High-bending-resistance injectable magnesium phosphate bone cement and preparation method thereof

Abstract

The invention provides high-bending-resistance injectable magnesium phosphate bone cement. The high-bending-resistance injectable magnesium phosphate bone cement is prepared from solid-phase powder, reinforcing filler and water, the solid-phase powder comprises the following components in parts by weight: 50-70 parts of magnesium phosphate salt and 30-50 parts of hydrogen phosphate, and the magnesium phosphate salt comprises trimagnesium phosphate; the reinforcing filler comprises a polyurethane modified epoxy resin emulsion; based on the polyurethane modified epoxy resin emulsion with the solid content of 30%-50%, the mass fractions of the solid phase powder, the reinforcing filler and the water in the bone cement are 66-70 wt%, 1-7 wt% and 23-33 wt% respectively. The high-bending-resistance injectable magnesium phosphate bone cement is high in bending strength and suitable for bone defect areas bearing multidirectional loads.

Description

Technical Field

[0001] The present invention relates to the technical field of bone cement, and particularly relates to a highly bend-resistant injectable magnesium phosphate bone cement and a preparation method thereof. Background Art

[0002] As a highly malleable and self-curing bone repair material, injectable bone cement is mostly used for filling bone defect sites. At present, the two bone cements most commonly used clinically are polymethyl methacrylate (ABCs) and calcium phosphate (CPCs). Among them, polymethyl methacrylate has high mechanical strength and good operability, but its disadvantages such as large heat release during the reaction, lack of bioactivity, and difficulty in degradation limit its clinical application. Calcium phosphate has good biocompatibility and osteoconductivity, but its mechanical strength is poor, especially the flexural strength, and its degradation rate is relatively fast, which cannot match the speed of new bone formation. Therefore, its application is limited to defect areas that only bear compressive loads.

[0003] A large number of studies have shown that magnesium ions play a decisive role in the formation of hydroxyapatite (HAP) crystals, promoting osteoblast adhesion, and increasing bone density. As a new type of bone repair material, magnesium phosphate bone cement (MPCs) has been widely studied due to its advantages such as rapid early strength development and good bone integration ability. The compressive strength of magnesium phosphate bone cement can reach 110 MPa, but the flexural strength is much less than the 30 MPa required clinically, and in some areas, it needs to be more than 50 MPa. In order to adapt to bone defect areas such as the distal radius that bear multi-directional loads, magnesium phosphate bone cement needs to be further compounded and strengthened in order to become a clinical alternative to polymethyl methacrylate bone cement. Summary of the Invention

[0004] In order to solve the problems in the background art, the present invention provides a highly bend-resistant injectable magnesium phosphate bone cement and a preparation method thereof. This bone cement has high flexural strength and is particularly suitable for bone defect areas that bear multi-directional loads.

[0005] The technical solution of the present invention to solve the above technical problems is as follows:

[0006] In the first aspect, the present invention provides a highly bend-resistant injectable magnesium phosphate bone cement, which includes a solid-phase powder, a reinforcing filler, and water;

[0007] The solid-phase powder includes the following components in parts by weight: 50-70 parts of magnesium phosphate salt and 30-50 parts of hydrogen phosphate salt, and the magnesium phosphate salt includes trimagnesium phosphate;

[0008] The reinforcing filler includes a polyurethane-modified epoxy resin emulsion;

[0009] Based on the polyurethane-modified epoxy resin emulsion with a solid content of 30% to 50%, the mass percentages of the solid phase powder, reinforcing filler, and water in the bone cement are 66 - 70 wt%, 1 - 7 wt%, and 23 - 33 wt% respectively.

[0010] According to the above scheme, the magnesium phosphate salt further includes at least one of magnesium pyrophosphate, magnesium hypophosphite, and magnesium hydrogen phosphate, and the mass percentage of magnesium phosphate tribasic in the magnesium phosphate salt is not less than 50%.

[0011] According to the above scheme, the hydrogen phosphate is at least one of sodium dihydrogen phosphate, calcium dihydrogen phosphate, potassium hydrogen phosphate, ammonium dihydrogen phosphate, and calcium hydrogen phosphate.

[0012] According to the above scheme, the polyurethane-modified epoxy resin is composed of the following raw materials by mass percentage: 25% - 35% of diisocyanate, 30% - 35% of polyethylene glycol, 5% - 10% of Ymer-N120, 25% - 30% of epoxy resin, and 0.05% - 0.1% of catalyst.

[0013] The diisocyanate is isophorone diisocyanate; the relative molecular weight of polyethylene glycol is one of 400, 800, and 2000; the epoxy resin is one or more of E-35, E-44, and E-51, and the catalyst is dibutyltin dilaurate (DBTDL).

