Temperature-responsive pulsed long-acting degradable calcium phosphate bone cement and preparation method thereof

Abstract

The present invention discloses a temperature-responsive pulsed long-acting degradable calcium phosphate bone cement, which is formed by mixing a solid phase and a liquid phase. The solid phase includes anhydrous calcium dihydrogen phosphate, β-tricalcium phosphate and a water-soluble curcumin-glucose pore former. The liquid phase includes citric acid, hyaluronic acid and a sorbitol-gelatin temperature-responsive composite microsphere loaded with salicylic acid. The present invention also discloses a preparation method of the bone cement, specifically: mixing β-tricalcium phosphate, anhydrous calcium dihydrogen phosphate and the water-soluble curcumin-glucose pore former, adding the sorbitol-gelatin temperature-responsive composite microsphere loaded with salicylic acid to obtain the solid phase of the bone cement; mixing hyaluronic acid and citric acid to obtain the liquid phase of the bone cement; mixing the solid phase and the liquid phase and curing to obtain the bone cement. Through the stimulation of the change in human oral temperature, a large amount of salicylic acid is released in a short period of time, etching the matrix of the calcium phosphate bone cement, thereby improving the degradation rate, realizing pulsed long-acting degradation, and achieving a degradation cycle that matches human bone healing.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedical material preparation, and in particular relates to temperature-responsive pulse-type long-acting degradable calcium phosphate bone cement, and also relates to a preparation method of temperature-responsive pulse-type long-acting degradable calcium phosphate bone cement. Background Art

[0002] Before artificial tooth implantation, biomedical materials need to be filled in the alveolar bone defect to support the implant. After implantation, the space-occupying materials gradually degrade to provide space for new bone growth. At present, the biomedical materials used for alveolar bone defect repair are mainly organic biopolymer materials and inorganic bioceramic materials. Organic biopolymer materials are mainly polyetheretherketone, which has good adhesion to soft tissue, but is non-degradable and has poor osteogenic activity, thus affecting the formation of new bone. Inorganic bioceramic materials are mainly calcium phosphate bioceramic materials, which have excellent biocompatibility and osteoconductivity, and are injectable, which makes it possible for their application in minimally invasive alveolar bone repair surgery. However, the degradation rate of calcium phosphate bone cement is low, and the degradation cycle does not match the new bone growth cycle. At present, the degradation performance of calcium phosphate bone cement is mainly improved by regulating the composition and modifying the structure, but the degradation rate is only about 25%, and the degradation cycle has not yet reached the sustainable degradation requirement of alveolar bone filling materials for about 3 to 6 months, which will affect the growth of new bone and slow down the speed of bone defect repair in patients. Therefore, significantly improving the degradation rate of injectable calcium phosphate bone cement implant materials and matching the degradation and osteogenesis cycles have become one of the current research focuses in this field.

[0003] A Chinese patent (application number: CN201610063506.6, publication number CN105561386A, publication date 2016-01-29) discloses a method for preparing a porous hydroxyapatite / calcium pyrophosphate composite bone repair material, wherein the formation of hydroxyapatite is inhibited by adding a mineralization inhibitor, calcium pyrophosphate, to the solid phase, and 10 to 30% of pores are obtained by adding an ammonium bicarbonate pore former. The degradation rate after 42 days is only 0.25%, and the cumulative degradation rate is low, so that the degradation requirement of the calcium phosphate bone cement material cannot be met, thereby inhibiting the growth of new bone.

[0004] A Chinese patent (application number: CN201810068344.4, publication number: CN108114323A, publication date 2018-01-24) discloses a method for preparing a rapidly degradable injectable brushite bone cement, which accelerates the degradation rate of calcium phosphate bone cement by adding glycerol to the liquid phase and changes the liquid phase components of calcium phosphate bone cement to accelerate degradation. The degradation rate in 30 days is 10%, and the degradation cycle cannot match the human bone healing cycle, which is not conducive to the patient's recovery.

[0005] Chinese Patent (Application No.: CN201410168136.3, Publication No.: CN104056305A, Publication Date: April 24, 2014) discloses a calcium phosphate-based composite self-setting bone repair material and its preparation method. By combining the rapidly degradable and osteoconductive brushite cement with the hydroxyapatite cement with good mechanical properties, the degradation rate is improved. However, only by changing the composition of the cement and adding brushite to increase solubility and promote degradation, the degradation rate reaches about 15% in 14 days, and the low degradation rate cannot provide enough growth space for the growth of new bone.

[0006] Chinese Patent (Application No.: CN201810068344.4, Publication No.: CN108114323A, Publication Date: January 24, 2018) discloses a porous injectable calcium phosphate cement composite. Using chondroitin sulfate particles as porogens and mixing them evenly with solid-phase calcium phosphate cement, the porosity of the prepared cement reaches about 60%, forming good pore connectivity. However, it only relies on increasing the contact surface area between body fluid and calcium phosphate cement to promote degradation. After the rapid degradation of chondroitin sulfate, the degradation rate of the cement decreases, and the degradation process is not continuous, resulting in too long a degradation period, so it cannot match the bone repair period.

[0007] Although the above-mentioned solutions modify and optimize the cement, there are still problems such as low cumulative degradation rate and non-matching of the degradation period with the human bone healing period, which cannot meet dental use. In addition, relevant research does not consider the influence of the oral application environment on degradation. The normal oral temperature of the human body is 36.3 - 37.2 °C, and the process of eating three meals a day and drinking water will cause the local oral temperature to rise to 40 - 60 °C. Therefore, designing a calcium phosphate cement that degrades in response to temperature stimulation has become an effective way to solve its degradation problem. Summary of the Invention

[0008] The purpose of the present invention is to provide a temperature-responsive pulsed long-acting degradable calcium phosphate cement to solve the problems of low degradation rate of existing calcium phosphate cements and non-matching of the degradation period with the human bone healing period.

[0009] Another purpose of the present invention is to provide a preparation method for the temperature-responsive pulsed long-acting degradable calcium phosphate cement.

[0010] The technical solution adopted by the present invention is that the temperature-responsive pulsed long-acting degradable calcium phosphate cement is formed by mixing a solid phase and a liquid phase in a solid-liquid ratio of 1 - 2 g / mL. The solid phase includes monocalcium phosphate anhydrous, β-tricalcium phosphate, and a water-soluble curcumin-glucose pore former with a mass ratio of 1 - 3:3 - 6:1 - 3, and the liquid phase includes citric acid, hyaluronic acid, and a temperature-responsive composite microsphere of sorbitol-gelatin loaded with salicylic acid.

