Bone cement composition and application thereof

Abstract

The invention discloses a bone cement composition and application thereof, and relates to the technical field of bone cement. The bone cement composition comprises a solid phase component and a liquid phase component, wherein the solid phase component comprises 60-75 parts of composite calcium phosphate, 10-20 parts of strontium glass powder, 8-12 parts of a reinforcing agent and 3-7 parts of a solidification reaction regulator; the liquid phase component comprises 20-30 parts of a phosphate buffer solution, 3-8 parts of a sodium citrate solution, 5-15 parts of an anti-inflammatory agent and 1-5 parts of a hyaluronic acid solution. The preparation method comprises the following steps: reacting 1, 10-phenanthrene-2, 9-dicarboxylic acid with 2-aminomethyl furan to obtain an intermediate 1, and reacting the intermediate 1 with poly (ethylene glycol) maleimide to prepare the reinforcing agent. The prepared bone cement composition has good mechanical properties, self-repairing performance and anti-inflammatory performance, and has a good application prospect in the field of bone repairing.

Description

Technical Field

[0001] The present invention relates to the technical field of bone cement, and in particular to a bone cement composition and application thereof. Background Art

[0002] Bone cement is a key material used in orthopedic surgery to fill bone defects, fix implants, or strengthen vertebral bodies. Currently, polymethyl methacrylate (PMMA) bone cement and calcium phosphate bone cement are the most widely used in clinical practice. PMMA bone cement offers advantages such as high mechanical strength and rapid curing, but it also suffers from bioinertness, high exotherm temperature, and elastic modulus mismatch. Calcium phosphate bone cement is gradually replacing PMMA due to its biodegradability and osteoconductivity, but its inherent brittleness and insufficient mechanical strength limit its application in load-bearing bone repair. Furthermore, traditional calcium phosphate bone cement lacks active osteoinduction and anti-inflammatory properties, resulting in a slow rate of bone integration.

[0003] Chinese invention patent publication number CN112533651A discloses a bone cement composition comprising a powder component comprising at least one acrylic polymer, a liquid component comprising a monomer, an antibiotic, and an acid-functionalized polymer, wherein the powder component and the liquid component react to form bone cement. The bone cement formed from this bone cement composition exhibits good antimicrobial activity and compression modulus, but its anti-inflammatory properties remain insufficient. Summary of the Invention

[0004] In view of the deficiencies in the prior art, the present invention aims to provide a bone cement composition and application thereof.

[0005] To achieve the above object, the present invention is implemented through the following technical solutions: A bone cement composition comprising a solid phase component and a liquid phase component; The solid phase component includes the following components in parts by weight: 60-75 parts of composite calcium phosphate salt, 10-20 parts of strontium glass powder, 8-12 parts of reinforcing agent, and 3-7 parts of setting reaction regulator; The liquid phase components include the following components in parts by weight: 20-30 parts of phosphate buffer, 3-8 parts of sodium citrate solution, 5-15 parts of anti-inflammatory agent, and 1-5 parts of hyaluronic acid solution.

[0006] The enhancer is prepared by the following method: S1: Under nitrogen protection, 1,10-phenanthroline-2,9-dicarboxylic acid was mixed with DMF, and activated by adding 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N-hydroxysuccinimide, and triethylamine. 2-Aminomethylfuran was then added in batches and reacted at 25-30°C for 8-9 h to obtain intermediate 1. S2: Under nitrogen, mix Intermediate 1, poly(ethylene glycol) maleimide, and anhydrous toluene and react at 100-110°C for 13-14 hours to obtain the enhancer. In this step, the carbon-carbon double bond of the furan ring in Intermediate 1 undergoes a Diels-Alder reaction with the carbon-carbon double bond of poly(ethylene glycol) maleimide.

[0007] In step S1, the molar ratio of 1,10-phenanthroline-2,9-dicarboxylic acid to 2-aminomethylfuran is 1:(2.1-2.3).

[0008] In step S2, the molar ratio of the intermediate 1 to poly(ethylene glycol)maleimide is 1:(2.05-2.2).