[0014] According to the above scheme, the polyurethane-modified epoxy resin emulsion is prepared by the following method:

[0015] 1) Catalytic reaction of polyethylene glycol and diisocyanate in a solvent to generate a polyurethane precursor, adding Ymer-N120 to continue the chain extension reaction, and then adding epoxy resin to react to obtain a polyurethane-modified epoxy resin;

[0016] 2) Adding deionized water to the polyurethane-modified epoxy resin obtained in step 1) and stirring at high speed for emulsification, and removing the solvent to obtain a polyurethane-modified epoxy resin emulsion.

[0017] Specifically, the preparation method is as follows:

[0018] 1) Polyethylene glycol is vacuum dehydrated at 120°C for 2 - 3 h, then cooled to room temperature, acetone is added, and then diisocyanate and catalyst are dissolved therein. The temperature is raised to 70 - 75°C and continuously stirred for 2 - 3 h to form a polyurethane precursor; the temperature is cooled to 60 - 65°C, Ymer-N120 is added, and the chain extension reaction is continued for 1 - 2 h. Then the temperature is raised to 70 - 90°C, epoxy resin is added, and kept warm for 2 - 3 h to obtain a polyurethane-modified epoxy resin;

[0019] 2) In the polyurethane-modified epoxy resin obtained in step 1), deionized water is added and emulsified under high-speed stirring for 0.5 - 1 h, and then acetone is removed to obtain a polyurethane-modified epoxy resin emulsion.

[0020] According to the above solution, the reinforcing filler further includes a macromolecular polysaccharide containing carboxyl groups. The polyurethane-modified epoxy resin emulsion and the macromolecular polysaccharide form a composite emulsion, and the mass ratio of the polyurethane-modified epoxy resin to the macromolecular polysaccharide in the composite emulsion is (30 - 50):(1 - 7).

[0021] Based on the composite emulsion formed by the polyurethane-modified epoxy resin emulsion with a solid content of 30 - 50% and the macromolecular polysaccharide, the mass fractions of the polyurethane-modified epoxy resin and the macromolecular polysaccharide in the composite emulsion are 30 - 50 wt% and 1 - 7 wt% respectively.

[0022] According to the above solution, the macromolecular polysaccharide is at least one of sodium alginate and chitosan.

[0023] Preferably, the macromolecular polysaccharide is sodium alginate.

[0024] In a second aspect, the present invention provides a method for preparing the above injectable magnesium phosphate bone cement, including the following steps:

[0025] 1) Prepare a solid-phase powder and a reinforcing filler respectively;

[0026] 2) After fully mixing the solid-phase powder, the reinforcing filler and water, a highly bendable injectable magnesium phosphate bone cement slurry is obtained. After the slurry is cured, the highly bendable injectable magnesium phosphate bone cement is obtained.

[0027] The beneficial effects of the present invention are:

[0028] 1) In the present invention, polyurethane-modified epoxy resin is added as a reinforcing filler to the magnesium phosphate bone cement. On the one hand, the polyurethane-modified epoxy resin has good hydrophilicity. On the other hand, its emulsion can quickly cure into a film at room temperature. The formed film has good viscoelasticity, and the film-forming rate will be increased in an alkaline environment. In summary, the hydrophilicity and the characteristic of quickly curing into a viscoelastic film of the polyurethane-modified epoxy resin enable it to form good compatibility with the magnesium phosphate bone cement as a reinforcing filler. Specifically, after introducing the polyurethane-modified epoxy resin emulsion into the magnesium phosphate bone cement, its strong hydrophilic property not only ensures the uniform dispersion with the inorganic powder, but also effectively inhibits the demulsification and two-phase separation phenomena. At the same time, the polyurethane-modified epoxy resin forms a continuous transverse film through crosslinking curing, playing a microstructure regulation role in the magnesium phosphate bone cement matrix. This film fully fills the large-size defect holes, blocks the penetration path of the connected pores, realizes the reduction of the apparent porosity, and finally improves the bending strength of the composite bone cement;

[0029] 2) Further, the present invention uses the composite emulsion formed by polyurethane-modified epoxy resin and macromolecular polysaccharide as the reinforcing filler of magnesium phosphate bone cement. A stable composite system is formed between the polyurethane-modified epoxy resin and the macromolecular polysaccharide through hydrogen bonds. After mixing with the solid-phase powder and water, the carboxyl groups on the macromolecular polysaccharide 2+ undergo coordination chelation with Mg, forming a cross-linked network such as magnesium alginate hydrogel, etc., and through adsorption actions such as hydrogen bonds, the polyurethane-modified epoxy resin is anchored on the surface of magnesium ions and continuously enriched, achieving the effect of in-situ reinforcement. During the nucleation and growth stage of magnesium phosphate bone cement crystals (struvite), through the bridging action of the macromolecular polysaccharide, the polyurethane-modified epoxy resin is directionally induced to deposit on the surface of the crystals in the magnesium phosphate bone cement, and an organic coating layer with a controllable thickness is formed through interfacial self-assembly, finally forming a stable and continuous organic-inorganic double-network structure composite bone cement material. At the same time, this in-situ embedding mechanism realizes precise interfacial engineering at the single-crystal scale. When bearing radial loads, this structure can effectively disperse the main crack into microcracks and spread them along the thin film network to the distal end, fully dissipating the stress. Therefore, on the one hand, the composite emulsion optimizes the harmful pore structures such as large pores inside the bone cement through physical filling, closes some connected pores, and reduces the porosity. On the other hand, through the chemical bonding action of sodium alginate, the bonding strength at the interface between the polyurethane-modified epoxy resin and the magnesium phosphate bone cement is improved, and nanoscale coating of the polyurethane-modified epoxy resin at the grain boundaries of struvite is achieved. Finally, through the synergistic effect of physical filling and chemical bonding, the flexural strength of the magnesium phosphate bone cement is significantly improved, making it more suitable for bone defect areas that bear multi-directional loads;