[0011] Another technical solution adopted by the present invention is a preparation method of a temperature-responsive pulsed long-acting degradable calcium phosphate bone cement, which is specifically implemented according to the following steps:

[0012] Step 1, prepare sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid;

[0013] Step 2, prepare water-soluble curcumin-glucose pore-forming agent;

[0014] Step 3, uniformly mix β-tricalcium phosphate, anhydrous calcium dihydrogen phosphate and the water-soluble curcumin-glucose pore-forming agent, and then add the sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid to obtain the solid phase of the temperature-responsive pulsed long-acting degradable calcium phosphate bone cement;

[0015] Step 4, uniformly mix hyaluronic acid and a citric acid solution to obtain the liquid phase of the temperature-responsive pulsed long-acting degradable calcium phosphate bone cement;

[0016] Step 5, mix the solid phase and the liquid phase, stir evenly to obtain a slurry, pour it into a mold, and cure it to obtain the temperature-responsive pulsed long-acting degradable calcium phosphate bone cement.

[0017] The characteristics of the present invention also lie in that

[0018] In step 1, specifically:

[0019] Step 1.1, add sorbitol and gelatin to deionized water, stir and dissolve to form a uniform solution, add it to liquid paraffin containing the emulsifier sorbitan monooleate, emulsify it, then cool it in an ice bath, add a glutaraldehyde solution, continuously stir and react, let it stand, remove the supernatant, and dehydrate it with isopropanol to obtain sorbitol-gelatin temperature-responsive composite microspheres;

[0020] Step 1.2, wash the sorbitol-gelatin temperature-responsive composite microspheres alternately with isopropanol, petroleum, and absolute ethanol three times, dry them, immerse the obtained composite microspheres in a salicylic acid solution for soaking, let it stand and filter, and wash them three times with deionized water to obtain sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid.

[0021] In step 1.1, the mass ratio of sorbitol to gelatin is 0.39-0.65:3, the emulsification time is 5-10 min; the cooling temperature is 5-10 °C; the stirring reaction temperature is 5-10 °C, the reaction time is 12-24 h, and the standing time is 12 h;

[0022] In step 1.2, the concentration of the salicylic acid solution is 1-2 mg / mL, and the soaking time is 12-24 h.

[0023] In step 2, specifically:

[0024] Add whey protein to deionized water and stir for 2 - 4 h to obtain a whey protein solution. Then perform hydration. Next, add curcumin dissolved in ethanol to the whey protein solution and stir for 10 - 12 h in the dark, followed by freeze - drying to obtain water - soluble curcumin. Mix the water - soluble curcumin, glucose powder and deionized water to prepare a slurry, then immerse the slurry in liquid nitrogen for freeze - drying. Grind the obtained crystals and sieve them to obtain a water - soluble curcumin - glucose pore - former.

[0025] The concentration of the whey protein solution is 40 - 60 mg / mL; the hydration temperature is 2 - 8 °C, and the hydration time is 12 - 14 h; the concentration of curcumin in the whey protein solution is 0.25 - 0.75 mg / mL; the freeze - drying time is 12 - 16 h, and the freeze - drying temperature is - 30 °C to - 20 °C; in the slurry, the mass ratio of water - soluble curcumin, glucose powder and deionized water is 2 - 5:35 - 45:15 - 20.

[0026] In step 3, the mass ratio of β - tricalcium phosphate, calcium dihydrogen phosphate anhydrous and the water - soluble curcumin - glucose pore - former is: 1 - 3:3 - 6:1 - 3.

[0027] In step 4, the mass fraction of the citric acid solution in the liquid phase is 15 - 25 wt%; the mass fraction of hyaluronic acid is 1 - 3 wt%.

[0028] In step 5, the mass - to - volume ratio of the solid phase and the liquid phase components is 1 g - 2 g:1 mL, and the curing temperature is 35 °C to 40 °C.

[0029] The beneficial effects of the present invention are as follows: Using brushite with higher solubility in calcium phosphate bone cement as the matrix, adding sorbitol - gelatin composite microspheres loaded with salicylic acid, through the stimulation of the change in human oral temperature, a large amount of salicylic acid is released in a short - time response, etching the calcium phosphate bone cement matrix, thereby improving the degradation rate, achieving pulsed long - term degradation, and ultimately reaching a degradation cycle that matches human bone healing. The addition of the water - soluble curcumin - glucose pore - former obtains interconnected pores, which can promote the adhesion and proliferation of osteoblasts while providing antibacterial properties in the initial stage of implantation through curcumin. Therefore, this temperature - responsive pulsed long - term degradation calcium phosphate bone cement has good application prospects in the field of biomedical materials technology. Specific embodiments

[0030] The present invention will be described in detail below in conjunction with specific embodiments.

[0031] The temperature-responsive pulsed long-acting degradable calcium phosphate bone cement of the present invention is formed by mixing a solid phase and a liquid phase in a solid-liquid ratio of 1-2 g / mL. The solid phase includes calcium dihydrogen phosphate anhydrous, β-tricalcium phosphate, and a water-soluble curcumin-glucose pore-forming agent in a mass ratio of 1-3:3-6:1-3. The liquid phase includes citric acid, hyaluronic acid, and sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid.

[0032] The addition amount of the sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid is 10%-20% of the total weight of the solid phase powder.