[0009] The anti-inflammatory agent is prepared by the following method: N1: Under nitrogen protection, 5-oxopentanoic acid, dicyclohexylcarbodiimide, 4-dimethylaminopyridine and anhydrous DMF were mixed and activated, and curcumin was added in batches. The reaction was carried out at 80-95°C for 6-8h to obtain intermediate A; N2: Under nitrogen protection, the intermediate A, 4-aminophenylphosphorylcholine, anhydrous ethanol and PBS buffer were mixed evenly, and the mixture was reacted at 35-40° C. for 10-12 h to obtain the anti-inflammatory agent.

[0010] In step N1, the molar ratio of curcumin to 5-oxopentanoic acid is 1:(2.1-2.3).

[0011] In step N2, the molar ratio of the intermediate A to 4-aminophenylphosphorylcholine is 1:(2.05-2.2).

[0012] The composite calcium phosphate salt includes α-tricalcium phosphate and tetracalcium phosphate, wherein the α-tricalcium phosphate accounts for 70% by weight and the tetracalcium phosphate accounts for 30% by weight; the coagulation reaction regulator is one of calcium hydrogen phosphate and calcium carbonate; the concentration of the sodium citrate solution is 0.1M; and the concentration of the hyaluronic acid solution is 0.2w / v%.

[0013] A bone cement composition is prepared by the following steps: (1) Weigh by weight: 60-75 parts of composite calcium phosphate salt, 10-20 parts of strontium glass powder, 8-12 parts of enhancer, 3-7 parts of coagulation reaction regulator, 20-30 parts of phosphate buffer, 3-8 parts of sodium citrate solution, 5-15 parts of anti-inflammatory agent, and 1-5 parts of hyaluronic acid solution; (2) mixing the composite calcium phosphate, strontium glass powder, reinforcing agent and setting reaction regulator in a three-dimensional mixer to obtain a solid phase component; (3) Mixing the phosphate buffer solution, sodium citrate solution, anti-inflammatory agent and hyaluronic acid solution, and degassing by ultrasonication to obtain a liquid phase component; (4) The solid phase component and the liquid phase component are mixed evenly in a mass ratio of 2:1 and stirred to obtain a bone cement composition.

[0014] Due to the adoption of the above technical solution, the beneficial effects of the present invention include: (1) The reinforcing agent prepared by the present invention combines the aromatic ring rigid core, the Diels-Alder dynamic bond and the oligoether flexible chain to form a rigid-dynamic-flexible synergistic structure, which can simultaneously improve the rigidity and toughness of the bone cement composition, thereby improving the mechanical properties of the bone cement composition, and can also give the bone cement composition a certain self-repair ability and enhance fatigue resistance.

[0015] (2) The anti-inflammatory agent prepared by the present invention comprises a curcumin anti-inflammatory core-pH sensitive Schiff base bond-phosphorylcholine structure, which can improve the anti-inflammatory properties and interfacial binding ability of the bone cement composition and achieve a long-lasting sustained-release anti-inflammatory effect. DETAILED DESCRIPTION

[0016] The present invention will be further described below with reference to the embodiments, but the present invention is not limited to these embodiments.

[0017] Example 1 Preparation of Enhancer: S1: Under nitrogen protection, 0.1 mol of 1,10-phenanthroline-2,9-dicarboxylic acid was added to 400 ml of DMF at room temperature and stirred. 0.21 mol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 0.2 mol of N-hydroxysuccinimide, and 0.2 mol of triethylamine were added. After activation for 45 min, 0.21 mol of 2-aminomethylfuran was added (equally added in 3 batches with a batch interval of 10 min). The reaction was carried out at 25°C for 9 h. The mixture was poured into 800 ml of ice water and filtered. The filter cake was washed with deionized water (3 × 200 ml) and purified by silica gel column chromatography (eluent: dichloromethane / methanol V / V = 10:1) and rotary evaporation at 60°C for 5 h to obtain intermediate 1. The reaction equation is as follows:

[0018] Its H-NMR spectrum data are as follows: 1 H NMR (500 MHz, DMSO- d 6) δ 9.22 (s, 2H), 8.35 (d, J = 0.5 Hz, 2H), 8.10 (s, 2H), 8.05 (d, J = 0.6 Hz, 2H), 7.46 (s, 2H), 6.32 (s, 2H), 6.24 (s,2H), 4.49 (d, J = 0.5 Hz, 4H).

