A low exothermic antibacterial and anti-inflammatory injectable bone cement and its preparation method and use

Abstract

The present invention discloses a low exothermic antibacterial and anti-inflammatory injectable bone cement, its preparation method and uses. The preparation method includes the following steps: performing double bond modification on hydroxyapatite powder; grafting the double bond-modified hydroxyapatite with sulfobetaine by means of free radical polymerization to obtain betaine-modified hydroxyapatite; using a polymethyl methacrylate prepolymer solution as the liquid phase, and using the betaine-modified hydroxyapatite and benzoyl peroxide mixed in a certain proportion as the solid phase, and after adding an appropriate amount of N,N-dimethylaniline, fully stirring until uniformly mixed, and heating and curing to obtain the low exothermic antibacterial and anti-inflammatory injectable bone cement. The low exothermic antibacterial and anti-inflammatory injectable bone cement prepared by the present invention inhibits the damage to tissues and cells caused by the release of a large amount of heat, and at the same time, the betaine molecules play an antibacterial and anti-inflammatory role. The manufacturing process of the present invention is simple and has good practicability.

Description

Technical Field

[0001] The invention relates to the field of orthopedic medical materials, and in particular to a low-exothermic, antibacterial and anti-inflammatory injectable bone cement and a preparation method and application thereof. Background Art

[0002] Chronic osteomyelitis is one of the difficult problems in the treatment of bone-related diseases. It is a bacterial infectious disease that occurs in bone tissue. The disease has a long course, is prone to relapse, and the treatment process is tortuous and complicated, which brings great troubles to patients and clinicians. The incidence of chronic osteomyelitis is higher in men than in women, and it is more common in young patients. Due to the severe inflammation and high risk of recurrence at the local lesion site, the radical treatment of chronic osteomyelitis is often long-term. If chronic osteomyelitis is not treated in time, it can turn into life-threatening diseases such as joint dysfunction and limb disability. In addition, patients need to undergo multiple surgeries and long-term antibiotic treatment, which invisibly increases the patient's pain and economic burden.

[0003] Polymethyl methacrylate (PMMA) has become the most widely used bone substitute in clinical practice due to its good mechanical strength and injectability, and is widely used in the repair and treatment of chronic osteomyelitis. Hydroxyapatite (HA), as one of the main components of natural bone, is similar to bone minerals, has good biocompatibility and bioactivity, can be firmly combined with bones and soft tissues, and has been widely used in the fields of bone tissue repair and replacement. Among them, nanohydroxyapatite (n-HA) has a smaller particle size, and its surface energy, solubility and bioactivity have been improved, making it more suitable for clinical applications.

[0004] However, single PMMA bone cement has many defects in clinical use of chronic osteomyelitis. First, the essence of the bone cement curing process is the free radical polymerization reaction of polymethyl methacrylate monomers. The violent exothermic temperature of bulk polymerization is generally above 70°C, which can cause damage to the tissues around the human bones, leading to cell and tissue damage and necrosis. Secondly, polymethyl methacrylate bone cement does not have biological activity, and after curing in the human body, it has poor adhesion to tissues, which can easily cause the prosthesis to loosen. Nanohydroxyapatite, as a bioactive material and the main component of natural bone, has good biocompatibility. However, the mechanical strength of the hydroxyapatite main material is insufficient, and when bioactive materials such as hydroxyapatite are compounded with polymers, inorganic hydroxyapatite nanoparticles are easy to agglomerate and have poor adhesion to the polymer interface, resulting in a significant decrease in its mechanical properties, making it difficult to meet the load-bearing requirements.

