Injectable magnesium phosphate bone cement modified by thermo-sensitive chitosan hydrogel and preparation method of injectable magnesium phosphate bone cement

Abstract

The invention discloses temperature-sensitive chitosan hydrogel modified injectable magnesium phosphate bone cement and a preparation method thereof. The bone cement is prepared from solid-phase powder and curing liquid, the solid-phase powder comprises trimagnesium phosphate and potassium hydrogen phosphate; the curing liquid is obtained by mixing 1-4% (w / v) of a chitosan aqueous solution and 10-50% (w / v) of a beta-sodium glycerophosphate aqueous solution according to the volume ratio of 5: (5-9); and mixing the solid-phase powder and the curing liquid to obtain the temperature-sensitive chitosan hydrogel modified injectable magnesium phosphate bone cement. The thermo-sensitive chitosan / beta-sodium glycerophosphate is used as a modifier, the aqueous solution of the modifier has good fluidity at low temperature, the injectability of the bone cement blended slurry is improved, and after the bone cement blended slurry is injected into a body, a copolymer is subjected to gel phase transformation to form a compact network to wrap calcium phosphate bone cement, so that the bone cement is prevented from collapsing.

Description

Technical Field

[0001] The invention relates to the technical field of biomedical materials, and in particular to an injectable magnesium phosphate bone cement modified by a temperature-sensitive chitosan hydrogel and a preparation method thereof. Background Art

[0002] Magnesium phosphate bone cement has the characteristics of fast solidification and high initial strength. Studies have shown that a certain concentration of extracellular magnesium ions can promote osteoblast activity and inhibit osteoclast activity. Therefore, magnesium phosphate bone cement has good biological activity and osteogenic ability, and has attracted widespread attention from researchers. Magnesium phosphate bone cement is usually made by mixing magnesium phosphate salt and potassium hydrogen phosphate powder with a solidifying liquid at a certain solid-liquid ratio to produce a hydration reaction. It can self-solidify at room temperature or in the human body environment, and has the characteristics of free shaping and mild solidification. By adding suitable modifiers to improve the fluidity and injectability of bone cement slurry, it can be used in minimally invasive interventional treatment. Good injectability and anti-disintegration properties of bone cement are basic conditions for clinical application [Tao Yan, Li Dongxu, Li Yanbao, Materials Guide A: Review, 2011]. If bone cement disintegrates after being injected into the body, a large amount of free calcium phosphate will be formed to cause thrombosis, endangering the patient's life. Poor anti-disintegration properties are often an important reason limiting the clinical application of calcium phosphate bone cement. Summary of the invention

[0003] Purpose of the invention: The first purpose of the present invention is to provide an injectable magnesium phosphate bone cement modified by a temperature-sensitive chitosan hydrogel that resists collapse; the second purpose of the present invention is to provide a preparation method of the injectable magnesium phosphate bone cement modified by a temperature-sensitive chitosan hydrogel.

[0004] Technical solution: The thermosensitive chitosan hydrogel-modified injectable magnesium phosphate bone cement described in the present invention comprises a solid phase powder and a solidifying liquid; the solid phase powder comprises trimagnesium phosphate and potassium hydrogen phosphate; the solidifying liquid is obtained by mixing a 1-4% (w / v) chitosan aqueous solution and a 10-50% (w / v) β-sodium glycerophosphate solution in a volume ratio of 5:5-9.

[0005] Preferably, the solid-to-liquid ratio of the solid phase powder to the solidifying liquid is 2-4 g / mL, and the prepared slurry has the most ideal fluidity.

[0006] Preferably, the chitosan has a deacetylation degree of 75-95%.

[0007] Preferably, the solid phase powder comprises, by weight: 50 to 80 parts of trimagnesium phosphate and 20 to 50 parts of potassium hydrogen phosphate.

[0008] Preferably, the potassium hydrogen phosphate salt is potassium dihydrogen phosphate, dipotassium hydrogen phosphate trihydrate or anhydrous dipotassium hydrogen phosphate.