[0033] The preparation method of the temperature-responsive pulsed long-acting degradable calcium phosphate bone cement of the present invention is specifically implemented according to the following steps:

[0034] Step 1, prepare sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid; specifically:

[0035] Step 1.1, add sorbitol and gelatin to deionized water, stir and dissolve to form a uniform solution, add the solution to liquid paraffin containing the emulsifier sorbitan monooleate, emulsify, then cool in an ice bath, add glutaraldehyde solution, continuously stir and react, let it stand, remove the supernatant, add isopropanol for dehydration, and obtain sorbitol-gelatin temperature-responsive composite microspheres;

[0036] The mass ratio of sorbitol to gelatin is 0.39-0.65:3, and the stirring and dissolving temperature is 50 °C;

[0037] The volume percentage concentration of the emulsifier sorbitan monooleate in liquid paraffin is 1.5% (v / v), and the emulsification time is 5-10 min; the cooling temperature is 5-10 °C, and the volume percentage concentration of the glutaraldehyde solution is 25% (v / v);

[0038] The stirring and reaction temperature is 5-10 °C, the reaction time is 12-24 h, and the standing time is 12 h;

[0039] Step 1.2, wash the sorbitol-gelatin temperature-responsive composite microspheres three times alternately with isopropanol, petroleum, and absolute ethanol, dry them, and obtain impurity-free sorbitol-gelatin temperature-responsive composite microspheres; immerse the obtained composite microspheres in a salicylic acid solution for soaking, let it stand and filter, and wash them three times with deionized water to obtain sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid;

[0040] The drying temperature is 60 °C, the concentration of the salicylic acid solution is 1-2 mg / mL, and the soaking time is 12-24 h.

[0041] Step 2, prepare a water-soluble curcumin-glucose pore-forming agent, specifically:

[0042] Add whey protein to deionized water and stir for 2 - 4 h to obtain a whey protein solution. Hydrate it, then add curcumin dissolved in ethanol to the whey protein solution and stir for 10 - 12 h in the dark. Freeze-dry to obtain water-soluble curcumin; mix the water-soluble curcumin, glucose powder and deionized water to prepare a slurry, then immerse the slurry in liquid nitrogen for freeze-drying. Grind the obtained crystals and sieve them to obtain a water-soluble curcumin-glucose pore-forming agent;

[0043] The concentration of the whey protein solution is 40 - 60 mg / mL; the hydration temperature is 2 - 8 °C and the hydration time is 12 - 14 h;

[0044] The concentration of curcumin in the whey protein solution is 0.25 - 0.75 mg / mL;

[0045] The freeze-drying time is 12 - 16 h and the freeze-drying temperature is -30 to -20 °C;

[0046] In the slurry, the mass ratio of water-soluble curcumin, glucose powder and deionized water is 2 - 5:35 - 45:15 - 20;

[0047] The freeze-drying time in liquid nitrogen is 10 - 15 min and the freeze-drying temperature is -30 to -20 °C;

[0048] When sieving, use a sieve mesh of 200 - 400 meshes.

[0049] Step 3, prepare the solid phase of the temperature-responsive pulse-type long-acting degradable calcium phosphate bone cement;

[0050] Uniformly mix β-tricalcium phosphate, anhydrous calcium dihydrogen phosphate and the water-soluble curcumin-glucose pore-forming agent, and then add the temperature-responsive composite microspheres of sorbitol-gelatin loaded with salicylic acid to obtain the solid phase of the temperature-responsive pulse-type long-acting degradable calcium phosphate bone cement;

[0051] The mass ratio of β-tricalcium phosphate, anhydrous calcium dihydrogen phosphate and the water-soluble curcumin-glucose pore-forming agent is: 1 - 3:3 - 6:1 - 3.

[0052] Step 4, prepare the liquid phase of the temperature-responsive pulse-type long-acting degradable calcium phosphate bone cement;

[0053] Mix hyaluronic acid and citric acid solution evenly to obtain the liquid phase of the temperature-responsive pulse-type long-acting degradable calcium phosphate bone cement;

[0054] The mass fraction of the citric acid solution in the liquid phase is 15 - 25 wt%; the mass fraction of hyaluronic acid is 1 - 3 wt%;

[0055] Step 5, prepare the temperature-responsive pulse-type long-acting degradable calcium phosphate bone cement:

[0056] Mix the solid phase of the temperature-responsive pulsed long-acting degradable calcium phosphate bone cement prepared in Step 3 with the liquid phase of the temperature-responsive pulsed long-acting degradable calcium phosphate bone cement prepared in Step 4. After stirring evenly, a slurry is obtained, which is poured into a mold and cured to obtain the temperature-responsive pulsed long-acting degradable calcium phosphate bone cement.

[0057] The mass-to-volume ratio of the solid phase and the liquid phase components is 1 g - 2 g : 1 mL, the self-curing temperature is 35°C to 40°C, and the humidity is 100%.

[0058] In the present invention, microspheres prepared from a thermosensitive material are used to load acidic substances. When the oral temperature rises due to eating and drinking, the material undergoes a phase transition to release the internally loaded salicylic acid, which promotes the acid-base reaction with the calcium phosphate matrix within a short period, generating water and soluble calcium salts, and efficiently improving the degradation rate. The daily stimulation of the oral temperature change provides continuous power for the degradation of the bone cement, realizing the pulsed long-acting degradation of the calcium phosphate bone cement. Among them, the thermosensitive material is gelatin, and by changing the content of sorbitol in the solvent mixture, the degree of β-sheet in the secondary structure of gelatin is changed, thereby forming different numbers of intermolecular hydrogen bonds to obtain different phase transition temperatures. The acidic substance selects salicylic acid, which is widely used in medical aesthetics and medicine and has excellent biocompatibility. The modified gelatin is prepared into microspheres by the water-in-oil (W / O) method to load salicylic acid, and then added to the solid phase of the bone cement. The calcium phosphate bone cement product - brushite with higher solubility obtained by the acid-base reaction of β-tricalcium phosphate and calcium dihydrogen phosphate anhydrous is selected as the matrix, and a highly water-soluble curcumin-glucose pore-forming agent is incorporated. After the pore-forming agent dissolves, interconnected pores are obtained, which can promote the adhesion and proliferation of osteoblasts and also provide antibacterial properties in the initial stage of implantation through the release of curcumin. The composite microspheres after being stimulated by temperature respond to release salicylic acid to etch the bone cement matrix, improve the degradation rate, achieve long-acting degradation, and further achieve the dynamic balance between the degradation period of the calcium phosphate filling material and the new alveolar bone formation period.