[0005] In addition, the method of adding antibiotics to polymethyl methacrylate (PMMA) bone cement has been widely used in the treatment of chronic osteomyelitis, but there are also many defects. First, antibiotics can make the human body develop drug resistance and are ineffective against drug-resistant bacteria; second, antibiotics can cause multiple internal contaminations caused by dysbacteriosis. Therefore, the use of a suitable antibacterial system is crucial for the treatment of osteomyelitis. Summary of the Invention

[0006] The purpose of the present invention is to provide a low-exothermic antibacterial and anti-inflammatory injectable bone cement, its preparation method and uses. By establishing a redox system of BPO-DMA, the activation energy of the polymerization reaction is reduced to reduce heat release, and tissue damage caused by a large amount of heat release during the polymerization process is inhibited. The betaine-modified hydroxyapatite is used as a filler and dispersed in the polymethyl methacrylate bone cement, improving the bioactivity of the bone cement and endowing it with antibacterial efficacy.

[0007] In one aspect of the present invention, a preparation method of a low-exothermic antibacterial and anti-inflammatory injectable bone cement is proposed. According to an embodiment of the present invention, it includes the following steps:

[0008] (1) Modify the double bonds of hydroxyapatite powder;

[0009] (2) Graft the double-bond modified hydroxyapatite with sulfobetaine by free radical polymerization to obtain betaine-modified hydroxyapatite;

[0010] (3) Use the polymethyl methacrylate prepolymer solution as the liquid phase, and use the betaine-modified hydroxyapatite and benzoyl peroxide mixed in a certain proportion as the solid phase. After adding an appropriate amount of N,N-dimethylaniline, stir well until evenly mixed, and heat and cure to obtain the low-exothermic antibacterial and anti-inflammatory injectable bone cement.

[0011] In addition, according to the preparation method of a low-exothermic antibacterial and anti-inflammatory injectable bone cement according to the above embodiment of the present invention, it may also have the following additional technical features:

[0012] In some embodiments of the present invention, the step (1) specifically includes the following steps: Dissolve hydroxyapatite, hexamethylene diisocyanate and dibutyltin dilaurate in anhydrous N,N-dimethylformamide, and heat for a certain time under the conditions of reflux condensation and nitrogen protection; dissolve an appropriate amount of 2-hydroxyethyl methacrylate in N,N-dimethylformamide, inject it into the above system, stir overnight, centrifuge, wash with dichloromethane multiple times and collect the powder, dry it thoroughly, and grind it into powder with a mortar to obtain the double-bond modified hydroxyapatite, and its structural formula is:

[0013]

[0014] The synthesis route of the double-bond modified hydroxyapatite HA-CH=CH2 is as follows:

[0015]

[0016] In some embodiments of the present invention, the molar ratio of the hydroxyapatite, hexamethylene diisocyanate, and 2-hydroxyethyl methacrylate is 1:1 - 3:3 - 10. The reaction temperature throughout the process is 40 - 60 °C, the heating time under the conditions of condensation reflux and nitrogen protection is 6 - 24 h, the drying temperature is 35 - 50 °C, and the drying time is 12 - 36 h.

[0017] In some embodiments of the present invention, in step (2), the double-bond modified hydroxyapatite, betaine monomer, and azobisisobutyronitrile are dissolved in anhydrous dimethyl sulfoxide, degassed by freezing three times under nitrogen, and flame-sealed under vacuum. After reacting in an oil bath for a sufficient time, it is cooled to terminate the reaction, washed several times with ethanol and deionized water respectively, and the powder is collected, dried, and pulverized to obtain the betaine-modified hydroxyapatite, and its structural formula is:

[0018]

[0019] The synthesis route of the betaine-modified hydroxyapatite is as follows:

[0020]

[0021] In some embodiments of the present invention, the molar ratio of the double-bond modified hydroxyapatite, betaine monomer, and azobisisobutyronitrile is 1:2 -5:0.1 - 0.5. The oil bath reaction temperature is 65 - 85 °C, the reaction time is 48 - 72 h, the vacuum oven drying temperature is 50 - 70 °C, and the freezing temperature is -50 - -80 °C.

[0022] In some embodiments of the present invention, in step (3), the preparation of the polymethyl methacrylate prepolymer solution includes the following steps: After heating a solution of methyl methacrylate (MMA) containing an appropriate amount of initiator in a water bath for a certain time, the heating is stopped and the reaction is terminated by cooling.