[0009] Preferably, the particle size of the potassium hydrogen phosphate salt is below 100 μm.

[0010] The preparation method of the thermosensitive chitosan hydrogel-modified injectable magnesium phosphate bone cement of the present invention comprises the following steps:

[0011] (1) mixing trimagnesium phosphate and potassium hydrogen phosphate to obtain a solid phase powder;

[0012] (2) mixing the chitosan aqueous solution and the β-sodium glycerophosphate aqueous solution to obtain a solidified solution;

[0013] (3) Mixing the solid phase powder and the solidifying liquid to obtain the injectable magnesium phosphate bone cement modified by the temperature-sensitive chitosan hydrogel.

[0014] Preferably, the preparation method of trimagnesium phosphate comprises the following steps:

[0015] (1) Magnesium hydrogen phosphate trihydrate and magnesium hydroxide are mixed uniformly in a solid phase at a molar ratio of 2:1;

[0016] (2) The material ground in step (1) is calcined in a furnace at 1150-1400° C. for 2-5 hours, and then ground again after cooling to obtain trimagnesium phosphate powder with a particle size of 1-30 μm.

[0017] Preferably, in step (1), the grinding is as follows: magnesium hydrogen phosphate trihydrate and magnesium hydroxide are mixed by ball milling at 300-400 rpm in an ethanol medium for 2-4 hours, and then dried at 60-100°C.

[0018] Preferably, in step (2), the grinding is: ball milling the sintered cake in an ethanol medium at 300-400 rpm for 4-18 hours, and drying at 60-100°C.

[0019] Invention mechanism:

[0020] Chitosan (CS) is a natural polymer with unique advantages such as biodegradability, biocompatibility, mucosal adhesion, non-toxicity and specific biological activity. The abundant amino and hydroxyl functional groups on CS make it react with crosslinkers to form polymers, thereby forming specific hydrogels in situ. Sodium β-glycerophosphate (β-GP) is a natural crosslinker that can catalyze the sol / gel transition in CS solutions in physiological environments.

[0021] Utilizing the phase transition properties of thermosensitive chitosan / β-sodium glycerophosphate hydrogel, a method for preparing injectable magnesium phosphate bone cement modified by thermosensitive chitosan hydrogel is proposed to improve the injectability of bone cement. At the same time, the copolymer is transformed into gel when injected into the body, which wraps the magnesium phosphate bone cement to prevent disintegration, thus proposing a new approach to solving the clinical safety problem of calcium phosphate bone cement.

[0022] In the present invention, the thermosensitive hydrogel is applied to the magnesium phosphate bone cement system. At 37°C, the chitosan gel and the potassium magnesium phosphate gel formed by the hydration of magnesium phosphate form a synergistic effect, so that the microstructure has special three-dimensional pores.

[0023] The hydration reaction of magnesium phosphate bone cement is essentially an acid-base neutralization exothermic reaction. This process can be roughly divided into three stages: first, the reactant trimagnesium phosphate dissolves to form a hydrogel; then an acid-base reaction occurs, and this reaction is an exothermic reaction, and more and more hydration products are generated; finally, as the reaction proceeds, more and more gel bodies are produced, and the crystals of the hydration products continue to grow and aggregate, and the connections of the gel bodies become more and more dense, eventually forming a hardened structure, so that the hardened body of magnesium phosphate has high mechanical properties.

[0024] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: (1) Thermosensitive chitosan / sodium β-glycerophosphate is used as a modifier, and its aqueous solution has good fluidity at low temperatures, which is beneficial to improving the injectability of bone cement slurry; after injection into the body, the copolymer undergoes a gel phase transition to form a dense network to wrap the calcium phosphate bone cement and prevent the bone cement from disintegrating; (2) The material has good biocompatibility and degradability, and magnesium phosphate bone cement has good osteogenic ability, promotes osteoblast growth, and accelerates the healing of bone defects; at the same time, the degradation of chitosan increases the porosity of magnesium phosphate, which is beneficial to the growth of cells and blood vessels inside the material, thereby enhancing the healing and repair ability of bone defects. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 This is a SEM image of the bone cement prepared in Example 1 after curing;

[0026] Figure 2 This is the anti-collapse diagram of the bone cement prepared in Example 1. DETAILED DESCRIPTION

[0027] The technical solution of the present invention is further described below in conjunction with embodiments.

