate porous microspheres synergistically doped with multiple trace elements is 5-600 μm. 5. The injectable composite material according to claim 1 or 3, characterized in that the particle size of said bioactive glass particles is 50-800 nm. 6. The preparation method of injectable composite material according to claim 1, is characterized in that comprising the following steps: 1) Add the inorganic salt containing SiO ₃ ^2- and PO ₄ ^3- into the aqueous solution of sodium polyaspartate or sodium polyacrylate at a molar ratio of 1:10, and control the concentration of sodium phosphate to 1-10%. The sodium mixed solution is maintained at 37-60°C, and the pH value of the mixed solution is adjusted to 4.8-7.0, and then a solution containing at least two ions of Ca ²⁺ , Sr ²⁺ , Zn ²⁺ and Mg ²⁺ is added dropwise to the In the sodium phosphate mixed solution, the ratio of the total number of moles of ions added dropwise to the total number of moles of SiO ₃ ^2- and PO ₄ ^3- is 8:6. After the addition is completed, maintain the temperature of the solution and continue to stir and age for 0 to 1000 minutes , and then filter the precipitated multi-element microelements synergistically doped calcium phosphate microspheres, and wash with deionized water and absolute ethanol in sequence, then filter, vacuum dry, and set aside; 2) Weigh an appropriate amount of calcium nitrate according to the molar ratio of the reaction product _CaO : _P2O5 : _{SiO2 : B2O3} : _Na2O : 32-50: 0-12: 40-56: 0-12: 3-8 , triethyl phosphate, ethyl orthosilicate, boric acid and sodium nitrate were added to ethanol in turn to fully react, aged at 60°C, and then calcined at 550-700°C to obtain bioactive glass nanopowder, called Disperse 0.05 to 0.15 g of bioactive glass nanoparticles into 2 to 6 g of cell culture medium to prepare a suspension, and set aside; 3) Weigh an appropriate amount of sodium alginate powder at room temperature, fully stir and dissolve it in an aqueous solution containing 500ppm Ca ²⁺ and 50ppm Sr ²⁺ , making it a sodium alginate hydrogel with a concentration of 5g/L, and set aside; 4) Weigh an appropriate amount of chitosan powder at room temperature and add it to a 5g/L acetic acid solution, stir it sufficiently to make it a chitosan solution with a concentration of 20g/L, and set aside; 5) Weigh 1-3g of multi-element microelements synergistically doped with calcium phosphate microspheres prepared according to step 1), and add them to 6g of sodium alginate hydrogel prepared according to step 3), stir evenly, and then add step 4) Slowly drop 0.5-1.0 g of the prepared chitosan solution into the hydrogel, stir evenly, then add the suspension prepared in step 2), and stir evenly to obtain the hydrogel-biologically active inorganic particle composite. Injection of bone repair material. 7. The preparation method of injectable composite material according to claim 6, characterized in that said inorganic salt containing Ca ²⁺ is Ca(CH ₃ COO) ₂ ·H ₂ O, Ca(NO ₃ ) ₂ and _One of CaCl ₂ or _any combination _of the _{three ;} the inorganic salt _containing PO ₄ ^3- is _{one or} Any combination of the three; the inorganic salt containing SiO ₃ ^2- uses Na ₂ SiO ₃ ; the inorganic salt containing Sr ²⁺ uses one of SrCl ₂ and Sr(NO ₃ ) ₂ or any of the two Combination, one of ZnCl ² _and Zn(NO ₃ ) ₂ or any combination of the two is used for Zn 2+ inorganic salt; one of MgCl ₂ and Mg(NO ₃ ) ₂ is used for Mg ²⁺ inorganic salt or any combination in between.

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