[0019] S2: Under nitrogen protection, 0.1 mol of intermediate 1 and 0.205 mol of poly(ethylene glycol)maleimide were added to 500 ml of anhydrous toluene, stirred and mixed, and reacted at 100°C for 14 h. After the reaction, the residue was rotary evaporated at 60°C for 4 h, and the residue was dissolved in 1000 ml of anhydrous ethanol / water (anhydrous ethanol:water volume ratio of 3:1). The residue was dialyzed against deionized water (molecular weight cutoff 1000 Da) for 48 h (the water was changed every 6 hours, with 2000 ml changed each time), and freeze-dried at -50°C for 24 h to obtain the enhancer. The reaction equation is shown below:

[0020] Example 2 Preparation of Enhancer: S1: Under nitrogen protection, 0.1 mol of 1,10-phenanthroline-2,9-dicarboxylic acid was added to 400 ml of DMF at room temperature and stirred. 0.21 mol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 0.2 mol of N-hydroxysuccinimide, and 0.2 mol of triethylamine were added. After activation for 45 min, 0.22 mol of 2-aminomethylfuran was added (equally added in 3 batches with a batch interval of 10 min). The reaction was carried out at 30°C for 8 h. The mixture was poured into 800 ml of ice water and filtered. The filter cake was washed with deionized water (3 × 200 ml) and purified by silica gel column chromatography (eluent: dichloromethane / methanol V / V = 10:1) and rotary evaporation at 60°C for 5 h to obtain intermediate 1. S2: Under nitrogen protection, 0.1 mol of intermediate 1 and 0.21 mol of poly(ethylene glycol)maleimide were added to 500 ml of anhydrous toluene, stirred and mixed, reacted at 110°C for 13 h, and rotary evaporated at 60°C for 4 h. The residue was dissolved in 1000 ml of anhydrous ethanol / water (anhydrous ethanol to water volume ratio of 3:1), dialyzed against deionized water (molecular weight cutoff 1000 Da) for 48 h (the water was changed every 6 hours, 2000 ml each time), and freeze-dried at -50°C for 24 h to obtain the enhancer.

[0021] Example 3 Preparation of Enhancer: S1: Under nitrogen protection, 0.1 mol of 1,10-phenanthroline-2,9-dicarboxylic acid was added to 400 ml of DMF at room temperature and stirred. 0.21 mol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 0.2 mol of N-hydroxysuccinimide, and 0.2 mol of triethylamine were added. After activation for 45 min, 0.23 mol of 2-aminomethylfuran was added (equally added in 3 batches with a batch interval of 10 min). The reaction was carried out at 30°C for 8 h. The mixture was poured into 800 ml of ice water and filtered. The filter cake was washed with deionized water (3 × 200 ml) and purified by silica gel column chromatography (eluent: dichloromethane / methanol V / V = 10:1) and rotary evaporation at 60°C for 5 h to obtain intermediate 1. S2: Under nitrogen protection, 0.1 mol of intermediate 1 and 0.22 mol of poly(ethylene glycol)maleimide were added to 500 ml of anhydrous toluene, stirred and mixed, and reacted at 110°C for 13 h. After the reaction, the residue was rotary evaporated at 60°C for 4 h, and the residue was dissolved in 1000 ml of anhydrous ethanol / water (anhydrous ethanol:water volume ratio of 3:1). The residue was dialyzed against deionized water (molecular weight cutoff 1000 Da) for 48 h (the water was changed every 6 hours, with 2000 ml changed each time), and freeze-dried at -50°C for 24 h to obtain the enhancer.