[0030] 3) The reinforcing filler reduces the viscosity of the magnesium phosphate bone cement, prolongs its curing time, and improves its underwater anti-collapse performance, which is beneficial to the improvement of the clinical operability of the bone cement and further ensures the operation safety during clinical application;

[0031] 4) The composite emulsion of the present invention is weakly acidic during the degradation process, can neutralize the pH value of the magnesium phosphate bone cement, avoid causing continuous cell damage at the long-term implantation site, and at the same time, the composite emulsion and Mg 2+ synergistically improve the new bone repair rate at the critical bone defect site. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 are the cross-sectional SEM images of the high-flexural-strength injectable magnesium phosphate bone cement of Example 1 and Example 4 of the present invention and the magnesium phosphate bone cement of Comparative Example 1 after curing;

[0033] Figure 2 is the XRD pattern of the hydration product of the high-flexural-strength injectable magnesium phosphate bone cement prepared in Example 2 of the present invention after curing;

[0034] Figure 3The thermogravimetric curve after curing of the highly bend-resistant injectable magnesium phosphate bone cement prepared in Example 3 of the present invention;

[0035] Figure 4 The stress-displacement curve of three-point bending after curing of the highly bend-resistant injectable magnesium phosphate bone cement prepared in Example 4 of the present invention and the magnesium phosphate bone cement of Comparative Example 1;

[0036] Figure 5 The viscosities of the slurries of the highly bend-resistant injectable magnesium phosphate bone cement prepared in Example 4 of the present invention and the magnesium phosphate bone cement of Comparative Example 1;

[0037] Figure 6 The curing times of the slurries of the highly bend-resistant injectable magnesium phosphate bone cement prepared in Example 4 of the present invention and the magnesium phosphate bone cement of Comparative Example 1;

[0038] Figure 7 The underwater anti-collapse test diagram of the highly bend-resistant injectable magnesium phosphate bone cement prepared in Example 4 of the present invention;

[0039] Figure 8 The SEM diagrams of surface cell adhesion after curing of the highly bend-resistant injectable magnesium phosphate bone cement prepared in Example 4 of the present invention and the magnesium phosphate bone cement of Comparative Example 1;

[0040] Figure 9 The repair condition of the highly bend-resistant injectable magnesium phosphate bone cement prepared in Example 5 of the present invention at the skull defect site of a mouse. Detailed implementation manners

[0041] The principles and features of the present invention are described below in conjunction with the accompanying drawings and specific embodiments. The examples given are only used to explain the present invention and are not intended to limit the scope of the present invention.

[0042] In order to improve the bending resistance of magnesium phosphate bone cement, the inventor added a polyurethane-modified epoxy resin emulsion or a composite emulsion formed by a polyurethane-modified epoxy resin and a macromolecular polysaccharide as a reinforcing filler, significantly improving the bending strength of the magnesium phosphate bone cement, making it more suitable for bone defect areas that bear multi-directional loads. At the same time, the clinical operability is improved through the reinforcing filler, promoting the repair rate of new bone.

[0043] The present invention provides a highly bend-resistant injectable magnesium phosphate bone cement, comprising a solid-phase powder, a reinforcing filler, and water;

[0044] The solid-phase powder comprises the following components in parts by weight: 50-70 parts of magnesium phosphate salt and 30-50 parts of hydrogen phosphate, and the magnesium phosphate salt includes trimagnesium phosphate;

[0045] The reinforcing filler includes a polyurethane-modified epoxy resin emulsion;

[0046] Based on the polyurethane-modified epoxy resin emulsion with a solid content of 30% to 50%, the mass percentages of the solid-phase powder, water, and reinforcing filler in the bone cement are 66 - 70 wt%, 23 - 33 wt%, and 1 - 7 wt% respectively.

[0047] Water in the above components serves as the curing liquid for the magnesium phosphate bone cement.