[0059] Example 1

[0060] The preparation method of the temperature-responsive pulsed long-acting degradable calcium phosphate bone cement of the present invention is specifically implemented according to the following steps:

[0061] Step 1, prepare sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid:

[0062] First, 0.39 g of sorbitol and 3 g of gelatin were added to deionized water, and stirred and dissolved at 50 °C to form a homogeneous solution. 100 ml of liquid paraffin containing 1.5% (v / v) emulsifier sorbitan monooleate was added to the mixed solution, emulsified for 10 min, and then cooled to 4 °C in an ice bath. 0.1 ml of 25% (v / v) glutaraldehyde solution was added to the solution after ice bath, and continuously stirred and reacted at 4 °C for 24 h. After standing for 12 h, the supernatant was removed, and after dehydration with 100 ml of isopropanol, sorbitol-gelatin temperature-responsive composite microspheres were obtained; the obtained composite microspheres were washed three times alternately with isopropanol, petroleum, and absolute ethanol, and dried at 60 °C to obtain impurity-free sorbitol-gelatin temperature-responsive composite microspheres; the obtained microspheres were immersed in a 1 mg / ml salicylic acid aqueous solution, soaked for 24 h, then stood and filtered, and washed three times with deionized water to prepare sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid;

[0063] Step 2: Prepare water-soluble curcumin-glucose pore former:

[0064] 1.5 g of whey protein was added to 30 ml of deionized water and stirred to obtain a whey protein solution. After hydrating at 4 °C for 12 h, 0.35 g of curcumin dissolved in ethanol was added to the protein solution and stirred for another 12 h. Freeze-drying was carried out at -20 °C for 12 h to obtain water-soluble curcumin; 2 g of water-soluble curcumin, 40 g of glucose powder, and 15 ml of deionized water were mixed to form a slurry, and then the slurry was immersed in liquid nitrogen for rapid freezing, and then freeze-dried at -20 °C for 12 h. The obtained crystals were ground and then passed through a 200-mesh sieve to obtain a water-soluble curcumin-glucose pore former.

[0065] Step 3: Take anhydrous calcium dihydrogen phosphate, β-tricalcium phosphate, and water-soluble curcumin-glucose pore former with a mass ratio of 3:6:1, mix them evenly, and add 10% sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid by the weight of the solid phase powder to obtain a solid phase of calcium phosphate bone cement with temperature-responsive pulsed long-term degradation.

[0066] Step 4: Take a mixed solution of citric acid and hyaluronic acid with concentrations of 20 wt% and 1 wt% respectively to obtain a liquid phase of calcium phosphate bone cement with temperature-responsive pulsed long-term degradation.

[0067] Step 5: Mix the solid phase components and the liquid phase components evenly at a ratio of 1 g:1 ml, pour them into a mold of a certain shape, and self-cure under the conditions of a temperature of 37 °C and a humidity of 100% to obtain calcium phosphate bone cement with temperature-responsive pulsed long-term degradation.

[0068] Example 2

[0069] The preparation method of the temperature-responsive pulsed long-acting degradable calcium phosphate bone cement of the present invention is specifically implemented according to the following steps:

[0070] Step 1, prepare sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid:

[0071] First, add 0.52 g of sorbitol and 3 g of gelatin to deionized water, stir and dissolve at 50 °C to form a uniform solution. Add 100 ml of liquid paraffin containing 1.5% (v / v) emulsifier sorbitan monooleate to the mixed solution, emulsify for 10 min, then place it in an ice bath and cool to 4 °C. Add 0.1 ml of 25% (v / v) glutaraldehyde solution to the solution after the ice bath, continuously stir and react at 4 °C for 24 h, let it stand for 12 h, then remove the supernatant, add 100 ml of isopropanol for dehydration to obtain sorbitol-gelatin temperature-responsive composite microspheres; after washing the obtained composite microspheres alternately with isopropanol, petroleum and absolute ethanol three times, dry them at 60 °C to obtain impurity-free sorbitol-gelatin temperature-responsive composite microspheres; immerse the obtained microspheres in a 1 mg / ml aqueous solution of salicylic acid, soak for 24 h, then let it stand and filter, and wash three times with deionized water to prepare sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid;

[0072] Step 2, prepare water-soluble curcumin-glucose pore former:

[0073] Add 1.5 g of whey protein to 30 ml of deionized water and stir to obtain a whey protein solution. After hydrating at 4 °C for 12 h, add 0.35 g of curcumin dissolved in ethanol to the protein solution and continue to stir for 12 h. Perform freeze-drying at -20 °C for 12 h to obtain water-soluble curcumin; mix 2 g of water-soluble curcumin, 40 g of glucose powder and 15 ml of deionized water to form a slurry, then immerse the slurry in liquid nitrogen for rapid freezing, and then perform freeze-drying at -20 °C for 12 h. Grind the obtained crystals, and then pass through a 200-mesh sieve to obtain a water-soluble curcumin-glucose pore former.

[0074] Step 3, take anhydrous calcium dihydrogen phosphate, β-tricalcium phosphate and water-soluble curcumin-glucose pore former with a mass ratio of 3:6:1, mix them evenly, and add 10% sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid by the weight of the solid phase powder to obtain the solid phase of the temperature-responsive pulsed long-acting degradable calcium phosphate bone cement.

[0075] Step 4, take a mixed solution of citric acid and hyaluronic acid with concentrations of 20 wt% and 1 wt% respectively to obtain the liquid phase of the temperature-responsive pulsed long-acting degradable calcium phosphate bone cement.

[0076] Step 5: Mix the solid phase component and the liquid phase component evenly at a ratio of 1 g: 1 ml, pour them into a mold of a certain shape, and self-cure under the conditions of a temperature of 37 °C and a humidity of 100% to obtain a calcium phosphate bone cement with temperature-responsive pulsed long-term degradation.

[0077] Example 3

[0078] The preparation method of the temperature-responsive pulsed long-term degradation calcium phosphate bone cement of the present invention is specifically implemented according to the following steps:

[0079] Step 1, prepare sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid:

[0080] First, add 0.65 g of sorbitol and 3 g of gelatin to deionized water, stir and dissolve at a temperature of 50 °C to form a uniform solution. Add 100 ml of liquid paraffin containing 1.5% (v / v) emulsifier sorbitan monooleate to the mixed solution, emulsify for 10 min, then cool to 4 °C in an ice bath. Add 0.1 ml of 25% (v / v) glutaraldehyde solution to the solution after the ice bath, continuously stir and react at 4 °C for 24 h, let stand for 12 h, then remove the supernatant. After adding 100 ml of isopropanol for dehydration, sorbitol-gelatin temperature-responsive composite microspheres are obtained; the obtained composite microspheres are washed alternately with isopropanol, petroleum and absolute ethanol three times, and then dried at 60 °C to obtain impurity-free sorbitol-gelatin temperature-responsive composite microspheres; immerse the obtained microspheres in a 1 mg / ml aqueous solution of salicylic acid, soak for 24 h, then let stand and filter, and wash three times with deionized water to prepare sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid.