[0022] Example 4 Preparation of anti-inflammatory agent: N1: Under nitrogen protection, 0.21 mol of 5-oxopentanoic acid, 0.21 mol of dicyclohexylcarbodiimide and 0.04 mol of 4-dimethylaminopyridine were added to 300 ml of anhydrous DMF, stirred and mixed, activated at room temperature for 45 min, and 0.1 mol of curcumin was added in batches (three equal batches, with an interval of 10 min between each batch). After reacting at 80°C for 8 h, the mixture was filtered, and the filtrate was rotary evaporated at 65°C for 3 h. The filtrate was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate V / V = 1:2) and rotary evaporated at 50°C for 2 h to obtain intermediate A. The reaction equation is as follows:

[0023] Its H-NMR spectrum data are as follows: 1 H NMR (500 MHz, DMSO- d6) δ 9.59 (s, 2H), 7.52 (t, J = 0.9 Hz, 2H), 7.37 (dd, J = 2.0, 1.0 Hz, 2H), 7.27 (ddd, J = 7.5, 1.9, 0.9 Hz, 2H), 7.23(d, J = 7.5 Hz, 2H), 7.00 (s, 2H), 3.96 (d, J = 12.4 Hz, 2H), 3.87 (s, 6H), 2.58 (s, 4H), 2.54 (s, 4H), 1.79 (s, 4H).

[0024] N2: Under nitrogen protection, 0.1 mol of intermediate A, 0.205 mol of 4-aminophenylphosphorylcholine, 450 ml of anhydrous ethanol and 150 ml of PBS buffer (PBS buffer concentration: 0.1 M, pH 7.2) were mixed and reacted at 35°C for 12 h. After cooling to room temperature, the reaction solution was transferred to a dialysis bag (molecular weight cutoff: 1000 Da) and dialyzed for 24 h (the solution was changed every 6 hours, 2000 ml each time, the first two dialysis were performed with 0.1 M, pH 7.2 PBS buffer, and the last two dialysis were performed with deionized water). The anti-inflammatory agent was then freeze-dried at -50°C for 24 h to obtain the anti-inflammatory agent. The reaction equation is shown below:

[0025] Its H-NMR spectrum data are as follows: 1 H NMR (500 MHz, DMSO- d 6) δ 7.52 (t, J = 0.9 Hz, 2H), 7.37 (dd, J =2.0, 1.0 Hz, 2H), 7.36 (s, 2H), 7.35-7.32 (m, 4H), 7.30-7.21 (m, 4H), 7.17-7.11 (m, 4H), 7.00 (s, 2H), 6.30 (s, 2H), 4.26 (s, 4H), 3.96 (d, J = 12.4 Hz,2H), 3.87 (s, 6H), 3.60 (s, 4H), 3.21 (s, 18H), 2.58 (s, 4H), 2.21 (s, 4H), 1.74 (s, 4H).

[0026] Example 5 Preparation of anti-inflammatory agent: N1: Under nitrogen protection, 0.22 mol of 5-oxopentanoic acid, 0.22 mol of dicyclohexylcarbodiimide, and 0.04 mol of 4-dimethylaminopyridine were added to 300 ml of anhydrous DMF, stirred and mixed, activated at room temperature for 45 min, and 0.1 mol of curcumin was added in batches (three equal batches, with an interval of 10 min between each batch). After reacting at 90°C for 7 h, the mixture was filtered, and the filtrate was rotary evaporated at 65°C for 3 h. The filtrate was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate V / V = 1:2) and rotary evaporated at 50°C for 2 h to obtain intermediate A; N2: Under nitrogen protection, 0.1 mol of intermediate A, 0.21 mol of 4-aminophenylphosphorylcholine, 450 ml of anhydrous ethanol and 150 ml of PBS buffer (PBS buffer concentration is 0.1 M, pH is 7.2) were mixed, reacted at 35°C for 12 h, cooled to room temperature, and the reaction solution was transferred to a dialysis bag (molecular weight cutoff 1000 Da) and dialyzed for 24 h (the solution was changed every 6 hours, 2000 ml each time, the first two times were dialyzed with 0.1 M, pH 7.2 PBS buffer, and the last two times were dialyzed with deionized water), and freeze-dried at -50°C for 24 h to obtain an anti-inflammatory agent.

