Injectable hydroxyapatite filler and preparation method thereof

Abstract

The present application discloses an injectable hydroxyapatite filler and a preparation method thereof, and belongs to the field of biomaterials. A preparation method of an injectable hydroxyapatite filler comprises the following steps: taking animal-derived bone and calcining it, crushing it to obtain natural hydroxyapatite, mixing it with a porogen in a thickening solution, forming a hydroxyapatite slurry, spray-drying the hydroxyapatite slurry into particles, obtaining hydroxyapatite microspheres, then calcining the hydroxyapatite microspheres to obtain porous hydroxyapatite; then epoxidizing to obtain epoxidized hydroxyapatite; cross-linking polyethylene glycol and guar gum to obtain polyethylene glycol-guar gum prepolymer, and then aminating to obtain amino polyethylene glycol-guar gum prepolymer; epoxidized hydroxyapatite, amino polyethylene glycol-guar gum prepolymer, and collagen aqueous solution are mixed and shaken to obtain an injectable hydroxyapatite filler. The present application has the advantages of improving the mechanical properties and biocompatibility of hydroxyapatite.

Description

Technical Field

[0001] The present application relates to the field of biomaterials, and in particular to an injectable hydroxyapatite filler and a preparation method thereof. Background Art

[0002] Hydroxyapatite is a promising filler material for use in the aesthetic medical industry. The chemical composition of hydroxyapatite (HA) is similar to the minerals in human bone tissue, allowing it to chemically bond with natural bone and exhibit excellent biological properties.

[0003] The disadvantages of hydroxyapatite are its high brittleness and mechanical properties that are difficult to match with bone tissue. The current improvement route is to compound hydroxyapatite with organic materials in order to achieve complementary performance advantages. However, in actual applications, it was found that the combination of hydroxyapatite and organic materials was poor, and it was difficult to balance the mechanical properties and biocompatibility of hydroxyapatite, which hindered its further application. Summary of the Invention

[0004] In order to improve the mechanical properties and biocompatibility of hydroxyapatite, the present application provides an injectable hydroxyapatite filler and a preparation method thereof.

[0005] In a first aspect, the present application provides a method for preparing an injectable hydroxyapatite filler using the following technical solution:

[0006] A method for preparing an injectable hydroxyapatite filler comprises the following steps:

[0007] Animal-derived bones are calcined and crushed to obtain natural hydroxyapatite;

[0008] Natural hydroxyapatite and a porogen are mixed and stirred in a thickening liquid to form a hydroxyapatite slurry, the hydroxyapatite slurry is spray-dried into particles to obtain hydroxyapatite microspheres, the particle size of the hydroxyapatite microspheres is 20-60 μm, and then the hydroxyapatite microspheres are calcined to obtain porous hydroxyapatite;

[0009] Dispersing porous hydroxyapatite in a first organic solvent, adding an epoxysilane coupling agent, heating for reaction, and filtering to obtain epoxidized hydroxyapatite;

[0010] Dissolving polyethylene glycol and guar gum in water, adjusting the pH to acidic, adding an aldehyde cross-linking agent, heating for reaction, and filtering to obtain a polyethylene glycol-guar gum prepolymer;

[0011] Dispersing the polyethylene glycol-guar gum prepolymer in a second organic solvent, adding an aminosilane coupling agent, heating for reaction, and filtering to obtain an amino polyethylene glycol-guar gum prepolymer;

[0012] Epoxidized hydroxyapatite, amino polyethylene glycol-guar gum prepolymer and collagen aqueous solution are mixed and shaken to obtain an injectable hydroxyapatite filler.

[0013] By adopting the above technical solution, compared with artificially synthesized hydroxyapatite, animal-derived bone as the source of hydroxyapatite has higher biological activity and safety, and is suitable for the fields of bone tissue regeneration and medical aesthetic filling.

[0014] Natural hydroxyapatite is modified by a porogen to improve the internal pore structure of natural hydroxyapatite and increase the specific surface area of natural hydroxyapatite, so as to promote the full binding of amino polyethylene glycol-guar gum prepolymer and collagen to hydroxyapatite; amino polyethylene glycol-guar gum prepolymer has good biocompatibility, and collagen is one of the components of bone tissue. Both of them form a strong binding ability with hydroxyapatite, which plays a role in improving the mechanical properties and bone induction ability of hydroxyapatite while meeting safety requirements.