[0048] The polyurethane-modified epoxy resin obtained by modifying epoxy resin with polyurethane not only has good hydrophilicity, can be physically mixed with the magnesium phosphate bone cement without phase separation or demulsification, and can be cured into a film, but also the formed film has good viscoelasticity and strong compatibility with the magnesium phosphate bone cement.

[0049] In some specific embodiments, the magnesium phosphate salt further includes at least one of magnesium pyrophosphate, magnesium hypophosphite, and magnesium hydrogen phosphate, and the mass percentage of the trimagnesium phosphate in the magnesium phosphate salt is not less than 50%.

[0050] In some specific embodiments, the hydrogen phosphate is at least one of sodium dihydrogen phosphate, calcium dihydrogen phosphate, potassium hydrogen phosphate, ammonium dihydrogen phosphate, and calcium hydrogen phosphate.

[0051] In some specific embodiments, the polyurethane-modified epoxy resin is composed of raw materials in the following mass percentages: 25% - 35% of diisocyanate, 30% - 35% of polyethylene glycol, 5% - 10% of Ymer-N120, 25% - 30% of epoxy resin, and 0.05% - 0.1% of catalyst.

[0052] The solid content of the polyurethane-modified epoxy resin emulsion is 30% - 50%.

[0053] In some specific embodiments, the diisocyanate is isophorone diisocyanate; the relative molecular weight of the polyethylene glycol is one of 400, 800, and 2000; the epoxy resin is one or more of E-35, E-44, and E-51, and the catalyst is dibutyltin dilaurate (DBTDL).

[0054] In some specific embodiments, the polyurethane-modified epoxy resin emulsion is prepared by the following method:

[0055] 1) Catalytic reaction of polyethylene glycol and diisocyanate in a solvent to generate a polyurethane precursor, adding Ymer-N120 to continue the chain extension reaction, and then adding epoxy resin for reaction to obtain the polyurethane-modified epoxy resin;

[0056] 2) Adding deionized water to the polyurethane-modified epoxy resin obtained in step 1) and stirring at high speed for emulsification, and removing the solvent to obtain the polyurethane-modified epoxy resin emulsion.

[0057] Specifically, the preparation method is as follows:

[0058] 1) Polyethylene glycol is dehydrated under vacuum at 120 °C for 2 - 3 h, then cooled to room temperature, acetone is added, and then diisocyanate and a catalyst are dissolved therein. The temperature is raised to 70 - 75 °C and continuously stirred for 2 - 3 h to form a polyurethane precursor; the temperature is cooled to 60 - 65 °C, and Ymer-N120 is added to continue the chain extension reaction for 1 - 2 h. Subsequently, the temperature is raised to 70 - 90 °C, and epoxy resin is added and kept warm for 2 - 3 h to obtain polyurethane-modified epoxy resin;

[0059] 2) Deionized water is added to the polyurethane-modified epoxy resin obtained in step 1) and emulsified under high-speed stirring for 0.5 - 1 h, and then acetone is removed to obtain a polyurethane-modified epoxy resin emulsion.

[0060] In some specific embodiments, the reinforcing filler further includes a macromolecular polysaccharide containing carboxyl groups. The polyurethane-modified epoxy resin emulsion and the macromolecular polysaccharide form a composite emulsion, and the mass ratio of the polyurethane-modified epoxy resin to the macromolecular polysaccharide in the composite emulsion is (30 - 50):(1 - 7).

[0061] In some specific examples, based on the composite emulsion formed by the polyurethane-modified epoxy resin emulsion with a solid content of 30 - 50% and the macromolecular polysaccharide, the mass fractions of the polyurethane-modified epoxy resin and the macromolecular polysaccharide in the composite emulsion are 30 - 50 wt% and 1 - 7 wt% respectively.

[0062] In some specific embodiments, the macromolecular polysaccharide is at least one of sodium alginate and chitosan.

[0063] Preferably, the macromolecular polysaccharide is sodium alginate.

[0064] The present invention also provides a preparation method of the above injectable magnesium phosphate bone cement, including the following steps:

[0065] 1) Prepare a solid-phase powder and a reinforcing filler respectively;

[0066] 2) After thoroughly mixing the solid-phase powder, the reinforcing filler and water, a high flexural strength injectable magnesium phosphate bone cement slurry is obtained, and the high flexural strength injectable magnesium phosphate bone cement is obtained after the slurry is cured.

[0067] The following are specific examples.

[0068] In the following specific embodiments, polyurethane-modified epoxy resin emulsions with solid contents of 30%, 40%, and 50% were respectively prepared. The raw material components of the polyurethane-modified epoxy resin are as follows: 8.88 g of diisocyanate (isophorone diisocyanate), 9.6 g of polyethylene glycol (molecular weight of 800), 2.48 g of Ymer-N120, 8 g of epoxy resin (E-44), and 2 drops of catalyst (DBTDL). They were prepared by the following method:

[0069] 1) Take 9.6 g of polyethylene glycol and put it into a three-necked flask. Vacuum dehydrate it at 120 °C for 2.5 h, then cool it to room temperature. Add 20 mL of acetone, and then add 8.88 g of diisocyanate and 2 - 3 drops of catalyst dissolved in it. Heat it up to 70 °C and continuously stir for 3 h to form a polyurethane precursor. Cool it to 60 °C, add 2.48 g of Ymer-N120, and continue the chain extension reaction for 2 h. Then heat it up to 85 °C, add 8 g of epoxy resin, and keep it warm for 3 h to finally obtain the polyurethane-modified epoxy resin.