[0027] Example 6 Preparation of anti-inflammatory agent: N1: Under nitrogen protection, 0.23 mol of 5-oxopentanoic acid, 0.22 mol of dicyclohexylcarbodiimide, and 0.04 mol of 4-dimethylaminopyridine were added to 300 ml of anhydrous DMF, stirred and mixed, activated at room temperature for 40 min, and 0.1 mol of curcumin was added in batches (three equal batches, with an interval of 10 min between each batch). After reacting at 95°C for 6 h, the mixture was filtered, and the filtrate was rotary evaporated at 65°C for 3 h. The filtrate was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate V / V = 1:2) and rotary evaporated at 50°C for 2 h to obtain intermediate A; N2: Under nitrogen protection, 0.1 mol of intermediate A, 0.22 mol of 4-aminophenylphosphorylcholine, 450 ml of anhydrous ethanol and 150 ml of PBS buffer (PBS buffer concentration is 0.1 M, pH is 7.2) were mixed and reacted at 40°C for 10 h. After the reaction, the mixture was cooled to room temperature and transferred to a dialysis bag (molecular weight cutoff 1000 Da). The mixture was dialyzed for 24 h (the solution was changed every 6 hours, 2000 ml each time, the first two times were dialyzed with 0.1 M, pH 7.2 PBS buffer, and the last two times were dialyzed with deionized water). The mixture was freeze-dried at -50°C for 24 h to obtain an anti-inflammatory agent.

[0028] Example 7 Preparation of bone cement composition: (1) Weigh by weight: 60 g of composite calcium phosphate (42 g of α-tricalcium phosphate, 18 g of tetracalcium phosphate), 10 g of strontium glass powder, 8 g of enhancer (prepared in Example 1), 3 g of coagulation regulator (calcium hydrogen phosphate), 20 g of phosphate buffer, 3 g of sodium citrate solution, 5 g of anti-inflammatory agent (prepared in Example 4), and 1 g of hyaluronic acid solution; (2) The composite calcium phosphate, strontium glass powder, reinforcing agent and setting reaction regulator were mixed in a three-dimensional mixer at 60 rpm for 2 h to obtain a solid phase component; (3) Mix the phosphate buffer, sodium citrate solution, anti-inflammatory agent and hyaluronic acid solution, and degas under 20 kHz ultrasonication for 10 minutes to obtain a liquid phase component; (4) The solid phase component and the liquid phase component were mixed in a mass ratio of 2:1 and stirred for 5 minutes to obtain a bone cement composition.

[0029] Example 8 Preparation of bone cement composition: (1) Weigh by weight: 70 g of composite calcium phosphate (49 g of α-tricalcium phosphate and 21 g of tetracalcium phosphate), 15 g of strontium glass powder, 10 g of a reinforcing agent (prepared in Example 2), 5 g of a coagulation regulator (calcium carbonate), 25 g of a phosphate buffer solution, 5 g of a sodium citrate solution, 10 g of an anti-inflammatory agent (prepared in Example 5), and 3 g of a hyaluronic acid solution; (2) The composite calcium phosphate, strontium glass powder, reinforcing agent and setting reaction regulator were mixed in a three-dimensional mixer at 60 rpm for 2 h to obtain a solid phase component; (3) Mix the phosphate buffer, sodium citrate solution, anti-inflammatory agent and hyaluronic acid solution, and degas under 20 kHz ultrasonication for 10 minutes to obtain a liquid phase component; (4) The solid phase component and the liquid phase component were mixed in a mass ratio of 2:1 and stirred for 5 minutes to obtain a bone cement composition.

[0030] Example 9 Preparation of bone cement composition: (1) Weigh by weight: 75 g of composite calcium phosphate (52.5 g of α-tricalcium phosphate and 22.5 g of tetracalcium phosphate), 20 g of strontium glass powder, 12 g of a reinforcing agent (prepared in Example 3), 7 g of a coagulation regulator (calcium hydrogen phosphate), 30 g of a phosphate buffer solution, 8 g of a sodium citrate solution, 15 g of an anti-inflammatory agent (prepared in Example 6), and 5 g of a hyaluronic acid solution; (2) The composite calcium phosphate, strontium glass powder, reinforcing agent and setting reaction regulator were mixed in a three-dimensional mixer at 60 rpm for 2 h to obtain a solid phase component; (3) Mix the phosphate buffer, sodium citrate solution, anti-inflammatory agent and hyaluronic acid solution, and degas under 20 kHz ultrasonication for 10 minutes to obtain a liquid phase component; (4) The solid phase component and the liquid phase component were mixed in a mass ratio of 2:1 and stirred for 5 minutes to obtain a bone cement composition.