[0023] In some embodiments of the present invention, the initiator is benzoyl peroxide or azobisisobutyronitrile, the water bath heating temperature is 70 - 90 °C, the mass of the initiator is 0.5% - 1.5% of the mass of the polymethyl methacrylate prepolymer solution, and the water bath heating time is 15 - 30 min.

[0024] In some embodiments of the present invention, in the step (3), the mass ratio of the liquid phase to the solid phase is 1:0.05 - 0.5, the mass of benzoyl peroxide is 0.2% - 2% of the mass of the polymethyl methacrylate prepolymer solution, the mass of N,N-dimethylaniline is 1% - 3% of the mass of the polymethyl methacrylate prepolymer solution, the curing temperature is 36 - 37 °C, and the demolding time is 15 - 60 min after mixing.

[0025] In another aspect of the present invention, the present invention provides a low exothermic antibacterial and anti-inflammatory injectable bone cement prepared by the preparation method of the low exothermic antibacterial and anti-inflammatory injectable bone cement described above.

[0026] In another aspect of the present invention, the present invention provides the application of the low exothermic antibacterial and anti-inflammatory injectable bone cement in the preparation of an implant material for the treatment of osteomyelitis.

[0027] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0028] 1) In the present invention, hydroxyapatite powder grafted with betaine is prepared and mixed and stirred with a liquid polymethyl methacrylate prepolymer solution in a certain proportion. At the same time, by adding a certain proportion of the oxidant benzoyl peroxide (BPO) and the reductant N,N-dimethylaniline (DMA), an injectable bone cement with an exothermic temperature ≤ 43 °C and antibacterial function is prepared. Each step of the reaction is safe and reliable, the operation is simple, and the conversion rate of each step is relatively high. In addition, the bone cement prepared by the present invention has good biocompatibility, injectability and adhesiveness, and has broad application prospects.

[0029] 2) The hydroxyapatite is modified with double bonds and grafted with a functional betaine polymer. The betaine monomer contained in the modified hydroxyapatite is used to treat osteomyelitis, avoiding many disadvantages of antibiotics while exerting antibacterial efficacy. At the same time, betaine also has the effect of anti-protein adsorption, which can improve the bioavailability of the material.

[0030] 3) In the present invention, betaine is grafted onto hydroxyapatite by free radical polymerization, which can greatly increase the content of functional monomers connected to hydroxyapatite, which is not only beneficial to improving the dispersibility of hydroxyapatite and polymethyl methacrylate, but also beneficial to enhancing the antibacterial efficacy of the bone cement to promote the repair and treatment of osteomyelitis. At the same time, a redox system is established to initiate further polymerization to cure the bone cement, reducing the activation energy of the reaction to reduce heat release. In addition, as a good heat dissipating agent, the hydroxyapatite filler can also play a role in reducing heat release. Through the synergistic effect of various aspects, the maximum polymerization temperature is suitable for the human body physiological temperature, effectively reducing tissue damage and necrosis caused by a large amount of heat release during the polymerization process. Description of the Drawings

[0031] Figure 1 Schematic diagram of the preparation process of the low exothermic antibacterial and anti-inflammatory injectable bone cement in the embodiments of the present invention;

[0032] Figure 2 FT-IR spectra of hydroxyapatite (HA), isocyanate group-modified hydroxyapatite (HA-NCO), and double bond-modified hydroxyapatite (HA-CH=CH2) in Example 1 of the present invention;

[0033] Figure 3 FT-IR spectra of betaine monomer (SBMA), double bond-modified hydroxyapatite (HA-CH=CH2), and betaine-modified hydroxyapatite (HA-PSBMA) in Example 1 of the present invention;

[0034] Figure 4 XRD patterns of hydroxyapatite (HA), double bond-modified hydroxyapatite (HA-CH=CH2), and betaine-modified hydroxyapatite (HA-PSBMA) in Example 1 of the present invention;