[0015] After epoxidation, hydroxyapatite can further chemically bond with amino polyethylene glycol-guar gum prepolymer and collagen aqueous solution through the reaction between epoxy groups and amino groups, forming a stable structure without the need for cross-linking, further improving the compressive resistance of the hydroxyapatite filler.

[0016] Optionally, in the step of preparing the polyethylene glycol-guar gum prepolymer, the weight ratio of polyethylene glycol, guar gum and aldehyde cross-linking agent is 1:(1.2~1.5):(0.2~0.35).

[0017] By adopting the above technical solution, the input amounts of polyethylene glycol and guar gum are controlled, and the degree of cross-linking of the prepolymer is controlled, so that the polyethylene glycol-guar gum prepolymer can not only undergo subsequent amino modification but also adhere to the surface of hydroxyapatite, thereby improving the mechanical properties and biocompatibility of the hydroxyapatite filler.

[0018] Optionally, the molecular weight of the polyethylene glycol is 400-1000, and the molecular weight of the guar gum is 75000-90000.

[0019] By adopting the above technical solution, the lower molecular weight polyethylene glycol and guar gum make the prepolymer more tough and easier to spread on the surface of hydroxyapatite, thereby promoting the improvement of the mechanical properties of hydroxyapatite.

[0020] Optionally, in the step of preparing an injectable hydroxyapatite filler, the weight ratio of the epoxidized hydroxyapatite, the amino polyethylene glycol-guar gum prepolymer and the collagen aqueous solution is 1:(0.5~1):(6~8), and the molecular weight of the collagen in the collagen aqueous solution is 20000~30000Da, and the concentration is 5~10wt%.

[0021] By adopting the above technical solution, the molecular weight and concentration of collagen are controlled, so that epoxidized hydroxyapatite and amino polyethylene glycol-guar gum prepolymer can be fully dispersed and combined with collagen to obtain an injectable hydroxyapatite filler with good stability.

[0022] Optionally, the preparation method of the porogen comprises the following steps:

[0023] The polyvinyl alcohol, emulsifier and water are mixed and stirred, the pH is adjusted to acidic, and formaldehyde solution is added dropwise. After the addition is completed, the mixture is heated for reaction. After the reaction is completed, the mixture is filtered and washed to obtain polyvinyl alcohol microspheres.

[0024] The polyvinyl alcohol microspheres are dispersed in water, acrylic acid, an initiator and concentrated sulfuric acid are added in sequence, and the mixture is heated for reaction. After the reaction is completed, the mixture is filtered and washed to obtain a porogen.

[0025] By adopting the above technical solution, the polyvinyl alcohol microspheres modified by acrylic acid grafting can fully contact the surface of natural hydroxyapatite, improve the surface and internal morphology of hydroxyapatite, form interconnected pores, and promote the combination of hydroxyapatite with amino-polyethylene glycol-guar gum prepolymer and collagen, thereby improving the toughness of the hydroxyapatite filler while ensuring safety.

[0026] Optionally, the weight ratio of the polyvinyl alcohol, emulsifier and formaldehyde is 1:(0.5~0.7):(0.15~0.25); the weight ratio of the polyvinyl alcohol microspheres, acrylic acid, initiator and concentrated sulfuric acid is 1:(0.3~0.4):(0.02~0.05):(0.08~0.12).

[0027] By adopting the above technical solution, the shape of the porogen microspheres is controlled and the porogenic effect on natural hydroxyapatite is improved.

[0028] Optionally, the thickening liquid is prepared by mixing sodium carboxymethyl cellulose, glycerin and water in a weight ratio of 1:(0.3-0.6):(15-20).

[0029] By adopting the above technical solution, hydroxypropyl methylcellulose makes the thickening liquid have a certain viscosity, promotes the adhesion of the porogen to the surface of natural hydroxyapatite, and then forms pores under high-temperature calcination.