[0070] 2) Add deionized water to the polyurethane-modified epoxy resin obtained in step 1), and emulsify it under high-speed stirring for 0.5 h. Then transfer it to a rotary evaporator to remove acetone, and obtain polyurethane-modified epoxy resin emulsions with different solid contents (30%, 40%, and 50%).

[0071] Example 1

[0072] In this example, a high flexural strength injectable magnesium phosphate bone cement was prepared. The raw materials were: 70 parts of Mg3(PO4)2, 30 parts of potassium dihydrogen phosphate, 40 parts of water, and 5 parts of polyurethane-modified epoxy resin with a solid content of 30%. Weighed the above raw materials by mass parts and prepared them by the following method:

[0073] Mix Mg3(PO4)2 and potassium dihydrogen phosphate evenly to prepare a solid-phase powder; after adding the polyurethane-modified epoxy resin emulsion with a solid content of 30% to the solid-phase powder, then add water, and stir at 20 °C for 3 min to obtain the high flexural strength injectable magnesium phosphate bone cement slurry.

[0074] Transfer the obtained slurry to a syringe and inject it into a mold for molding. After taking it out, hydrate it for 3 days and measure its average flexural strength.

[0075] Example 2

[0076] In this example, a highly bend-resistant injectable magnesium phosphate bone cement was prepared. The reinforcing filler was a composite emulsion composed of polyurethane-modified epoxy resin and sodium alginate. In the composite emulsion, the mass fraction of polyurethane-modified epoxy resin was 30 wt%, and the mass fraction of sodium alginate was 3 wt%. The raw materials for the highly bend-resistant injectable magnesium phosphate bone cement were: 60 parts of Mg3(PO4)2, 15 parts of calcium dihydrogen phosphate, 25 parts of potassium dihydrogen phosphate, 40 parts of water, and 3 parts of reinforcing filler. Weighed the above raw materials by mass parts and prepared them by the following method:

[0077] Mix Mg3(PO4)2, calcium dihydrogen phosphate, and potassium dihydrogen phosphate evenly to obtain a solid powder; after adding the composite emulsion to the solid powder, add water and stir at 20 °C for 3 min to obtain the highly bend-resistant injectable magnesium phosphate bone cement slurry.

[0078] Transfer the obtained slurry to a syringe and inject it into a mold for molding. After taking it out, hydrate it for 3 days and measure its average flexural strength.

[0079] Example 3

[0080] In this example, a highly bend-resistant injectable magnesium phosphate bone cement was prepared. The reinforcing filler was a composite emulsion composed of polyurethane-modified epoxy resin and sodium alginate. In the composite emulsion, the mass fraction of polyurethane-modified epoxy resin was 40 wt%, and the mass fraction of sodium alginate was 5 wt%. The raw materials for the highly bend-resistant injectable magnesium phosphate bone cement were: 70 parts of Mg3(PO4)2, 15 parts of sodium dihydrogen phosphate, 15 parts of disodium hydrogen phosphate, 45 parts of water, and 5 parts of reinforcing filler. Weighed the above raw materials by mass parts and prepared them by the following method:

[0081] Mix Mg3(PO4)2, sodium dihydrogen phosphate, and disodium hydrogen phosphate evenly to obtain a solid powder; after adding the composite emulsion to the solid powder, add water and stir at 20 °C for 3 min to obtain the highly bend-resistant injectable magnesium phosphate bone cement slurry.

[0082] Transfer the obtained slurry to a syringe and inject it into a mold for molding. After taking it out, hydrate it for 3 days and measure its average flexural strength.

[0083] Example 4

[0084] In this example, a highly bend-resistant injectable magnesium phosphate bone cement was prepared. The reinforcing filler was a composite emulsion composed of polyurethane-modified epoxy resin and sodium alginate. In the composite emulsion, the mass fraction of polyurethane-modified epoxy resin was 50 wt%, and the mass fraction of sodium alginate was 7 wt%. The raw materials for the highly bend-resistant injectable magnesium phosphate bone cement were: 70 parts of Mg3(PO4)2, 30 parts of potassium dihydrogen phosphate, 40 parts of water, and 5 parts of reinforcing filler. Weighed the above raw materials by mass parts and prepared them by the following method:

[0085] Mix Mg3(PO4)2 and potassium dihydrogen phosphate evenly to obtain a solid powder; add the composite emulsion to the solid powder, then add water, and stir at 20 °C for 3 min to obtain a highly bend-resistant injectable magnesium phosphate bone cement slurry.