[0031] Comparative Example 1 The raw material composition and preparation method of the bone cement composition are basically the same as those of Example 8, except that no reinforcing agent is added to the composition.

[0032] Comparative Example 2 The raw material composition and preparation method of the bone cement composition are basically the same as those of Example 8, except that no anti-inflammatory agent is added to the composition.

[0033] Comparative Example 3 The raw material composition and preparation method of the bone cement composition are substantially the same as those of Example 8, except that the reinforcing agent is replaced by an equal weight of a reinforcing agent prepared by the following method: The preparation method of the enhancer is substantially the same as that of Example 2, except that the 1,10-phenanthroline-2,9-dicarboxylic acid in step S1 is replaced by an equimolar amount of phthalic acid.

[0034] Comparative Example 4 The raw material composition and preparation method of the bone cement composition are substantially the same as those of Example 8, except that the reinforcing agent is replaced by an equal weight of a reinforcing agent prepared by the following method: The preparation method of the enhancer is basically the same as that of Example 2, except that the poly(ethylene glycol)maleimide in step S2 is replaced by an equimolar amount of N-(2-hydroxyethyl)maleimide.

[0035] Comparative Example 5 The raw material composition and preparation method of the bone cement composition are basically the same as those of Example 8, except that the anti-inflammatory agent is replaced by an equal weight of the intermediate A prepared in Example 5.

[0036] Comparative Example 6 The raw material composition and preparation method of the bone cement composition are basically the same as those of Example 8, except that the anti-inflammatory agent is replaced by an equal weight of an anti-inflammatory agent prepared by the following method: The preparation method of the anti-inflammatory agent is basically the same as that of Example 5, except that the 5-oxopentanoic acid in step N1 is replaced by 0.105 mol of 5-oxopentanoic acid.

[0037] The strontium glass powder used in the Examples and Comparative Examples of this application is QZ-0020, produced by Jiangsu Qiuzheng New Materials Technology Co., Ltd.; the number-average molecular weight of hyaluronic acid is 10 kDa; the number-average molecular weight of poly(ethylene glycol) maleimide is 625 Da. The phosphate buffer used in Examples 7-9 and Comparative Examples of this application has a concentration of 0.2 M and a pH of 7.2; the sodium citrate solution has a concentration of 0.1 M and a pH of 6.5; and the hyaluronic acid solution has a concentration of 0.2 w / v%.

[0038] Preparation of phosphate buffer (0.2 M, pH 7.2): Weigh 35.814 g of disodium hydrogen phosphate dodecahydrate (Na2HPO4·H2O) and 13.609 g of potassium dihydrogen phosphate (KH2PO4), dissolve each in 400 ml of deionized water, combine and transfer to a 1000 ml volumetric flask after complete dissolution, dilute to 1-2 cm below the scale with deionized water, shake well, adjust the pH to 7.20 ± 0.02 with 1 M NaOH or HCl, and finally dilute to 1000 ml to obtain 0.2 M phosphate buffer with a pH of 7.2.

[0039] The bone cement compositions prepared in Examples 7-9 and Comparative Examples 1-6 were tested for compressive strength, self-repairing properties, and anti-inflammatory properties. The test results are shown in Table 1.

[0040] The compressive strength test of the bone cement composition was conducted with reference to the YY 0459-2003 standard. The compressive strength test was conducted using a universal testing machine at a loading speed of 20 mm / min. The sample was kept at 23° C. for 24 h before the test.

[0041] Preparation of compressive strength test specimens: 100 g of bone cement prepared in the comparative example and the example were poured into a polytetrafluoroethylene cylindrical mold, cured at 37° C. for 1 h, and demolded to obtain specimens (specimen size: 6 mm in diameter, 12 mm in length).

[0042] Specimen destruction test: A damaged incision (0.5 mm deep, 10 mm long) was made in the center of the gauge section of the specimen using a blade. The specimen was then immersed in 50 ml of PBS buffer at 37°C, 0.1 M, pH 7.4 for 24 h to obtain the repaired bone cement.

[0043] The anti-inflammatory properties of the bone cement composition were determined by macrophage inflammatory factor inhibition experiment and characterized by inflammatory factor inhibition rate.