[0081] Step 2, prepare water-soluble curcumin-glucose pore-forming agent:

[0082] Add 1.5 g of whey protein to 30 ml of deionized water and stir to obtain a whey protein solution. After hydrating at 4 °C for 12 h, add 0.35 g of curcumin dissolved in ethanol to the protein solution and continue to stir for 12 h. Perform freeze-drying at -20 °C for 12 h to obtain water-soluble curcumin; mix 2 g of water-soluble curcumin, 40 g of glucose powder and 15 ml of deionized water to form a slurry, then immerse the slurry in liquid nitrogen for rapid freezing, and then perform freeze-drying at -20 °C for 12 h. Grind the obtained crystals, and then pass through a 200-mesh sieve to obtain a water-soluble curcumin-glucose pore-forming agent.

[0083] Step 3, take anhydrous calcium dihydrogen phosphate, β-tricalcium phosphate and water-soluble curcumin-glucose pore-forming agent with a mass ratio of 3: 6: 1, mix them evenly, and add sorbitol-gelatin temperature-responsive composite microspheres loaded with 10% of the solid phase powder weight of salicylic acid to obtain a solid phase of calcium phosphate bone cement with temperature-responsive pulsed long-term degradation.

[0084] Step 4: Take the mixed solutions of citric acid and hyaluronic acid with concentrations of 20 wt% and 1 wt% respectively to obtain the liquid phase of calcium phosphate bone cement with temperature-responsive pulsed long-term degradation.

[0085] Step 5: Mix the solid-phase component and the liquid-phase component evenly at a ratio of 1 g:1 ml, pour them into a mold of a certain shape, and self-cure at a temperature of 37°C and a humidity of 100% to obtain calcium phosphate bone cement with temperature-responsive pulsed long-term degradation.

[0086] Example 4

[0087] The preparation method of the calcium phosphate bone cement with temperature-responsive pulsed long-term degradation of the present invention is specifically implemented according to the following steps:

[0088] Step 1: Prepare sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid:

[0089] First, add 0.65 g of sorbitol and 3 g of gelatin to deionized water, stir and dissolve at a temperature of 50°C to form a homogeneous solution. Add 100 ml of liquid paraffin containing 1.5% (v / v) emulsifier sorbitan monooleate to the mixed solution, emulsify for 10 min, then cool to 4°C in an ice bath. Add 0.1 ml of 25% (v / v) glutaraldehyde solution to the solution after ice bath, continuously stir and react at 4°C for 24 h, let it stand for 12 h, then remove the supernatant. After adding 100 ml of isopropanol for dehydration, sorbitol-gelatin temperature-responsive composite microspheres are obtained; the obtained composite microspheres are washed alternately with isopropanol, petroleum, and absolute ethanol three times, and then dried at 60°C to obtain sorbitol-gelatin temperature-responsive composite microspheres without impurities; immerse the obtained microspheres in a 1.5 mg / ml aqueous solution of salicylic acid, soak for 24 h, then let it stand and filter, and wash three times with deionized water to prepare sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid.

[0090] Step 2: Prepare water-soluble curcumin-glucose pore-forming agent:

[0091] Add 1.5 g of whey protein to 30 ml of deionized water and stir to obtain a whey protein solution. After hydrating at 4°C for 12 h, add 0.35 g of curcumin dissolved in ethanol to the protein solution and continue to stir for 12 h. Perform freeze-drying at -20°C for 12 h to obtain water-soluble curcumin; mix 2 g of water-soluble curcumin, 40 g of glucose powder, and 15 ml of deionized water to form a slurry, then immerse the slurry in liquid nitrogen for rapid freezing, and then perform freeze-drying at -20°C for 12 h. Grind the obtained crystals, and then pass through a 200-mesh sieve to obtain a water-soluble curcumin-glucose pore-forming agent.

[0092] Step 3: Mix anhydrous calcium dihydrogen phosphate, β-tricalcium phosphate and water-soluble curcumin-glucose pore-forming agent with a mass ratio of 3:6:1 evenly, and add sorbitol-gelatin temperature-responsive composite microspheres loaded with 10% solid-phase powder weight of salicylic acid to obtain a solid phase of calcium phosphate bone cement with temperature-responsive pulsed long-term degradation.

[0093] Step 4: Take a mixed solution of citric acid and hyaluronic acid with concentrations of 20 wt% and 1 wt% respectively to obtain a liquid phase of calcium phosphate bone cement with temperature-responsive pulsed long-term degradation.

[0094] Step 5: Mix the solid-phase component and the liquid-phase component evenly at a ratio of 1 g:1 ml, pour them into a mold of a certain shape, and self-cure at a temperature of 37 °C and a humidity of 100% to obtain calcium phosphate bone cement with temperature-responsive pulsed long-term degradation.

[0095] Example 5

[0096] The preparation method of the temperature-responsive pulsed long-term degradation calcium phosphate bone cement of the present invention is specifically implemented according to the following steps:

[0097] Step 1, prepare sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid:

[0098] First, add 0.65 g of sorbitol and 3 g of gelatin to deionized water, stir and dissolve at a temperature of 50 °C to form a homogeneous solution. Add 100 ml of liquid paraffin containing 1.5% (v / v) emulsifier sorbitan monooleate to the mixed solution, emulsify for 10 min, then cool to 4 °C in an ice bath. Add 0.1 ml of 25% (v / v) glutaraldehyde solution to the solution after the ice bath, continuously stir and react at 4 °C for 24 h, let it stand for 12 h, then remove the supernatant. After adding 100 ml of isopropanol for dehydration, sorbitol-gelatin temperature-responsive composite microspheres are obtained; the obtained composite microspheres are washed alternately with isopropanol, petroleum and absolute ethanol three times, and then dried at 60 °C to obtain impurity-free sorbitol-gelatin temperature-responsive composite microspheres; immerse the obtained microspheres in a 2 mg / ml aqueous solution of salicylic acid, soak for 24 h, then let it stand and filter, and wash three times with deionized water to prepare sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid;

[0099] Step 2, prepare water-soluble curcumin-glucose pore-forming agent:

[0100] 1.5 g of whey protein was added to 30 ml of deionized water and stirred to obtain a whey protein solution. After hydrating at 4 °C for 12 h, 0.35 g of curcumin dissolved in ethanol was added to the protein solution and stirred for another 12 h. Then, it was freeze-dried at -20 °C for 12 h to obtain water-soluble curcumin. 2 g of water-soluble curcumin, 40 g of glucose powder and 15 ml of deionized water were mixed to form a slurry, and the slurry was immersed in liquid nitrogen for rapid freezing, and then freeze-dried at -20 °C for 12 h. The obtained crystals were ground and then passed through a 200-mesh sieve to obtain a water-soluble curcumin-glucose pore former.