[0030] Optionally, in the step of preparing porous hydroxyapatite, the weight ratio of the natural hydroxyapatite, the porogen and the thickening liquid is 1:(0.3-0.45):(3-5).

[0031] Optionally, in the step of preparing epoxidized hydroxyapatite, the weight ratio of the porous hydroxyapatite to the epoxysilane coupling agent is 1:(0.08~0.15); in the step of preparing the amino polyethylene glycol-guar gum prepolymer, the weight ratio of the polyethylene glycol-guar gum prepolymer to the aminosilane coupling agent is 1:(0.15~0.25).

[0032] In a second aspect, the present application provides an injectable hydroxyapatite filler, which is prepared based on the above preparation method.

[0033] In summary, this application has the following beneficial effects:

[0034] 1. This application modifies natural hydroxyapatite with a porogen to increase the pore structure within the natural hydroxyapatite and its specific surface area, thereby promoting the full binding of the amino-polyethylene glycol-guar gum prepolymer and the collagen solution to the hydroxyapatite. The amino-polyethylene glycol-guar gum prepolymer has good biocompatibility, and collagen is a component of bone tissue. Both of them form a strong binding ability with hydroxyapatite, which plays a role in improving the mechanical properties and osteoinduction ability of hydroxyapatite while meeting safety requirements. After epoxidation, the hydroxyapatite can further chemically bond with the amino-polyethylene glycol-guar gum prepolymer and the collagen solution through the reaction between the epoxy group and the amino group, forming a stable structure without the need for further cross-linking, further improving the compressive strength of the hydroxyapatite filler.

[0035] 2. The porogen of the present application is polyvinyl alcohol microspheres modified by acrylic acid grafting. The porogen can fully contact the surface of natural hydroxyapatite, improve the surface and internal morphology of hydroxyapatite, form interconnected pores, and promote the combination of hydroxyapatite with amino polyethylene glycol-guar gum prepolymer and collagen, thereby improving the toughness of the hydroxyapatite filler while ensuring safety. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 This is a SEM image of the hydroxyapatite filler prepared in Example 1 of the present application. DETAILED DESCRIPTION

[0037] The application is described in further detail below.

[0038] Preparation Example 1

[0039] The preparation method of the porogen comprises the following steps:

[0040] Weigh 1000 g of polyvinyl alcohol, 500 g of emulsifier, 8 L of water, and 375 g of formaldehyde solution.

[0041] The molecular weight of polyvinyl alcohol is 35,000, the emulsifier is Span-80, and the concentration of formaldehyde solution is 40 wt%.

[0042] Polyvinyl alcohol, emulsifier and water were mixed and stirred, sulfuric acid solution was added to adjust the pH of the reaction system to 3.5, and then formaldehyde solution was added dropwise. After the addition was completed, the mixture was heated to 65°C and reacted for 2 hours. After the reaction was completed, the mixture was filtered and washed with water to obtain polyvinyl alcohol microspheres.

[0043] Weigh 500 g of polyvinyl alcohol microspheres, 5 L of water, 150 g of acrylic acid, 10 g of initiator, and 40 g of concentrated sulfuric acid.

[0044] The initiator is ammonium cerium sulfate, and the concentration of concentrated sulfuric acid is 98wt%.

[0045] Polyvinyl alcohol microspheres were dispersed in water, acrylic acid, initiator and concentrated sulfuric acid were added in sequence, heated to 50°C, reacted for 3 hours, and filtered and washed with water after the reaction to obtain a porogen.

[0046] Preparation Example 2

[0047] The preparation method of the porogen comprises the following steps:

[0048] Weigh 1000 g of polyvinyl alcohol, 700 g of emulsifier, 9 L of water, and 625 g of formaldehyde solution.

[0049] The molecular weight of polyvinyl alcohol is 35,000, the emulsifier is Span-80, and the concentration of formaldehyde solution is 40 wt%.

[0050] Polyvinyl alcohol, emulsifier and water were mixed and stirred, sulfuric acid solution was added to adjust the pH of the reaction system to 3.5, and then formaldehyde solution was added dropwise. After the addition was completed, the mixture was heated to 65°C and reacted for 2 hours. After the reaction was completed, the mixture was filtered and washed with water to obtain polyvinyl alcohol microspheres.

