Modified PMMA (polymethyl methacrylate) microspheres and preparation method thereof, and bone cement and preparation method thereof

Abstract

The invention discloses modified PMMA (polymethyl methacrylate) microspheres and a preparation method thereof as well as bone cement and a preparation method thereof, and the preparation method of the modified PMMA microspheres comprises the following steps: providing medicine powder, and dispersing the medicine powder into emulsion to obtain dispersion liquid; mixing deionized water, an emulsifier, an acrylic monomer, a methyl methacrylate monomer, the dispersion liquid, a first initiator and a cross-linking agent, and fully reacting at 60-80 DEG C to enable the drug powder to coat the PMMA core obtained by the reaction; and separating, cleaning and drying the reaction product to obtain the required modified PMMA microspheres. According to the preparation method of the modified PMMA microspheres, drug particles are introduced into a polymerization reaction process, and in the prepared modified PMMA microspheres, the drug particles are uniformly loaded and stably coated on the surfaces of the PMMA microspheres. In combination with a test case, compared with the traditional drug-doped bone cement, the drug in the bone cement disclosed by the invention has better slow release performance.

Description

Technical Field

[0001] The present invention relates to the technical field of medical materials, and in particular to a modified PMMA microsphere and a preparation method thereof, as well as bone cement comprising the modified PMMA microsphere and a preparation method thereof. Background Art

[0002] Bone cement is a medical material widely used in orthopedic surgery. Bone cement has good mechanical strength and bone conductivity. It is also the earliest local drug delivery system carrier used to treat bone infections. Polymethyl methacrylate (PMMA) bone cement is currently the most widely used bone cement in clinical practice.

[0003] Bone cement is widely used in the treatment of orthopedic diseases and bone repair. Bone cement doped with drugs (antibiotics) can effectively increase the concentration of drugs at the lesion site, thereby playing a role in preventing and controlling bone infection.

[0004] However, when traditional drug-doped bone cement is used, the drug on the surface of the bone cement is released quickly, while the drug inside the bone cement is difficult to release, which results in poor sustained-release performance of the drug in traditional bone cement. Summary of the invention

[0005] Based on this, it is necessary to provide a modified PMMA microsphere and a preparation method thereof that can solve the above problems.

[0006] In addition, it is also necessary to provide the modified PMMA microsphere bone cement and its preparation method.

[0007] A method for preparing modified PMMA microspheres comprises the following steps:

[0008] Providing drug powder, and dispersing the drug powder into an emulsion to obtain a dispersion;

[0009] Deionized water, an emulsifier, an acrylic acid monomer, a methyl methacrylate monomer, the dispersion, a first initiator and a crosslinking agent are mixed, and the mixture is reacted at 60° C. to 80° C. so that the drug powder is coated on the outside of the PMMA core obtained by the reaction, wherein the ratio of the deionized water, the emulsifier, the acrylic acid monomer, the methyl methacrylate monomer, the drug powder, the first initiator and the crosslinking agent is 100 mL to 120 mL: 0.5 g to 2.0 g: 0.5 g to 1 g: 10 g to 20 g: 1 g to 5 g: 0.1 g to 0.5 g: 0.05 g to 0.3 g;

[0010] The reaction product is separated, cleaned and dried to obtain the desired modified PMMA microspheres.

[0011] In one embodiment, the operation of providing the drug powder is: dissolving the drug in deionized water to prepare a 0.1w / v% to w / v1% drug solution; performing surface modification on the drug solution to achieve hydrophobic modification of the drug surface to form a preliminary hydrophobic coating; and preparing the drug powder having a particle size of 1μm to 5μm from the surface-modified drug solution through spray drying or freeze drying technology.

[0012] In one embodiment, the operation of surface modification treatment of the drug solution is: at least one of electrostatic spraying, chemical coupling and dispersant treatment;

[0013] The electrostatic spraying is to form a uniform charge distribution on the surface of the drug to enhance the binding force of the drug;

[0014] The chemical coupling is: adding a coupling agent to the drug solution to form a hydrophobic modification on the drug surface, wherein the coupling agent is a silane coupling agent or a functional coupling agent with a carboxyl group, and the mass ratio of the coupling agent to the drug is 1-5:100-200;

[0015] The dispersant treatment is: adding a dispersant with hydrophilic / hydrophobic properties to the drug solution so that the dispersant covers the drug to enhance the dispersibility and interface binding properties of the drug, wherein the mass ratio of the dispersant to the drug is 1-5:100-200;

[0016] The drug is selected from at least one of gentamicin, vancomycin, tigecycline, cefuroxime, rifampicin, clindamycin, tobramycin, erythromycin and colistin sulfate.