[0086] Transfer the obtained slurry to a syringe, inject it into a mold to form, take it out and hydrate for 3 days, and measure its average flexural strength.

[0087] Example 5

[0088] In this example, a highly bend-resistant injectable magnesium phosphate bone cement was prepared. The reinforcing filler was a composite emulsion composed of polyurethane-modified epoxy resin and sodium alginate. The mass fraction of polyurethane-modified epoxy resin in the composite emulsion was 30 wt%, and the mass fraction of sodium alginate was 7 wt%. The raw materials of the highly bend-resistant injectable magnesium phosphate bone cement were: 60 parts of Mg3(PO4)2, 40 parts of sodium dihydrogen phosphate, 45 parts of water, and 5 parts of reinforcing filler. Weigh the above raw materials by mass parts and prepare them by the following method:

[0089] Mix Mg3(PO4)2 and sodium dihydrogen phosphate evenly to obtain a solid powder; add 1 part of the composite emulsion to the solid powder, then add water, and stir at 25 °C for 3 min to obtain a highly bend-resistant injectable magnesium phosphate bone cement slurry.

[0090] Transfer the obtained slurry to a syringe, inject it into a mold to form, take it out and hydrate for 3 days, and measure its average flexural strength.

[0091] Comparative Example 1

[0092] This comparative example provides a magnesium phosphate bone cement, and the raw materials include: 70 parts of Mg3(PO4)2, 30 parts of potassium dihydrogen phosphate, and 40 parts of water. Weigh the above raw materials by mass parts and prepare them by the following method:

[0093] Mix Mg3(PO4)2 and potassium dihydrogen phosphate evenly to obtain a solid powder; add water to the solid powder, and stir at 25 °C for 3 min to obtain a magnesium phosphate bone cement slurry.

[0094] Transfer the obtained magnesium phosphate bone cement to a syringe, inject it into a mold to form, take it out and hydrate for 3 days, and measure its average flexural strength.

[0095] Comparative Example 2

[0096] This comparative example provides a magnesium phosphate bone cement, and the raw materials include: 70 parts of Mg3(PO4)2, 30 parts of potassium dihydrogen phosphate, 45 parts of water, and 5 parts of 3 wt% SA solution. Weigh the above raw materials by mass parts and prepare them by the following method:

[0097] Mix Mg3(PO4)2 and potassium dihydrogen phosphate evenly to prepare a solid powder; add 5 parts of 3wt% SA solution to the solid powder, and then add water, and stir at 25°C for 3 min to obtain a magnesium phosphate-polysaccharide bone cement slurry.

[0098] Transfer the obtained magnesium phosphate-polysaccharide bone cement to a syringe and inject it into a mold for molding. After taking it out, hydrate it for 3 days and measure its average flexural strength.

[0099] Performance test

[0100] (1) Flexural strength test

[0101] Transfer the high-flexural-strength injectable magnesium phosphate bone cement prepared in Examples 1-5 and the magnesium phosphate bone cement obtained in Comparative Example 1 and Comparative Example 2 to a syringe and inject it into a mold for molding. After taking it out, hydrate it for 1 day and measure its average flexural strength. The results are shown in the following table:

[0102]

[0103] The average flexural strength of the magnesium phosphate bone cement in Comparative Example 1 is 17 MPa. In Example 1, due to the addition of polyurethane-modified epoxy resin as a reinforcing filler in the magnesium phosphate bone cement, its flexural strength is increased by 59%. In Examples 2-4, a composite emulsion formed by polyurethane-modified epoxy resin emulsion and macromolecular polysaccharide is added as a reinforcing filler, further increasing the flexural strength of the magnesium phosphate bone cement. Among them Figure 4 Figure 20 is the stress-displacement curve of three-point bending after curing of the high-flexural-strength injectable magnesium phosphate bone cement prepared in Example 4. Compared with the magnesium phosphate bone cement (Comparative Example 1), its flexural strength is increased by 206%.

[0104] (2) Characterization test

[0105] The SEM images of the magnesium phosphate bone cement in Comparative Example 1, the high-flexural-strength injectable magnesium phosphate bone cement in Example 1 and Example 4 after curing are as Figure 1 shown. Among them, at the fracture cross-section of Comparative Example 1, blocky crystals and plate-like crystal structures with clear edges can be observed, and no obvious cracks are found; in Example 1, the film formed by curing of polyurethane-modified epoxy resin forms a continuous layered structure on the surface of the bone cement, completely covering the crystals; in Example 4, the polymer layer covering the single crystals can be clearly observed on the cross-section, and there are cracks on the polymer layer, which may be due to the dispersion of the fracture load.

[0106] The XRD pattern of the magnesium phosphate bone cement in Example 2 after curing is as Figure 2 shown, indicating that the main component of the obtained bone cement is potassium magnesium phosphate.