[0051] Weigh 500 g of polyvinyl alcohol microspheres, 5 L of water, 200 g of acrylic acid, 25 g of initiator, and 60 g of concentrated sulfuric acid.

[0052] The initiator is ammonium cerium sulfate, and the concentration of concentrated sulfuric acid is 98wt%.

[0053] Polyvinyl alcohol microspheres were dispersed in water, acrylic acid, initiator and concentrated sulfuric acid were added in sequence, heated to 50°C, reacted for 3 hours, and filtered and washed with water after the reaction to obtain a porogen.

[0054] Preparation Example 3

[0055] The difference between this preparation example and preparation example 1 is that polyvinyl alcohol microspheres are not grafted with acrylic acid, that is, polyvinyl alcohol microspheres are used as porogens.

[0056] Example 1

[0057] A method for preparing an injectable hydroxyapatite filler comprises the following steps:

[0058] Animal-derived bones, specifically sheep bones, are taken, calcined at 950° C. for 2 h, and crushed to obtain natural hydroxyapatite.

[0059] A thickening solution prepared by mixing sodium carboxymethyl cellulose with a degree of polymerization of 500, glycerol and water in a weight ratio of 1:0.3:15 was taken.

[0060] Take 500 g of natural hydroxyapatite, 150 g of the porogen of Preparation Example 1, and 1500 g of the thickening liquid, mix and stir, and soak for 1 hour to form a hydroxyapatite slurry. The hydroxyapatite slurry is spray-dried into granules at a spray temperature of 200°C to obtain hydroxyapatite microspheres with a particle size of 20~60 μm. Then, the hydroxyapatite microspheres are calcined at 1100°C for 3 hours to obtain porous hydroxyapatite.

[0061] Take 100 g of porous hydroxyapatite and disperse it in 1 L of a first organic solvent, specifically a 95 wt% ethanol solution, add 8 g of an epoxy silane coupling agent, specifically γ-glycidyloxypropyltrimethoxysilane, heat to 60 ° C and react for 1.5 hours, filter, and wash with ethanol and water to obtain epoxidized hydroxyapatite.

[0062] Take 100g of polyethylene glycol, 120g of guar gum, and 20g of aldehyde cross-linking agent.

[0063] The molecular weight of polyethylene glycol is 400, the molecular weight of guar gum is 75,000, and the aldehyde cross-linking agent is specifically a 50 wt% glutaraldehyde solution.

[0064] Polyethylene glycol and guar gum were dissolved in 3 L of water, phosphoric acid was added to adjust the pH to 5, an aldehyde cross-linking agent was added, the mixture was heated to 85° C. and stirred for 2 h, filtered, and washed with water to obtain a polyethylene glycol-guar gum prepolymer.

[0065] Take 100 g of polyethylene glycol-guar gum prepolymer and disperse it in 1 L of a second organic solvent, specifically toluene, add 15 g of an aminosilane coupling agent and 5 g of triethylamine, the aminosilane coupling agent is specifically 3-amino-trimethoxysilane, heat to 90 ° C and stir to react for 2 h, filter, and wash with ethanol and water to obtain an amino polyethylene glycol-guar gum prepolymer.

[0066] Take 100 g of epoxidized hydroxyapatite, 50 g of amino polyethylene glycol-guar gum prepolymer, and 600 g of collagen aqueous solution.

[0067] The molecular weight of collagen in the collagen aqueous solution is 20,000 Da, and the concentration is 10 wt%.

[0068] The epoxidized hydroxyapatite, amino polyethylene glycol-guar gum prepolymer and collagen aqueous solution were mixed and shaken for 3 hours to obtain an injectable hydroxyapatite filler, such as Figure 1 shown.

[0069] Example 2

[0070] A method for preparing an injectable hydroxyapatite filler comprises the following steps:

[0071] Animal-derived bones, specifically sheep bones, are taken, calcined at 950° C. for 2 h, and crushed to obtain natural hydroxyapatite.

[0072] A thickening liquid was prepared by mixing sodium carboxymethyl cellulose with a degree of polymerization of 500, glycerol and water in a weight ratio of 1:0.6:20.