[0035] Figure 5 Thermogravimetric curves of hydroxyapatite (HA), double bond-modified hydroxyapatite (HA-CH=CH2), and betaine-modified hydroxyapatite (HA-PSBMA) in Example 1 of the present invention;

[0036] Figure 6 In, the left figure is the SEM image of hydroxyapatite (HA) in Example 1 of the present invention, and the right figure is the SEM image of the powder of betaine-modified hydroxyapatite (HA-PSBMA) in Example 1 of the present invention;

[0037] Figure 7 Temperature-time diagrams of the low exothermic antibacterial and anti-inflammatory injectable bone cement in Examples 1-4 of the present invention, where 10%, 20%, 30%, and 40% represent Examples 1-4 respectively;

[0038] Figure 8 Setting time diagrams of the low exothermic antibacterial and anti-inflammatory injectable bone cement in Examples 1-4 of the present invention;

[0039] Figure 9 Compressive strength diagrams of the low exothermic antibacterial and anti-inflammatory injectable bone cement in Examples 1-4 of the present invention;

[0040] Figure 10 Flexural strength diagrams of the low exothermic antibacterial and anti-inflammatory injectable bone cement in Examples 1-4 of the present invention;

[0041] Figure 11The water contact angle diagrams of the low exothermic antibacterial and anti-inflammatory injectable bone cements in Examples 1-4 of the present invention and the control group were detected by a water contact angle detector. Among them, (a) is the control group, and (b-e) are Examples 1-4 in sequence;

[0042] Figure 12 The water absorption rate diagrams of the low exothermic antibacterial and anti-inflammatory injectable bone cements in Examples 1-4 of the present invention after being soaked in plasma solution for 7 days;

[0043] Figure 13 The SEM diagrams of the cross-sections of the low exothermic antibacterial and anti-inflammatory injectable bone cements in Examples 2 and 4 of the present invention. Detailed implementation manners

[0044] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0045] Example 1

[0046] A preparation method of a low exothermic antibacterial and anti-inflammatory injectable bone cement, comprising the following steps:

[0047] (1) Synthesis of HA-CH=CH2: Dissolve 1 g of hydroxyapatite (HA), 1 g of hexamethylene diisocyanate (HDI), and 10 mg of dibutyltin dilaurate (DBTDL) in 10 mL of anhydrous DMF, and react in an oil bath at 50 °C for 8 h under the conditions of condensation reflux and nitrogen protection to obtain isocyanate group-modified hydroxyapatite (HA-NCO). Dissolve 1.30 g of 2-hydroxyethyl methacrylate (HEMA) in 2 mL of DMF, slowly inject it into the above reaction system, stir overnight at 50 °C and then centrifuge, and separate the particles by centrifugation with dichloromethane and redispersion in a cycle for multiple times. Collect the powder and place it in a vacuum oven at 35 °C to dry thoroughly for 24 h, and grind it with a mortar to obtain white powder double bond-modified hydroxyapatite (HA-CH=CH2), and its structural formula is:

[0048]

[0049] Figure 2 In, the successful synthesis of HA-NCO was proved by the absorption peak of -NCO at 2273 cm -1 . The successful synthesis of HA-CH=CH2 was proved by the appearance of the absorption peak of carbon-carbon double bond at 1680 cm -1 and the absorption peak of carbonyl at 1729 cm -1 and the disappearance of the isocyanate group absorption peak.

[0050] (2) Synthesis of HA-PSBMA: 0.67 g of double bond modified hydroxyapatite (HA-CH=CH2), 0.75 g of betaine monomer (SBMA) and 10 mg of azobisisobutyronitrile (AIBN) were dissolved in 15 mL of anhydrous DMSO and placed in a sealed tube. The mixture was degassed three times under nitrogen atmosphere and minus 80°C, and flame sealed under vacuum. The mixture was placed in an 80°C oil bath for reaction for 48 h and then cooled to terminate the reaction. The particles were separated by centrifugation-redispersion cycles with ethanol and deionized water for multiple times. The collected powder was placed in a 50°C vacuum oven and dried for 24 h. The mixture was ground with a mortar to obtain a light yellow powder of betaine modified hydroxyapatite (HA-PSBMA), the structural formula of which is:

[0051]

[0052] like Figure 3 As shown, after the reaction, the -1 The carbonyl absorption peak at 1185 cm -1 The absorption peak of the sulfur-oxygen bond at 1470 nm proved the successful grafting of HA-PSBMA. Figure 4 As shown in the figure, the functionalized products HA-CH=CH2 and HA-PSBMA show the same peaks as HA, which confirms that the grafting reaction does not cause any crystal changes and the formation of secondary phases, and still has good crystallinity. Figure 5 As shown in the figure, it is calculated that the grafting rate of the double bond of hydroxyapatite is 23.1%, and the reactivity ratio of HA-CH=CH2 and betaine monomer is 2.8:1, that is, on average, 1.73 betaine monomers are grafted onto each hydroxyl group of hydroxyapatite. Figure 6 As shown in the figure, the surface of pure hydroxyapatite particles is smooth and rod-shaped, while a large number of rough areas appear on the surface of HA-PSBMA, which contain granular polymer molecules, proving the successful grafting of the polymer.

[0053] (3) Preparation of polymethyl methacrylate prepolymer solution: Dissolve 100 mg of dibenzoyl peroxide (BPO) in 20 g of polymethyl methacrylate solution, place in a conical flask and heat in a 75°C water bath for 20 min, then stop heating and place the conical flask in cold water to cool and terminate the reaction.

[0054] (4) Preparation of bone cement: Using 2 g of poly(methyl methacrylate) (PMMA) prepolymer solution as the liquid phase, 10 mg of benzoyl peroxide (BPO) and a certain mass of betaine-modified hydroxyapatite as the solid phase, with the mass percentage of HA-PSBMA in the PMMA prepolymer being 10%, and the mass of HA-PSBMA being 200 mg. After adding an additional 10 mg of N,N-dimethylaniline (DMA), the two phases were fully stirred until evenly mixed and then injected into a mold. It was placed in an oven at 37 °C for heat curing, and after 45 minutes, the mold was removed to obtain the final bone cement sample.

[0055] Example 2

[0056] The preparation method of a low-exothermic antibacterial and anti-inflammatory injectable bone cement in this example is different from that in Example 1. In this example, 10 mg of benzoyl peroxide (BPO) and a certain mass of betaine-modified hydroxyapatite are used as the solid phase, the mass percentage of HA-PSBMA in the PMMA prepolymer is 20%, and the mass of HA-PSBMA is 400 mg.

[0057] Example 3

[0058] The preparation method of a low-exothermic antibacterial and anti-inflammatory injectable bone cement in this example is different from that in Example 1. In this example, 10 mg of benzoyl peroxide (BPO) and a certain mass of betaine-modified hydroxyapatite are used as the solid phase, the mass percentage of HA-PSBMA in the PMMA prepolymer is 30%, and the mass of HA-PSBMA is 600 mg.

[0059] Example 4

[0060] The preparation method of a low-exothermic antibacterial and anti-inflammatory injectable bone cement in this example is different from that in Example 1. In this example, 10 mg of benzoyl peroxide (BPO) and a certain mass of betaine-modified hydroxyapatite are used as the solid phase, the mass percentage of HA-PSBMA in the PMMA prepolymer is 40%, and the mass of HA-PSBMA is 800 mg.

[0061] Table 1 Quantities of solid and liquid phase raw materials in Examples 1-4

[0062]

[0063] As Figure 7 shown, the maximum temperature during the polymerization process is lower than 43 °C, far lower than the requirement of less than 90 °C in the international standard for surgical implants - acrylic resin cement (ISO-5833), which can inhibit tissue damage caused by a large amount of heat release during polymerization. As Figure 8As shown, the setting times of the four groups of bone cements were between 10 - 14 min, all meeting the requirement of less than 15 min in the international standard for surgical implants - acrylic resin cement (ISO - 5833).