[0028] Example 1

[0029] The preparation method of the injectable magnesium phosphate bone cement modified by the temperature-sensitive chitosan hydrogel of the present invention comprises the following steps:

[0030] (1) 120 g of magnesium hydrogen phosphate trihydrate and 20 g of magnesium hydroxide were mixed by ball milling at 300 rpm in an ethanol medium for 4 h, dried at 60° C., and then calcined in a muffle furnace at 1150° C. for 5 h. The product was ball milled at 400 rpm in an ethanol medium for 18 h and dried at 60° C. to obtain trimagnesium phosphate powder with a particle size of 1 to 10 μm.

[0031] (2) 60 parts (by mass) of trimagnesium phosphate and 40 parts (by mass) of potassium dihydrogen phosphate (with a particle size of less than 100 μm) obtained in step (1) were ball-milled in an ethanol medium at 400 rpm for 2 h, and then dried at 60° C. to prepare a bone cement solid phase powder.

[0032] (3) Dissolve chitosan (acetylation degree 95%) in 0.5 mol / L citric acid solution to prepare a 4% (w / v) chitosan solution, and prepare a 50% (w / v) solution of sodium β-glycerophosphate. Mix the two solutions in a volume ratio of 9:1 to obtain a bone cement curing solution.

[0033] (4) The above-mentioned bone cement solid phase powder and bone cement solidification liquid are blended at a solid-liquid ratio of 2 g / mL to obtain an injectable magnesium phosphate bone cement modified with a temperature-sensitive chitosan hydrogel.

[0034] Depend on Figure 1 The SEM image of the bone cement prepared in Example 1 after curing shows that the bone cement has a porous structure after curing.

[0035] Depend on Figure 2 The anti-collapse diagram of the bone cement prepared in Example 1 shows that the bone cement slurry does not collapse when injected into deionized water.

[0036] The bone cement prepared in Example 1 has an injectability of 99% and a compressive strength of 17 MPa.

[0037] Example 2

[0038] The preparation method of the injectable magnesium phosphate bone cement modified by the temperature-sensitive chitosan hydrogel of the present invention comprises the following steps:

[0039] (1) The preparation method of trimagnesium phosphate powder is the same as that in Example 1;

[0040] (2) 60 parts (by mass) of trimagnesium phosphate and 40 parts (by mass) of anhydrous dipotassium hydrogen phosphate (with a particle size of less than 100 μm) were ball-milled in an ethanol medium at 400 rpm for 2 h, and then dried at 60° C. to prepare a bone cement solid phase powder;

[0041] (3) Dissolve chitosan (acetylation degree 95%) in 0.1 mol / L citric acid solution to prepare a 3% (w / v) chitosan solution, and prepare a 50% (w / v) solution of sodium β-glycerophosphate. Mix the two solutions in a volume ratio of 9:1 to obtain a bone cement curing solution;

[0042] (4) The above-mentioned bone cement solid phase powder and bone cement solidification liquid are blended at a solid-liquid ratio of 4 g / mL to obtain an injectable magnesium phosphate bone cement modified with a thermosensitive chitosan hydrogel.

[0043] The bone cement prepared in Example 2 has an injectability of 99% and a compressive strength of 27 MPa.

[0044] Example 3

[0045] The preparation method of the injectable magnesium phosphate bone cement modified by the temperature-sensitive chitosan hydrogel of the present invention comprises the following steps:

[0046] (1) The preparation method of trimagnesium phosphate powder is the same as that in Example 1;

[0047] (2) 75 parts of trimagnesium phosphate and 25 parts of potassium dihydrogen phosphate (particle size of less than 100 μm) were ball-milled in an ethanol medium at 400 rpm for 2 h, and dried at 60° C. to prepare a bone cement solid phase powder;

[0048] (3) Dissolve chitosan (acetylation degree 95%) in 0.1 mol / L citric acid solution to prepare a 3% (w / v) chitosan solution, and prepare a 50% (w / v) solution of sodium β-glycerophosphate. Mix the two solutions in a volume ratio of 9:1 to obtain a bone cement curing solution;

[0049] (4) The above-mentioned bone cement solid phase powder and bone cement solidification liquid are blended at a solid-liquid ratio of 4 g / mL to obtain an injectable magnesium phosphate bone cement modified with a thermosensitive chitosan hydrogel.