[0073] 500 g of natural hydroxyapatite, 225 g of the porogen prepared in Preparation Example 2, and 2500 g of a thickening liquid were mixed and stirred to form a hydroxyapatite slurry. The hydroxyapatite slurry was spray-dried into granules at a spray temperature of 200 ° C to obtain hydroxyapatite microspheres having a particle size of 20 to 60 μm. The hydroxyapatite microspheres were then calcined at 1100 ° C for 3 h to obtain porous hydroxyapatite.

[0074] Take 100 g of porous hydroxyapatite and disperse it in 1 L of a first organic solvent, specifically a 95 wt% ethanol solution, add 15 g of an epoxy silane coupling agent, specifically γ-glycidyloxypropyltrimethoxysilane, heat to 60 ° C and react for 1.5 hours, filter, and wash with ethanol and water to obtain epoxidized hydroxyapatite.

[0075] Take 100g of polyethylene glycol, 150g of guar gum, and 35g of aldehyde cross-linking agent.

[0076] The molecular weight of polyethylene glycol is 400, the molecular weight of guar gum is 75,000, and the aldehyde cross-linking agent is specifically a 50 wt% glutaraldehyde solution.

[0077] Polyethylene glycol and guar gum were dissolved in 3 L of water, phosphoric acid was added to adjust the pH to 5, an aldehyde cross-linking agent was added, the mixture was heated to 85° C. and stirred for 2 h, filtered, and washed with water to obtain a polyethylene glycol-guar gum prepolymer.

[0078] Take 100 g of polyethylene glycol-guar gum prepolymer and disperse it in 1 L of a second organic solvent, specifically toluene, add 25 g of an aminosilane coupling agent and 5 g of triethylamine, the aminosilane coupling agent is specifically 3-amino-trimethoxysilane, heat to 90 ° C and stir to react for 2 h, filter, and wash with ethanol and water to obtain an amino polyethylene glycol-guar gum prepolymer.

[0079] Take 100 g of epoxidized hydroxyapatite, 10 g of amino polyethylene glycol-guar gum prepolymer, and 800 g of collagen aqueous solution.

[0080] The molecular weight of collagen in the collagen aqueous solution is 30,000 Da, and the concentration is 5 wt%.

[0081] The epoxidized hydroxyapatite, the amino polyethylene glycol-guar gum prepolymer and the collagen aqueous solution were mixed and shaken for 3 hours to obtain an injectable hydroxyapatite filler.

[0082] Example 3

[0083] A preparation method of injectable hydroxyapatite filler

[0084] The difference between this embodiment and embodiment 1 is that, in the step of preparing porous hydroxyapatite, the porogen used is the porogen of preparation example 3.

[0085] Comparative Example 1

[0086] A method for preparing an injectable hydroxyapatite filler comprises the following steps:

[0087] Animal-derived bones, specifically sheep bones, are taken, calcined at 950° C. for 2 h, and crushed to obtain natural hydroxyapatite.

[0088] 100 g of natural hydroxyapatite and 20 g of chitosan were mixed and stirred in a 2 wt% aqueous acetic acid solution for 4 h, and then 5 g of a 50 wt% glutaraldehyde solution was added and stirred for another 4 h. The precipitate was filtered, washed with water, and then dispersed in a 0.01 M PBS buffer solution at a weight ratio of precipitate to PBS buffer of 1:10. The mixture was shaken to obtain an injectable hydroxyapatite filler.

[0089] Comparative Example 2

[0090] A preparation method of injectable hydroxyapatite filler

[0091] The difference between this comparative example and Example 1 is that the step of preparing porous hydroxyapatite is not provided, that is, natural hydroxyapatite is used to prepare epoxidized hydroxyapatite.

[0092] Comparative Example 3

[0093] A preparation method of injectable hydroxyapatite filler

[0094] The difference between this comparative example and Example 1 is that, in the step of preparing the polyethylene glycol-guar gum prepolymer, an equal amount of gelatin is used to replace the guar gum, and the molecular weight of the gelatin used is 75,000.