[0107] (3) Thermogravimetric analysis

[0108] The high-bending-strength injectable magnesium phosphate bone cement prepared in Example 3 was cured and then subjected to thermogravimetric analysis. The results are as Figure 3 shown. An endothermic peak appeared at 600 - 650 °C, which was due to the carbonization and decomposition of the reinforcing filler at this temperature, indicating the presence of the composite film formed by polyurethane-modified epoxy resin and macromolecular polysaccharide.

[0109] (4) Tests on the viscosity, setting time, and underwater anti-collapse property of the high-bending-strength injectable magnesium phosphate bone cement

[0110] Figure 5 This is the shear rate-viscosity curve of the high-bending-strength injectable magnesium phosphate bone cement slurry prepared in Example 4 of the present invention. Compared with magnesium phosphate bone cement (Comparative Example 1), its initial viscosity decreased significantly, and it had better fluidity and injectability;

[0111] Figure 6 This is the setting time of the high-bending-strength injectable magnesium phosphate bone cement slurry prepared in Example 4 of the present invention. Compared with magnesium phosphate bone cement (Comparative Example 1), its setting time was extended by about 1 min. Although the difference was not significant, it still improved the workability of magnesium phosphate bone cement to a certain extent;

[0112] Figure 7 This is the test chart of the underwater anti-collapse property of the high-bending-strength injectable magnesium phosphate bone cement prepared in Example 4 of the present invention. When the bone cement was injected underwater, its injectability was not affected, and there was no obvious disintegration on the surface of the bone cement, indicating that the bone cement had stable anti-collapse ability;

[0113] The above results show that by adding a reinforcing filler to magnesium phosphate bone cement in the present invention, the viscosity, setting time, and anti-collapse property of magnesium phosphate bone cement are improved, and the obtained high-bending-strength injectable magnesium phosphate bone cement has better clinical workability;

[0114] (5) Cell adhesion of the high-bending-strength injectable magnesium phosphate bone cement

[0115] For cell morphology and adhesion analysis, the high-bending-strength injectable magnesium phosphate bone cements prepared in Comparative Example 1 and Example 4 were transferred to 48-well plates. 1 mL of complete medium was inoculated on the surface of the bone cement at a density of 2×10 4 Cell / mL -1 . After culturing for 24 h, the supernatant was removed from the wells. Subsequently, the cells were fixed with 4% paraformaldehyde. The fixed cells were washed three times with PBS, and the composite bone cement inoculated with cells was eluted stepwise with ethanol (20%, 40%, 60%, 80%), and the cell morphology on the surface of the composite bone cement was observed under a scanning electron microscope.

[0116] Figure 8SEM images of cell adhesion on the surface of the magnesium phosphate bone cement prepared in Comparative Example 1 and the highly bendable injectable magnesium phosphate bone cement prepared in Example 4 after curing. In Comparative Example 1, due to gradient elution, new crystals were formed by recrystallization on the surface of the bone cement, and no cells were observed. In Example 4, due to the chelation of Mg 2+ by polysaccharides in the composite emulsion, the growth of new crystals was restricted, and at the same time, cells adhered and spread on the surface of the bone cement. It shows that the highly bendable injectable magnesium phosphate bone cement prepared in the present invention has good cell compatibility and promotes cell adhesion;

[0117] (6) In-vivo osteogenic ability of the highly bendable injectable magnesium phosphate bone cement

[0118] When establishing the cranial model, the anesthesia of the mice was maintained by intraperitoneal injection of 1% sodium pentobarbital (50 mg / kg -1 ). After removing the cranial hair using an electric hair clipper, the mice were fixed in the prone position on a thermostatic operating table (37 °C), and the surgical area was alternately disinfected three times with iodophor and 75% ethanol. The upper layer of the cranial skin was incised in sequence, a round hole with a diameter of 3 mm was made on the skull using a puncher, and the bone chip was removed, thus establishing a cranial defect model. Subsequently, 6 mice were randomly selected and directly sutured as the blank control group, 10 mice were sutured after placing the magnesium phosphate bone cement of Comparative Example 1 with corresponding dimensions at the defect, and 10 mice were sutured after placing the highly bendable injectable magnesium phosphate bone cement of Example 5 with corresponding dimensions at the bone defect. After suturing the skin, an antibiotic ointment was applied locally. After the operation, the mice were housed individually in cages and fed with drinking water containing 0.1% antibiotic for analgesia for 3 days. The incision healing, activity, and body weight changes were observed daily, and individuals with infection or abnormal rejection were excluded.

[0119] At 6 weeks after the operation, half of the experimental group mice were sacrificed for sampling, and the remaining experimental mice were sacrificed at 12 weeks. During sampling, the mice were decapitated, and the cranial part was cut off and immersed in paraformaldehyde. After the above samples were taken out and washed, the paraformaldehyde on the surface was removed. The cranial defect site was scanned using micro-computed tomography (Micro-CT, Scanco Medical), and then the samples were reconstructed to form three-dimensional images.