[0044] Sample preparation: 100 g of the bone cement compositions prepared in Comparative Examples 7-9 and Examples 1-6 were poured into a polytetrafluoroethylene cylindrical mold, cured at 37°C for 1 h, and demolded to obtain samples (sample size: 6 mm diameter, 12 mm length); the bone cement composition of Comparative Example 2 was used as a control.

[0045] The samples were sterilized by irradiation with γ-rays at a dose of 15 kGy. The sterile samples were placed in a 96-well plate and sterilized at a dose of 5 × 10 3 RAW264.7 cells were inoculated at a concentration of 100 cells / ml (before cell inoculation, RAW264.7 was placed in a 75 cm 2 The cells were cultured in flasks at 95% humidity, 37°C, and 5% CO2 for expansion. Fresh complete medium was replaced every other day. The culture medium used during the culture process consisted of 90 vol.% H-DMEM and 10 vol.% FBS. The RAW264.7 cells inoculated in the experiment were cells of passages 3-6. After 3 days of culture, the cells growing on the specimens were dissociated using 0.25 wt.% trypsin / EDTA and then centrifuged at 1000 rpm for 5 min. The cells were blocked with 1 wt.% BSA in PBS for 30 min and rinsed three times with PBS. Diluted CD11c (eBioscience) and CD206 (eBioscience) antibodies were added and incubated at room temperature for 10 min. The cells were then rinsed three times with PBS. The cells were placed in serum-free DMEM medium (containing 1 wt.% penicillin-streptomycin) and 1 μg / ml lipopolysaccharide (E. coli) was added. Inflammation was induced in the presence of O111:B4 for 2 h, and a blank control group (medium only) and a lipopolysaccharide control group (lipopolysaccharide + medium) were set up. After 24 h of culture, the supernatant was collected, and TNF-α and IL-6 concentrations were measured using ELISA kits. The inflammatory factor inhibition rate = (lipopolysaccharide control group concentration - experimental group concentration) / lipopolysaccharide control group concentration × 100%.

[0046] Table 1

[0047] It can be seen from Table 1 that the bone cement compositions prepared in Examples 7-9 of the present application have excellent compressive strength, self-repairing properties and anti-inflammatory properties.

[0048] As can be seen from Table 1, when no reinforcing agent is added in Comparative Example 1, the tensile and compressive strength and self-repair performance of the bone cement composition prepared therefrom are poor. When no anti-inflammatory agent is added in Comparative Example 2, the inflammatory factor inhibition rate is significantly lower than that of the embodiment.

[0049] The compressive strength of the bone cement composition prepared in Comparative Example 3 is worse than that in Example 1, mainly because the rigid structure of the phthalic acid used is worse than that of 1,10-phenanthroline-2,9-dicarboxylic acid, resulting in a decrease in the rigidity of the reinforcing agent, thereby reducing the compressive strength of the bone cement composition.

[0050] The compressive strength of the bone cement composition prepared in Comparative Example 4 is worse than that in Example 1, mainly because the N-(2-hydroxyethyl)maleimide used has a short-chain structure and lacks a polyethylene glycol segment structure, which increases the brittleness of the prepared reinforcing agent and leads to a decrease in the compressive strength of the bone cement composition.

[0051] The anti-inflammatory performance of the bone cement composition prepared in Example 5 is lower than that of Example 1, mainly because the anti-inflammatory agent is replaced by an equal weight of intermediate A, and the pH-sensitive Schiff base bond and phosphorylcholine structure are missing in the anti-inflammatory agent molecule, resulting in a weakening of the long-acting sustained-release anti-inflammatory effect, thereby reducing the anti-inflammatory performance.

[0052] The anti-inflammatory performance of the bone cement composition prepared in Comparative Example 6 is lower than that in Example 6 because the prepared anti-inflammatory agent contains only one aldehyde group, the Schiff base sites are reduced, and the drug loading of the anti-inflammatory agent is reduced, resulting in a decrease in anti-inflammatory performance.

[0053] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. However, any equivalent changes, modifications and evolutions made by ordinary technicians in this field without departing from the scope of the technical solution of the present invention by using the technical content disclosed above are all equivalent embodiments of the present invention. At the same time, any equivalent changes, modifications and evolutions made to the above embodiments based on the essential technology of the present invention are still within the scope of protection of the technical solution of the present invention.