[0095] Comparative Example 4

[0096] A preparation method of injectable hydroxyapatite filler

[0097] The difference between this comparative example and Example 1 is that in the step of preparing the polyethylene glycol-guar gum prepolymer, an equal amount of polyvinyl alcohol is used to replace the polyethylene glycol, and the molecular weight of the polyvinyl alcohol used is 35,000.

[0098] Comparative Example 5

[0099] A preparation method of injectable hydroxyapatite filler

[0100] The difference between this comparative example and Example 1 is that the step of preparing the amino polyethylene glycol-guar gum prepolymer is not provided, that is, the injectable hydroxyapatite filler is prepared by using epoxidized hydroxyapatite, polyethylene glycol-guar gum prepolymer and hydrolyzed collagen solution.

[0101] Performance Testing

[0102] The injectable hydroxyapatite filler was placed in a molding mold and freeze-dried at -60°C for 24 hours to obtain a test sample.

[0103] Mechanical properties test: The test sample is cylindrical with a diameter of 8 mm and a height of 10 mm. The test sample is compressed using a universal mechanical testing machine at a test speed of 5 mm / min and a compression height ratio of 50%. The compressive strength of the injectable hydroxyapatite filler is measured.

[0104] The injectable hydroxyapatite filler was sterilized, and then immersed in a growth medium containing 10% bovine serum, 100 U / mL penicillin, and 100 U / mL streptomycin for 24 hours to obtain a hydroxyapatite extract.

[0105] Cell proliferation test: MC3T3-E1 cells were diluted to a cell concentration of 3.5×108 L -10.1 mL of cell suspension was aspirated with a pipette and added to four 6-well plates. Each 6-well plate was divided into an experimental group and a control group. Growth medium was added to the culture wells of the control group, and the hydroxyapatite extract prepared in each embodiment and comparative example was added to the experimental group. The cells were cultured on the 3rd and 5th days. The corresponding culture wells were removed, the original culture medium and extract were discarded, and 100 μL of growth medium and 10 μL of CCK-8 reagent were added to each well. The cells were incubated in the dark for 1 hour, and the absorbance was read using a microplate reader at a wavelength of 450 nm.

[0106] Traditional hydroxyapatite composites, such as those in Comparative Example 1, exhibit low compressive strength, less than 2 MPa, making them less suitable for aesthetic medical applications. However, the hydroxyapatite fillers of Examples 1 and 2 of the present application, combined with an amino-polyethylene glycol-guar gum prepolymer and a collagen aqueous solution, achieve a compressive strength approaching 3 MPa, significantly improving mechanical properties and promising application prospects.

[0107] Comparative Examples 2-5 and Example 3 show that hydroxyapatite treated with a porogen enhances its binding ability with the amino-polyethylene glycol-guar gum prepolymer and the collagen aqueous solution. Furthermore, the grafting of polyvinyl alcohol microspheres with polypropionic acid in the porogen significantly improves the porous structure of hydroxyapatite. Furthermore, polyethylene glycol and guar gum can form a prepolymer well-suited to hydroxyapatite, enhancing the binding ability of the prepolymer with hydroxyapatite through amination.

[0108] The absorbance value of the experimental group was higher than that of the control group, indicating that the material has the effect of promoting the proliferation of osteoblasts and has good biocompatibility, thereby stimulating bone induction and accelerating bone formation.

[0109] The absorbance values of the hydroxyapatite fillers of Examples 1 and 2 of the present application were significantly higher than those of the control group, thus demonstrating a higher osteoblast proliferation capacity. Comparative Example 1, which represents a traditional hydroxyapatite composite method, did not show a significant increase in absorbance compared to the control group, indicating poor biocompatibility.

[0110] Combining Comparative Examples 2 to 5 and Example 3, it can be seen that the biocompatibility of the hydroxyapatite filler can be greatly improved by treating with a porogen and combining with an amino polyethylene glycol-guar gum prepolymer.

[0111] This specific implementation manner is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make non-creative modifications to the specific implementation manner as needed, but as long as they are within the scope of the claims of the present application, they are protected by the patent law.