[0064] As Figure 9 shown, the bone cement splines of Examples 1 - 4 were all cylinders with a diameter of 6 mm and a height of 12 mm. Among them, for the four groups of bone cements, the strengths of the three groups of Examples 1, 2, and 3 all met the requirement of 70 MPa in the international standard for surgical implants - acrylic resin cement (ISO - 5833), maintaining good compressive mechanical properties. As Figure 10 shown, the bone cement splines of Examples 1 - 4 were all cuboids with a length of 75 mm, a width of 10 mm, and a height of 3.3 mm. Among them, for the four groups of bone cements, the two groups of 10% and 20% met the requirement of greater than 50 MPa in the international standard for surgical implants - acrylic resin cement (ISO - 5833), having good flexural mechanical properties.

[0065] As Figure 11 shown, with the increase in the content of betaine - modified hydroxyapatite, the hydrophilicity was improved, so the water contact angle decreased, indicating its good wetting performance. As Figure 12 shown, with the increase in the solid content, the content of the hydrophilic polymer betaine also increased, so its water absorption rate increased, which could, to a certain extent, inhibit the problem of volume shrinkage after the bone cement solidified.

[0066] As Figure 13 shown, with the increase in the content of HA - PSBMA, the bone cement surface contained more crystalline hydroxyapatite structures and had more excellent in - vitro bioactivity. In addition, with the increase in the content of modified hydroxyapatite, more pore structures appeared on the bone cement surface, which was beneficial to the colonization of capillaries.

[0067] The contents of the mRNAs of the pro - inflammatory cytokines iNOS and IL - 1 in the low - exothermic antibacterial and anti - inflammatory injectable bone cements in Examples 1 - 4 were detected by fluorescence quantitative polymerase chain reaction, and the results are shown in the following table:

[0068] Table 2 Contents of the mRNAs of iNOS and IL - 1 in the bone cements in Examples 1 - 4

[0069]

[0070]

[0071] As can be seen from Table 2, when the control group without bone cement was set as 100%, with the increase in the content of betaine - modified hydroxyapatite, the expression of the relevant mRNAs also decreased, indicating that the bone cement had good anti - inflammatory effects.

[0072] An antibacterial activity test was conducted on the low exothermic antibacterial and anti-inflammatory injectable bone cement in Examples 1-4. That is, the bone cement powder was soaked in deionized water for 24 h, the supernatant was extracted and mixed with the original Staphylococcus aureus bacterial solution in a culture medium, and they were co-cultured overnight in a shaker. After diluting the culture medium suspension, it was diffused onto an LB plate, and the number of bacterial colonies was detected after incubating at 37 °C for 24 h. The test results are shown in the following table:

[0073] Table 3 Number of bacterial colonies detected after co-culturing the bone cement in Examples 1-4 with Staphylococcus aureus

[0074] Experimental group Number of Staphylococcus aureus colonies Control group 230 Example 1 154 Example 2 92 Example 3 77 Example 4 35

[0075] As can be seen from Table 3, the bone cement has good antibacterial effects.

[0076] The above content is only an example and explanation of the structure of the present invention. Those skilled in the art of the present technology can make various modifications or supplements to the described specific embodiments or use similar methods for substitution, as long as they do not deviate from the structure of the present invention or exceed the scope defined by this claim book, they should fall within the protection scope of the present invention.

Claims

1. A preparation method of a low-heat-release antibacterial and anti-inflammatory injectable bone cement, characterized in that, It includes the following steps: (1) Double-bond modification of hydroxyapatite powder; (2) Grafting the double-bond modified hydroxyapatite with sulfobetaine by free radical polymerization to obtain betaine-modified hydroxyapatite; (3) Using the polymethyl methacrylate prepolymer solution as the liquid phase, and the betaine-modified hydroxyapatite and benzoyl peroxide mixed in a certain proportion as the solid phase. After adding an appropriate amount of N,N-dimethylaniline, stirring thoroughly until evenly mixed, and heating and curing to obtain the low exothermic antibacterial and anti-inflammatory injectable bone cement.