[0101] Step 3: Mix anhydrous calcium dihydrogen phosphate, β-tricalcium phosphate and the water-soluble curcumin-glucose pore former with a mass ratio of 3:6:1 evenly, and add sorbitol-gelatin temperature-responsive composite microspheres loaded with 10% by weight of solid-phase powder of salicylic acid to obtain a solid phase of calcium phosphate bone cement with temperature-responsive pulsed long-acting degradation.

[0102] Step 4: Take a mixed solution of citric acid and hyaluronic acid with concentrations of 20 wt% and 1 wt% respectively to obtain a liquid phase of calcium phosphate bone cement with temperature-responsive pulsed long-acting degradation.

[0103] Step 5: Mix the solid-phase component and the liquid-phase component evenly at a ratio of 1 g:1 ml, pour them into a mold of a certain shape, and self-cure under the conditions of a temperature of 37 °C and a humidity of 100% to obtain a calcium phosphate bone cement with temperature-responsive pulsed long-acting degradation.

[0104] Example 6

[0105] The preparation method of the temperature-responsive pulsed long-acting degradation calcium phosphate bone cement of the present invention is specifically implemented according to the following steps:

[0106] Step 1, prepare sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid:

[0107] First, 0.65 g of sorbitol and 3 g of gelatin were added to deionized water, and stirred and dissolved at 50 °C to form a homogeneous solution. 100 ml of liquid paraffin containing 1.5% (v / v) of emulsifier sorbitan monooleate was added to the mixed solution, emulsified for 10 min, and then cooled to 4 °C in an ice bath. 0.1 ml of 25% (v / v) glutaraldehyde solution was added to the solution after ice bath, and continuously stirred and reacted at 4 °C for 24 h. After standing for 12 h, the supernatant was removed, and after dehydration with 100 ml of isopropanol, sorbitol-gelatin temperature-responsive composite microspheres were obtained; the obtained composite microspheres were washed three times alternately with isopropanol, petroleum, and absolute ethanol, and dried at 60 °C to obtain sorbitol-gelatin temperature-responsive composite microspheres without impurities; the obtained microspheres were immersed in a 1.5 mg / ml salicylic acid aqueous solution, soaked for 24 h, then stood and filtered, and washed three times with deionized water to prepare sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid;

[0108] Step 2: Prepare water-soluble curcumin-glucose pore former:

[0109] 1.5 g of whey protein was added to 30 ml of deionized water and stirred to obtain a whey protein solution. After hydrating at 4 °C for 12 h, 0.35 g of curcumin dissolved in ethanol was added to the protein solution and stirred for another 12 h, and freeze-dried at -20 °C for 12 h to obtain water-soluble curcumin; 2 g of water-soluble curcumin, 40 g of glucose powder, and 15 ml of deionized water were mixed to form a slurry, and then the slurry was immersed in liquid nitrogen for rapid freezing, and then freeze-dried at -20 °C for 12 h. The obtained crystals were ground and then passed through a 300-mesh sieve to obtain a water-soluble curcumin-glucose pore former.

[0110] Step 3: Mix anhydrous calcium dihydrogen phosphate, β-tricalcium phosphate, and water-soluble curcumin-glucose pore former in a mass ratio of 3:6:1, and add 10% of sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid by the weight of the solid phase powder to obtain a solid phase of calcium phosphate bone cement with temperature-responsive pulsed long-term degradation.

[0111] Step 4: Take a mixed solution of citric acid and hyaluronic acid with concentrations of 20 wt% and 1 wt% respectively to obtain a liquid phase of calcium phosphate bone cement with temperature-responsive pulsed long-term degradation.

[0112] Step 5: Mix the solid phase component and the liquid phase component evenly at a ratio of 1 g:1 ml, pour them into a mold of a certain shape, and self-cure at a temperature of 37 °C and a humidity of 100% to obtain calcium phosphate bone cement with temperature-responsive pulsed long-term degradation.

[0113] Example 7

[0114] The preparation method of the temperature-responsive pulsed long-acting degradable calcium phosphate bone cement of the present invention is specifically implemented according to the following steps:

[0115] Step 1, prepare sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid:

[0116] First, add 0.65 g of sorbitol and 3 g of gelatin to deionized water, stir and dissolve at 50 °C to form a uniform solution. Add 100 ml of liquid paraffin containing 1.5% (v / v) emulsifier sorbitan monooleate to the mixed solution, emulsify for 10 min, then place it in an ice bath and cool to 4 °C. Add 0.1 ml of 25% (v / v) glutaraldehyde solution to the solution after the ice bath, continuously stir and react at 4 °C for 24 h, let it stand for 12 h, then remove the supernatant. After adding 100 ml of isopropanol for dehydration, sorbitol-gelatin temperature-responsive composite microspheres are obtained; the obtained composite microspheres are washed three times alternately with isopropanol, petroleum, and absolute ethanol, and then dried at 60 °C to obtain impurity-free sorbitol-gelatin temperature-responsive composite microspheres; immerse the obtained microspheres in a 1.5 mg / ml aqueous solution of salicylic acid, soak for 24 h, then let it stand and filter, and wash three times with deionized water to prepare sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid;

[0117] Step 2, prepare water-soluble curcumin-glucose pore-forming agent:

[0118] Add 1.5 g of whey protein to 30 ml of deionized water and stir to obtain a whey protein solution. After hydrating at 4 °C for 12 h, add 0.35 g of curcumin dissolved in ethanol to the protein solution and continue to stir for 12 h. Perform freeze-drying at -20 °C for 12 h to obtain water-soluble curcumin; mix 2 g of water-soluble curcumin, 40 g of glucose powder, and 15 ml of deionized water to form a slurry, then immerse the slurry in liquid nitrogen for rapid freezing, and then perform freeze-drying at -20 °C for 12 h. Grind the obtained crystals, and then pass through a 400-mesh sieve to obtain a water-soluble curcumin-glucose pore-forming agent.