Claims

1. A method for preparing an injectable hydroxyapatite filler, characterized in that: The following steps are involved: Animal-derived bones are calcined and crushed to obtain natural hydroxyapatite; Natural hydroxyapatite and a porogen are mixed and stirred in a thickening liquid to form a hydroxyapatite slurry, the hydroxyapatite slurry is spray-dried into granules to obtain hydroxyapatite microspheres, the particle size of the hydroxyapatite microspheres is 20-60 μm, and then the hydroxyapatite microspheres are calcined to obtain porous hydroxyapatite microspheres; Dispersing porous hydroxyapatite in a first organic solvent, adding an epoxysilane coupling agent, heating for reaction, and filtering to obtain epoxidized hydroxyapatite; Dissolving polyethylene glycol and guar gum in water, adjusting the pH to acidic, adding an aldehyde cross-linking agent, heating for reaction, and filtering to obtain a polyethylene glycol-guar gum prepolymer; Dispersing the polyethylene glycol-guar gum prepolymer in a second organic solvent, adding an aminosilane coupling agent, heating for reaction, and filtering to obtain an amino polyethylene glycol-guar gum prepolymer; Epoxidized hydroxyapatite, amino polyethylene glycol-guar gum prepolymer and collagen aqueous solution are mixed and shaken to obtain an injectable hydroxyapatite filler.

2. The method for preparing an injectable hydroxyapatite filler according to claim 1, wherein: In the step of preparing the polyethylene glycol-guar gum prepolymer, the weight ratio of polyethylene glycol, guar gum and aldehyde cross-linking agent is 1:(1.2-1.5):(0.2-0.35).

3. The method for preparing an injectable hydroxyapatite filler according to claim 2, wherein: The molecular weight of the polyethylene glycol is 400-1000, and the molecular weight of the guar gum is 75000-90000.

4. The method for preparing an injectable hydroxyapatite filler according to claim 1, wherein: In the step of preparing the injectable hydroxyapatite filler, the weight ratio of the epoxidized hydroxyapatite, the amino polyethylene glycol-guar gum prepolymer, and the collagen aqueous solution is 1:(0.5-1):(6-8), and the collagen in the collagen aqueous solution has a molecular weight of 20,000-30,000 Da and a concentration of 5-10 wt%.

5. The method for preparing an injectable hydroxyapatite filler according to claim 1, wherein: The preparation method of the porogen comprises the following steps: The polyvinyl alcohol, emulsifier and water are mixed and stirred, the pH is adjusted to acidic, and formaldehyde solution is added dropwise. After the addition is completed, the mixture is heated for reaction. After the reaction is completed, the mixture is filtered and washed to obtain polyvinyl alcohol microspheres. The polyvinyl alcohol microspheres are dispersed in water, acrylic acid, an initiator and concentrated sulfuric acid are added in sequence, and the mixture is heated for reaction. After the reaction is completed, the mixture is filtered and washed to obtain a porogen.

6. The method for preparing an injectable hydroxyapatite filler according to claim 5, characterized in that: The weight ratio of the polyvinyl alcohol, emulsifier and formaldehyde is 1:(0.5~0.7):(0.15~0.25); the weight ratio of the polyvinyl alcohol microspheres, acrylic acid, initiator and concentrated sulfuric acid is 1:(0.3~0.4):(0.02~0.05):(0.08~0.12).

7. The method for preparing an injectable hydroxyapatite filler according to claim 1, wherein: The thickening liquid is prepared by mixing sodium carboxymethyl cellulose, glycerin and water in a weight ratio of 1:(0.3-0.6):(15-20).

8. The method for preparing an injectable hydroxyapatite filler according to claim 1, characterized in that: In the step of preparing porous hydroxyapatite, the weight ratio of the natural hydroxyapatite, the porogen and the thickening liquid is 1:(0.3-0.45):(3-5).

9. The method for preparing an injectable hydroxyapatite filler according to claim 1, wherein: In the step of preparing epoxidized hydroxyapatite, the weight ratio of the porous hydroxyapatite to the epoxysilane coupling agent is 1:(0.08-0.15); in the step of preparing the amino polyethylene glycol-guar gum prepolymer, the weight ratio of the polyethylene glycol-guar gum prepolymer to the aminosilane coupling agent is 1:(0.15-0.25).

10. An injectable hydroxyapatite filler, prepared according to the preparation method according to any one of claims 1 to 9.

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