[0017] In one embodiment, the operation of mixing deionized water, emulsifier, acrylic acid monomer, methyl methacrylate monomer, the dispersion, the first initiator and the crosslinking agent and reacting them sufficiently so that the drug powder is coated on the PMMA core obtained by the reaction is as follows:

[0018] The deionized water, the emulsifier, the first acrylic acid monomer and the first methyl methacrylate monomer are mixed, and dissolved oxygen is removed to obtain an emulsion system, and the dispersion is added to the emulsion system under stirring, and stirring is continued until a stable emulsion is formed; then the first initiator is added to start the polymerization reaction to obtain semi-finished microspheres, wherein the semi-finished microspheres include a PMMA core obtained by the reaction and a portion of the drug powder coated on the outside of the PMMA core obtained by the reaction; then the second acrylic acid monomer and the second methyl methacrylate monomer are added, and the reaction is continued so that the PMMA obtained by the reaction is coated on the outside of the semi-finished microspheres to form a PMMA layer, and so that another part of the drug powder is coated outside the PMMA layer; finally, the cross-linking agent is added to fix the other part of the drug powder coated outside the PMMA layer and form a protective coating, wherein the acrylic acid monomer consists of the first acrylic acid monomer and the second acrylic acid monomer, the methyl methacrylate monomer consists of the first methyl methacrylate monomer and the second methyl methacrylate monomer, the mass ratio of the first acrylic acid monomer to the second acrylic acid monomer is 1-2:0-2, and the mass ratio of the first methyl methacrylate monomer to the second methyl methacrylate monomer is 3-7:3-7.

[0019] In one embodiment, the emulsion is an emulsifier solution with a concentration of 0.5 wt% to 2 wt%, and the concentration of the drug powder in the dispersion is 0.1 w / v% to 1 w / v%;

[0020] The emulsifier is selected from at least one of sodium lauryl sulfate, polyvinyl pyrrolidone (PVP) and polysorbate-80 (Tween-80);

[0021] The first initiator is selected from at least one of potassium persulfate and azobisisobutyronitrile;

[0022] The cross-linking agent is selected from at least one of polyethylene glycol derivatives and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.

[0023] In one embodiment, the mass ratio of the acrylic acid monomer, the methyl methacrylate monomer and the drug powder is 10:89:1, and the particle size of the modified PMMA microspheres is 20 μm to 50 μm.

[0024] A modified PMMA microsphere is prepared by the above-mentioned preparation method of the modified PMMA microsphere.

[0025] A method for preparing bone cement comprises the following steps:

[0026] 3 wt % to 10 wt % of the modified PMMA microspheres, 70 wt % to 85 wt % of PMMA prepolymer powder, 5 wt % to 10 wt % of a developer and 1 wt % to 3 wt % of a second initiator are uniformly mixed to obtain a mixed powder;

[0027] The mixed powder and the solidifying liquid are mixed evenly at a solid-liquid ratio of 1.5 g / mL to 2.5 g / mL, and the evenly mixed mixture is solidified at 17° C. to 25° C. to obtain the required PMMA bone cement.

[0028] In one embodiment, the developer is selected from at least one of zirconium oxide, barium sulfate and titanium oxide;

[0029] The second initiator is selected from at least one of benzoyl peroxide, tri-n-butylborane (TBB) and an azo compound;

[0030] The curing liquid consists of methyl methacrylate and N,N-dimethyl-p-toluidine in a mass ratio of 80-100:5.

[0031] A bone cement is prepared by the above-mentioned method for preparing bone cement.

[0032] The preparation method of the modified PMMA microspheres of the present invention introduces drug particles into a polymerization reaction process, and in the prepared modified PMMA microspheres, the drug particles are uniformly loaded and stably coated on the surface of the PMMA microspheres.

[0033] In the bone cement including the above-mentioned modified PMMA, the modified PMMA microspheres are uniformly distributed in the bone cement, and some drug particles are combined with other components in the bone cement, and then together with some drug particles grown in the modified PMMA microspheres, form a network distribution. As a result, when the bone cement is used, after the drug particles on the surface of the bone cement are dissolved and released, the remaining drugs in the network distribution inside the bone cement will also be slowly dissolved and released, thereby achieving the slow release of the drug particles in the bone cement, so that the bone cement has a long-term effect (anti-infection).

[0034] Combined with the test examples, compared with the traditional drug-doped bone cement, the sustained-release performance of the drug in the bone cement of the present invention is better.

[0035] Preferably, in the present invention, acrylic acid monomer and methyl methacrylate are divided into two parts and then added to the polymerization reaction successively (secondary addition). The addition of the second acrylic acid monomer and the second methyl methacrylate during the polymerization reaction allows some drug particles to penetrate into the middle region of the prepared modified PMMA microspheres. In the bone cement including such modified PMMA microspheres, each modified PMMA microsphere forms a node of a drug particle, so that the drug particles in the bone cement can form a larger network structure with a wider coverage, thereby further improving the sustained release performance of the drug in the bone cement.

[0036] Combined with the test examples, the modified PMMA microspheres prepared by secondary addition were applied to bone cement, which can significantly improve the sustained release performance of drugs in bone cement.