Claims

1. A bone cement composition, characterized in that including solid phase components and liquid phase components; The solid phase component includes the following components in parts by weight: 60-75 parts of composite calcium phosphate salt, 10-20 parts of strontium glass powder, 8-12 parts of reinforcing agent, and 3-7 parts of setting reaction regulator; The liquid phase components include the following components in parts by weight: 20-30 parts of phosphate buffer, 3-8 parts of sodium citrate solution, 5-15 parts of anti-inflammatory agent, and 1-5 parts of hyaluronic acid solution.

2. A bone cement composition according to claim 1, characterized in that, The enhancer is prepared by the following method: S1: Under nitrogen protection, 1,10-phenanthroline-2,9-dicarboxylic acid was mixed with DMF, and activated by adding 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N-hydroxysuccinimide, and triethylamine. 2-Aminomethylfuran was then added in batches and reacted at 25-30°C for 8-9 h to obtain intermediate 1. S2: Under nitrogen protection, the intermediate 1, poly (ethylene glycol) maleimide and anhydrous toluene were mixed and reacted at 100-110° C. for 13-14 h to obtain the enhancer.

3. A bone cement composition according to claim 2, characterized in that, In step S1, the molar ratio of 1,10-phenanthroline-2,9-dicarboxylic acid to 2-aminomethylfuran is 1:(2.1-2.3).

4. A bone cement composition according to claim 2, characterized in that, In step S2, the molar ratio of the intermediate 1 to poly(ethylene glycol)maleimide is 1:(2.05-2.2).

5. A bone cement composition according to claim 1, characterized in that, The anti-inflammatory agent is prepared by the following method: N1: Under nitrogen protection, 5-oxopentanoic acid, dicyclohexylcarbodiimide, 4-dimethylaminopyridine and anhydrous DMF were mixed and activated, and curcumin was added in batches. The reaction was carried out at 80-95°C for 6-8h to obtain intermediate A; N2: Under nitrogen protection, the intermediate A, 4-aminophenylphosphorylcholine, anhydrous ethanol and PBS buffer were mixed evenly, and the mixture was reacted at 35-40° C. for 10-12 h to obtain the anti-inflammatory agent.

6. A bone cement composition according to claim 5, characterized in that, In step N1, the molar ratio of curcumin to 5-oxopentanoic acid is 1:(2.1-2.3).

7. A bone cement composition according to claim 5, characterized in that, In step N2, the molar ratio of the intermediate A to 4-aminophenylphosphorylcholine is 1:(2.05-2.2).

8. A bone cement composition according to claim 1, characterized in that, The composite calcium phosphate salt includes α-tricalcium phosphate and tetracalcium phosphate, wherein the α-tricalcium phosphate accounts for 70% by weight and the tetracalcium phosphate accounts for 30% by weight; the coagulation reaction regulator is one of calcium hydrogen phosphate and calcium carbonate; the concentration of the sodium citrate solution is 0.1M; and the concentration of the hyaluronic acid solution is 0.2w / v%.

9. The bone cement composition according to any one of claims 1 to 8, characterized in that Prepared by the following steps: (1) Weigh by weight: 60-75 parts of composite calcium phosphate salt, 10-20 parts of strontium glass powder, 8-12 parts of enhancer, 3-7 parts of coagulation reaction regulator, 20-30 parts of phosphate buffer, 3-8 parts of sodium citrate solution, 5-15 parts of anti-inflammatory agent, and 1-5 parts of hyaluronic acid solution; (2) mixing the composite calcium phosphate, strontium glass powder, reinforcing agent and setting reaction regulator in a three-dimensional mixer to obtain a solid phase component; (3) Mixing the phosphate buffer solution, sodium citrate solution, anti-inflammatory agent and hyaluronic acid solution, and degassing by ultrasonication to obtain a liquid phase component; (4) The solid phase component and the liquid phase component are mixed evenly in a mass ratio of 2:1 and stirred to obtain a bone cement composition.

10. Use of the bone cement composition according to claims 1 to 8 in bone repair.

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