[0119] Step 3, take anhydrous calcium dihydrogen phosphate, β-tricalcium phosphate, and water-soluble curcumin-glucose pore-forming agent with a mass ratio of 3:6:1, mix them evenly, and add 10% sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid by the weight of the solid phase powder to obtain the solid phase of the temperature-responsive pulsed long-acting degradable calcium phosphate bone cement.

[0120] Step 4, take a mixed solution of citric acid and hyaluronic acid with concentrations of 20 wt% and 1 wt% respectively to obtain the liquid phase of the temperature-responsive pulsed long-acting degradable calcium phosphate bone cement.

[0121] Step 5: Mix the solid-phase component and the liquid-phase component evenly at a ratio of 1 g: 1 ml, pour them into a mold of a certain shape, and self-cure under the conditions of a temperature of 37 °C and a humidity of 100% to obtain a calcium phosphate bone cement with temperature-responsive pulsed long-term degradation.

[0122] Example 8

[0123] The preparation method of the temperature-responsive pulsed long-term degradation calcium phosphate bone cement of the present invention is specifically implemented according to the following steps:

[0124] Step 1: Prepare sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid:

[0125] First, add 0.65 g of sorbitol and 3 g of gelatin to deionized water, stir and dissolve at a temperature of 50 °C to form a uniform solution. Add 100 ml of liquid paraffin containing 1.5% (v / v) emulsifier sorbitan monooleate to the mixed solution, emulsify for 10 min, then cool to 4 °C in an ice bath. Add 0.1 ml of 25% (v / v) glutaraldehyde solution to the solution after the ice bath, continuously stir and react at 4 °C for 24 h, let it stand for 12 h, then remove the supernatant. After adding 100 ml of isopropanol for dehydration, sorbitol-gelatin temperature-responsive composite microspheres are obtained; the obtained composite microspheres are washed alternately with isopropanol, petroleum, and absolute ethanol three times, and then dried at 60 °C to obtain impurity-free sorbitol-gelatin temperature-responsive composite microspheres; immerse the obtained microspheres in a 1.5 mg / ml aqueous solution of salicylic acid, soak for 24 h, then let it stand and filter, and wash three times with deionized water to prepare sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid.

[0126] Step 2: Prepare water-soluble curcumin-glucose pore-forming agent:

[0127] Add 1.5 g of whey protein to 30 ml of deionized water and stir to obtain a whey protein solution. After hydrating at 4 °C for 12 h, add 0.35 g of curcumin dissolved in ethanol to the protein solution and continue to stir for 12 h. Perform freeze-drying at -20 °C for 12 h to obtain water-soluble curcumin; mix 2 g of water-soluble curcumin, 40 g of glucose powder, and 15 ml of deionized water to form a slurry, then immerse the slurry in liquid nitrogen for rapid freezing, and then perform freeze-drying at -20 °C for 12 h. Grind the obtained crystals, and then pass through a 300-mesh sieve to obtain a water-soluble curcumin-glucose pore-forming agent.

[0128] Step 3: Take anhydrous calcium dihydrogen phosphate, β-tricalcium phosphate, and water-soluble curcumin-glucose pore-forming agent with a mass ratio of 3: 6: 1, mix them evenly, and add sorbitol-gelatin temperature-responsive composite microspheres loaded with 15% of the solid-phase powder weight of salicylic acid to obtain a solid phase of calcium phosphate bone cement with temperature-responsive pulsed long-term degradation.

[0129] Step 4: Take a mixed solution of citric acid and hyaluronic acid with concentrations of 20 wt% and 1 wt% respectively to obtain the liquid phase of calcium phosphate bone cement with temperature-responsive pulsed long-term degradation.

[0130] Step 5: Mix the solid phase component and the liquid phase component evenly at a ratio of 1 g: 1 ml, pour them into a mold of a certain shape, and self-cure under the conditions of a temperature of 37 °C and a humidity of 100% to obtain calcium phosphate bone cement with temperature-responsive pulsed long-term degradation.

[0131] Example 9

[0132] The preparation method of the calcium phosphate bone cement with temperature-responsive pulsed long-term degradation of the present invention is specifically implemented according to the following steps:

[0133] Step 1: Prepare sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid:

[0134] First, add 0.56 g of sorbitol and 3 g of gelatin to deionized water, stir and dissolve at a temperature of 50 °C to form a uniform solution. Add 100 ml of liquid paraffin containing 1.5% (v / v) emulsifier sorbitan monooleate to the mixed solution, emulsify for 10 min, then cool to 4 °C in an ice bath. Add 0.1 ml of 25% (v / v) glutaraldehyde solution to the solution after ice bath, and continuously stir and react at 4 °C for 24 h. After standing for 12 h, remove the supernatant, add 100 ml of isopropanol for dehydration to obtain sorbitol-gelatin temperature-responsive composite microspheres; after washing the obtained composite microspheres alternately with isopropanol, petroleum, and absolute ethanol three times, dry them at 60 °C to obtain impurity-free sorbitol-gelatin temperature-responsive composite microspheres; immerse the obtained microspheres in a 1.5 mg / ml aqueous solution of salicylic acid, soak for 24 h, then stand and filter, and wash three times with deionized water to prepare sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid;

[0135] Step 2: Prepare water-soluble curcumin-glucose pore-forming agent:

[0136] Add 1.5 g of whey protein to 30 ml of deionized water and stir to obtain a whey protein solution. After hydrating at 4 °C for 12 h, add 0.35 g of curcumin dissolved in ethanol to the protein solution and continue to stir for 12 h. Perform freeze-drying at -20 °C for 12 h to obtain water-soluble curcumin; mix 2 g of water-soluble curcumin, 40 g of glucose powder, and 15 ml of deionized water to prepare a slurry, then immerse the slurry in liquid nitrogen for rapid freezing, and then perform freeze-drying at -20 °C for 12 h. Grind the obtained crystals, and then pass through a 300-mesh sieve to obtain a water-soluble curcumin-glucose pore-forming agent.