[0120] Figure 9 Shown are the surface structures of the mice at 6 weeks and 12 weeks after the operation. No obvious new bone ingrowth was observed in the blank control group after 12 weeks. At 6 weeks, a small amount of new bone appeared at the defect and the edge of the bone cement in Comparative Example 1, while the amount of new bone in Example 5 was significantly increased. After 12 weeks, the surface of the bone cement in Example 5 was completely covered by new bone, and there was no gap between the host bone and the bone cement, forming a continuous bone bridge. However, there were still some pores at the interface in Comparative Example 1. The above data show that Example 5 exhibits significant bone integration advantages, which is due to Mg 2+The synergistic effect with the composite emulsion jointly promotes new bone formation.

[0121] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A highly flexurally resistant injectable magnesium phosphate bone cement, characterized in that: It includes solid phase powder, reinforcing filler and water; The solid phase powder comprises the following components in parts by weight: 50-70 parts of magnesium phosphate salt and 30-50 parts of hydrogen phosphate salt, wherein the magnesium phosphate salt comprises trimagnesium phosphate; The reinforcing filler includes polyurethane modified epoxy resin emulsion; Calculated on the basis of the polyurethane modified epoxy resin emulsion with a solid content of 30% to 50%, the mass fractions of the solid phase powder, the reinforcing filler and the water in the bone cement are 66-70wt%, 1-7wt% and 23-33wt% respectively.

2. The highly flexurally resistant injectable magnesium phosphate bone cement according to claim 1, characterized in that: The magnesium phosphate salt further comprises at least one of magnesium pyrophosphate, magnesium hypophosphite and magnesium hydrogen phosphate, and the mass percentage of the trimagnesium phosphate in the magnesium phosphate salt is not less than 50%.

3. The highly flexurally resistant injectable magnesium phosphate bone cement according to claim 1, characterized in that: The hydrogen phosphate is at least one of sodium dihydrogen phosphate, calcium dihydrogen phosphate, dipotassium hydrogen phosphate, ammonium dihydrogen phosphate and calcium dihydrogen phosphate.

4. The highly flexurally resistant injectable magnesium phosphate bone cement according to any one of claims 1 to 3, characterized in that: The polyurethane modified epoxy resin is composed of the following raw materials in percentage by mass: 25%-35% of diisocyanate, 30%-35% of polyethylene glycol, 5%-10% of Ymer-N120, 25%-30% of epoxy resin, and 0.05%-0.1% of catalyst.

5. The highly bending-resistant injectable magnesium phosphate bone cement according to claim 4, characterized in that: The polyurethane modified epoxy resin emulsion is prepared by the following method: 1) Polyethylene glycol and diisocyanate are catalytically reacted in a solvent to generate a polyurethane precursor, Ymer-N120 is added to continue the chain extension reaction, and then epoxy resin is added to react to obtain a polyurethane-modified epoxy resin; 2) adding deionized water to the polyurethane-modified epoxy resin obtained in step 1) and stirring at high speed for emulsification, and removing the solvent to obtain a polyurethane-modified epoxy resin emulsion.

6. The highly bending-resistant injectable magnesium phosphate bone cement according to claim 5, characterized in that: Step 1) is specifically as follows: the temperature of the catalytic reaction to generate the polyurethane precursor is 70-75°C and the time is 2-3h; the temperature of adding Ymer-N120 for chain extension reaction is 60-65°C and the time is 1-2h; the temperature of adding epoxy resin for reaction is 70-90°C and the time is 2-3h.

7. The highly bending-resistant injectable magnesium phosphate bone cement according to any one of claims 1 to 6, characterized in that: The reinforcing filler also includes a macromolecular polysaccharide containing a carboxyl group. The polyurethane modified epoxy resin emulsion and the macromolecular polysaccharide form a composite emulsion. The mass ratio of the polyurethane modified epoxy resin to the macromolecular polysaccharide in the composite emulsion is (30-50):(1-7).

8. The highly bending-resistant injectable magnesium phosphate bone cement according to claim 7, characterized in that: The macromolecular polysaccharide is at least one of sodium alginate and chitosan.

9. The highly bending-resistant injectable magnesium phosphate bone cement according to claim 8, characterized in that: The macromolecular polysaccharide is sodium alginate.

10. The method for preparing the highly flexurally resistant injectable magnesium phosphate bone cement according to any one of claims 1 to 9, characterized in that: The steps include: 1) preparing solid phase powder and reinforcing filler respectively; 2) After the solid phase powder, the reinforcing filler and water are fully mixed, a high bending resistance injectable magnesium phosphate bone cement slurry is obtained, and after the slurry is solidified, the high bending resistance injectable magnesium phosphate bone cement is obtained.

Images