2. The preparation method of a low-heat-emitting antibacterial and anti-inflammatory injectable bone cement according to claim 1, characterized in that, The specific steps of step (1) include: dissolving hydroxyapatite, hexamethylene diisocyanate and dibutyltin dilaurate in anhydrous N,N-dimethylformamide, heating for a certain time under the conditions of condensation reflux and nitrogen protection; dissolving an appropriate amount of 2-hydroxyethyl methacrylate in N,N-dimethylformamide, injecting it into the above system, stirring overnight, centrifuging, washing with dichloromethane multiple times and collecting the powder, drying thoroughly, grinding and crushing with a mortar to obtain the double-bond modified hydroxyapatite, and its structural formula is:

3. The preparation method of a low heat-emitting antibacterial and anti-inflammatory injectable bone cement according to claim 2, characterized in that: The molar ratio of the hydroxyapatite, hexamethylene diisocyanate and 2-hydroxyethyl methacrylate is 1:1-3:3-10. The reaction temperature of the whole process is 40-60 °C, the heating time under the conditions of condensation reflux and nitrogen protection is 6-24 h, the drying temperature is 35-50 °C, and the drying time is 12-36 h.

4. The preparation method of a low heat-releasing antibacterial and anti-inflammatory injectable bone cement according to claim 1, wherein: In step (2), the double-bond modified hydroxyapatite, betaine monomer and azobisisobutyronitrile are dissolved in anhydrous dimethyl sulfoxide, frozen and degassed three times under nitrogen, and sealed by flame under vacuum, placed in an oil bath to react for a sufficient time and then cooled to terminate the reaction, washed with ethanol and deionized water multiple times respectively and collect the powder, dried and crushed to obtain the betaine-modified hydroxyapatite, and its structural formula is:

5. The preparation method of a low heat - releasing antibacterial and anti - inflammatory injectable bone cement according to claim 4, characterized in that: The molar ratio of the double-bond modified hydroxyapatite, betaine monomer and azobisisobutyronitrile is 1:2-5:0.1-0.

5. The oil bath reaction temperature is 65-85 °C, the reaction time is 48-72 h, the vacuum oven drying temperature is 50-70 °C, and the freezing temperature is -50 to -80 °C.

6. The preparation method of a low heat-emitting antibacterial and anti-inflammatory injectable bone cement according to claim 1, characterized in that, In step (3), the preparation of the polymethyl methacrylate prepolymer solution includes the following steps: heating the methyl methacrylate solution dissolved with an appropriate initiator in a water bath for a certain time, then stopping heating and cooling to terminate the reaction.

7. The preparation method of a low heat-emitting antibacterial and anti-inflammatory injectable bone cement according to claim 6, characterized in that: The initiator is benzoyl peroxide or azobisisobutyronitrile. The water bath heating temperature is 70-90 °C, the water bath heating time is 15-30 min, the mass of the initiator is 0.5%-1.5% of the mass of the polymethyl methacrylate prepolymer solution, and the cooling temperature is 0-10 °C.

8. The preparation method of a low heat-releasing antibacterial and anti-inflammatory injectable bone cement according to claim 1, characterized in that: In step (3), the mass ratio of the liquid phase to the solid phase is 1:0.05-0.

5. The mass of benzoyl peroxide is 0.2%-2% of the mass of the polymethyl methacrylate prepolymer solution. The mass of N,N-dimethylaniline is 1%-3% of the mass of the polymethyl methacrylate prepolymer solution. The heating temperature is 36-37 °C, and the demolding time is 15-60 min after mixing.

9. A low exothermic antibacterial and anti-inflammatory injectable bone cement prepared by the preparation method of the low exothermic antibacterial and anti-inflammatory injectable bone cement according to any one of claims 1-8.

10. Use of a low exothermic antibacterial and anti-inflammatory injectable bone cement according to claim 9 in the preparation of an implant material for treating osteomyelitis.

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