[0137] Step 3: Mix anhydrous calcium dihydrogen phosphate, β-tricalcium phosphate, and water-soluble curcumin-glucose pore-forming agent with a mass ratio of 3:6:1 evenly, and add sorbitol-gelatin temperature-responsive composite microspheres loaded with 20% of the solid-phase powder weight of salicylic acid to obtain a solid phase of calcium phosphate bone cement with temperature-responsive pulsed long-term degradation.

[0138] Step 4: Take a mixed solution of citric acid and hyaluronic acid with concentrations of 20 wt% and 1 wt% respectively to obtain a liquid phase of calcium phosphate bone cement with temperature-responsive pulsed long-term degradation.

[0139] Step 5: Mix the solid-phase component and the liquid-phase component evenly at a ratio of 1 g:1 ml, pour them into a mold of a certain shape, and self-cure under the conditions of a temperature of 37°C and a humidity of 100% to obtain calcium phosphate bone cement with temperature-responsive pulsed long-term degradation.

[0140] The results of in vitro degradation tests of the calcium phosphate bone cement with temperature-responsive pulsed long-term degradation in the examples and the currently available rapidly degradable calcium phosphate bone cement are shown in Tables 1-3 below:

[0141] Table 1 Comparison of in vitro degradation rate results between the present invention and rapidly degradable calcium phosphate bone cement

[0142]

[0143]

[0144] Table 2 Comparison of in vitro degradation rates after standing at 50°C for 30 min and then for 24 h

[0145] Example 1 2 3 4 5 6 7 8 9 CPC Degradation rate (%) 0.26 0.28 0.29 0.37 0.37 0.44 0.39 0.45 0.46 0.12

[0146] Table 3 Comparison of in vitro degradation cycles of the pulsed long-term degradation calcium phosphate bone cement of the present invention

[0147] Example 1 2 3 4 5 6 7 8 9 Degradation period (d) 132 168 156 170 172 174 166 170 173

[0148] As can be seen from the above table, compared with the currently available rapidly degradable calcium phosphate bone cement, the cumulative degradation rate of the temperature-responsive pulsed long-term degradation calcium phosphate bone cement prepared in the present invention is higher, and the degradation cycle can also match the cycle required for the repair of alveolar bone defects. Therefore, the temperature-responsive pulsed long-term degradation calcium phosphate bone cement prepared in the present invention has good application prospects.

Claims

1. Preparation method of temperature-responsive pulsed long-acting degradable calcium phosphate bone cement, characterized in that The implementation is specifically carried out according to the following steps: Step 1, prepare sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid; specifically: Step 1.1, add sorbitol and gelatin into deionized water, stir and dissolve to form a uniform solution, add it into liquid paraffin containing emulsifier sorbitan monooleate, emulsify and then cool in an ice bath, add glutaraldehyde solution, continuously stir and react, let it stand and then remove the supernatant, add isopropanol for dehydration to obtain sorbitol-gelatin temperature-responsive composite microspheres; The mass ratio of sorbitol to gelatin is 0.39 - 0.65:3, the emulsification time is 5 - 10 min; the cooling temperature is 5 - 10 °C; the stirring reaction temperature is 5 - 10 °C, the reaction time is 12 - 24 h, and the standing time is 12 h; Step 1.2, wash the sorbitol-gelatin temperature-responsive composite microspheres three times alternately with isopropanol, petroleum, and absolute ethanol, dry them, immerse the obtained composite microspheres in salicylic acid solution for soaking, let it stand and filter, wash three times with deionized water to obtain sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid; the concentration of the salicylic acid solution is 1 - 2 mg / mL, and the soaking time is 12 - 24 h; Step 2, prepare water-soluble curcumin-glucose pore former; Step 3, uniformly mix β-tricalcium phosphate, anhydrous calcium dihydrogen phosphate and water-soluble curcumin-glucose pore former, and then add sorbitol-gelatin temperature-responsive composite microspheres loaded with salicylic acid to obtain the solid phase of temperature-responsive pulsed long-acting degradable calcium phosphate bone cement; The mass ratio of β-tricalcium phosphate, anhydrous calcium dihydrogen phosphate and water-soluble curcumin-glucose pore former is: 1 - 3:3 - 6:1 - 3; Step 4, uniformly mix hyaluronic acid and citric acid solution to obtain the liquid phase of temperature-responsive pulsed long-acting degradable calcium phosphate bone cement; The mass fraction of the citric acid solution in the liquid phase is 15 - 25 wt%; the mass fraction of hyaluronic acid is 1 - 3 wt%; Step 5, mix the solid phase and the liquid phase, stir evenly to obtain a slurry, pour it into a mold and cure to obtain temperature-responsive pulsed long-acting degradable calcium phosphate bone cement; The mass-volume ratio of the solid phase and the liquid phase components is 1 g - 2 g:1 mL, and the curing temperature is 35 °C - 40 °C.

2. The preparation method of the temperature-responsive pulsed long-acting degradable calcium phosphate bone cement according to claim 1, characterized in that, In the said Step 2, specifically: Add whey protein into deionized water and stir for 2 - 4 h to obtain a whey protein solution, then carry out hydration, and then add curcumin dissolved in ethanol to the whey protein solution, stir for 10 - 12 h under light-shielded conditions, and freeze-dry to prepare water-soluble curcumin; mix water-soluble curcumin, glucose powder and deionized water to prepare a slurry, then immerse the slurry in liquid nitrogen for freeze-drying, grind the obtained crystals and sieve them to obtain a water-soluble curcumin-glucose pore former.

3. The preparation method of the temperature-responsive pulsed long-acting degradable calcium phosphate bone cement according to claim 2, characterized in that, The concentration of the whey protein solution is 40 - 60 mg / mL; the hydration temperature is 2 - 8 °C, and the hydration time is 12 - 14 h; the concentration of curcumin in the whey protein solution is 0.25 - 0.75 mg / mL; the freeze-drying time is 12 - 16 h, and the freeze-drying temperature is -30 ~ -20 °C; in the slurry, the mass ratio of water-soluble curcumin, glucose powder to deionized water is 2 - 5:35 - 45:15 - 20.

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