[0050] The bone cement prepared in Example 3 has an injectability of 99% and a compressive strength of 46 MPa.

Claims

1. An injectable magnesium phosphate bone cement modified with a temperature-sensitive chitosan hydrogel, characterized in that: It comprises solid phase powder and solidifying liquid; the solid phase powder comprises trimagnesium phosphate and potassium hydrogen phosphate; the solidifying liquid is obtained by mixing 1-4% (w / v) chitosan aqueous solution and 10-50% (w / v) beta-sodium glycerophosphate aqueous solution in a volume ratio of 5:5-9.

2. The injectable magnesium phosphate bone cement modified by thermosensitive chitosan hydrogel according to claim 1, characterized in that: The solid-to-liquid ratio of the solid phase powder to the solidified liquid is 2-4 g / mL.

3. The injectable magnesium phosphate bone cement modified by thermosensitive chitosan hydrogel according to claim 1, characterized in that: The chitosan has a deacetylation degree of 75-95%.

4. The injectable magnesium phosphate bone cement modified by thermosensitive chitosan hydrogel according to claim 1, characterized in that: The solid phase powder comprises, by weight: 50 to 80 parts of trimagnesium phosphate and 20 to 50 parts of potassium hydrogen phosphate.

5. The injectable magnesium phosphate bone cement modified by thermosensitive chitosan hydrogel according to claim 1, characterized in that: The potassium hydrogen phosphate salt is potassium dihydrogen phosphate, dipotassium hydrogen phosphate trihydrate or anhydrous dipotassium hydrogen phosphate.

6. The injectable magnesium phosphate bone cement modified by thermosensitive chitosan hydrogel according to claim 1, characterized in that: The particle size of the potassium hydrogen phosphate salt is below 100 μm.

7. A method for preparing the injectable magnesium phosphate bone cement modified by the temperature-sensitive chitosan hydrogel according to claim 1, characterized in that: The following steps are involved: (1) mixing trimagnesium phosphate and potassium hydrogen phosphate to obtain a solid phase powder; (2) mixing the chitosan aqueous solution and the β-sodium glycerophosphate aqueous solution to obtain a solidified solution; (3) Mixing the solid phase powder and the solidifying liquid to obtain the injectable magnesium phosphate bone cement modified by the temperature-sensitive chitosan hydrogel.

8. The method for preparing the injectable magnesium phosphate bone cement modified by thermosensitive chitosan hydrogel according to claim 7, characterized in that: The preparation method of trimagnesium phosphate comprises the following steps: (1) Magnesium hydrogen phosphate trihydrate and magnesium hydroxide are mixed uniformly in a solid phase at a molar ratio of 2:1; (2) The material ground in step (1) is calcined in a furnace at 1150-1400° C. for 2-5 hours, and then ground again after cooling to obtain trimagnesium phosphate powder with a particle size of 1-30 μm.

9. The method for preparing the injectable magnesium phosphate bone cement modified by thermosensitive chitosan hydrogel according to claim 7, characterized in that: In step (1), the mixing is as follows: magnesium hydrogen phosphate trihydrate and magnesium hydroxide are mixed by ball milling at 300-400 rpm in an ethanol medium for 2-4 hours, and then dried at 60-100°C.

10. The method for preparing the injectable magnesium phosphate bone cement modified by thermosensitive chitosan hydrogel according to claim 7, characterized in that: In step (2), the grinding is as follows: the sintered cake is ball-milled in an ethanol medium at 300-400 rpm for 4-18 hours, and then dried at 60-100°C.

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