[0037] Preferably, in the present invention, by surface modification treatment of the drug solution, not only the binding force between the prepared drug particles and PMMA is improved, but also the particle size distribution of the obtained drug particles is made more uniform (1 μm to 5 μm), so that the drug particles can be uniformly loaded and stably coated on the PMMA surface, thereby improving the loading efficiency of the drug particles.

[0038] In addition, the uniformity of drug particle dispersion in the bone cement including the modified PMMA microspheres has also been greatly improved. Specifically, by adding surface-modified drug particles and functional coupling agents during the emulsion polymerization process, the compatibility of the particles with the PMMA matrix is ​​enhanced by using drug surface modifiers (such as KH570 or PEGDA), and the functional coupling agent copolymerizes with the monomer during the reaction process, thereby achieving stable embedding of drug particles in the PMMA microspheres. After adding PEG cross-linking agents, the network structure formed further improves the uniform deposition of drug particles on the surface of PMMA microspheres and avoids aggregation.

[0039] Combined with the test examples, the drug release time of the bone cement of the present invention in PBS (phosphate buffer) is 20 to 30 days, and its compressive strength is not less than 70 MPa, which meets the standard requirements of medical implants. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0041] in:

[0042] Figure 1The present invention is a flow chart of a method for preparing modified PMMA microspheres according to one embodiment. DETAILED DESCRIPTION

[0043] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0044] Combination Figure 1 The present invention discloses a method for preparing modified PMMA microspheres according to an embodiment of the present invention, comprising the following steps:

[0045] S10, providing drug powder, and dispersing the drug powder into an emulsion to obtain a dispersion.

[0046] Preferably, in this embodiment, the emulsion is an emulsifier solution with a concentration of 0.5 wt% to 2 wt%, and the concentration of the drug powder in the dispersion is 0.1 w / v% to 1 w / v%.

[0047] Preferably, in this embodiment, the emulsifier is selected from at least one of sodium dodecyl sulfate (SDS), polyvinyl pyrrolidone (PVP) and polysorbate-80 (Tween-80).

[0048] Preferably, in this embodiment, the operation of providing the drug powder is: dissolving the drug in deionized water to prepare a 0.1w / v% to w / v1% drug solution; performing surface modification on the drug solution to achieve hydrophobic modification of the drug surface to form a preliminary hydrophobic coating; and preparing a drug powder with a particle size of 1μm to 5μm from the surface modified drug solution through spray drying or freeze drying technology.

[0049] By surface modification of the drug solution, not only the binding force between the prepared drug particles and PMMA is improved, but also the particle size distribution of the obtained drug particles is made more uniform (1μm~5μm), so that the drug particles can be evenly loaded and stably coated on the PMMA surface, thereby improving the loading efficiency of the drug particles.

[0050] Specifically, in this embodiment, the operation of performing surface modification treatment on the drug solution is: performing surface modification treatment on the drug solution by at least one of electrostatic spraying, chemical coupling and dispersant treatment.

[0051] Electrostatic spraying can be used to form a uniform charge distribution on the surface of the drug to enhance the binding force of the drug.

[0052] Chemical coupling can be: adding a coupling agent to the drug solution to form a hydrophobic modification on the drug surface, wherein the coupling agent is a silane coupling agent or a functional coupling agent with a carboxyl group, and the mass ratio of the coupling agent to the drug is 1 to 5: 100 to 200. Specifically, the coupling agent can be a silane coupling agent KH570 or polyethylene glycol diacrylate (PEGDA).

[0053] The dispersant treatment may be: adding a dispersant having hydrophilic / hydrophobic properties to the drug solution so that the dispersant coats the drug to enhance the dispersibility and interface binding properties of the drug, wherein the mass ratio of the dispersant to the drug is 1-10:100-200. Specifically, the dispersant may be polyammonium acrylate (PAM).

[0054] Preferably, in this embodiment, the drug is selected from at least one of gentamicin, gentamicin sulfate, vancomycin, tigecycline, cefuroxime, rifampicin and clindamycin.

[0055] S20, mixing deionized water, emulsifier, acrylic acid monomer, methyl methacrylate monomer, dispersion, first initiator and crosslinking agent, and reacting them at 60° C. to 80° C. so that the drug powder is coated on the PMMA core obtained by the reaction.

[0056] Among them, the ratio of deionized water, emulsifier, acrylic acid monomer, methyl methacrylate monomer, drug powder, first initiator and cross-linking agent is 100mL~120mL: 0.5g~2.0g: 0.5g~1g: 10g~20g: 1g~5g: 0.1g~0.5g: 0.05g~0.3g.

[0057] Preferably, in this embodiment, the first initiator is selected from at least one of potassium persulfate and azobisisobutyronitrile (AIBN).

[0058] Preferably, in this embodiment, the cross-linking agent is selected from at least one of polyethylene glycol derivatives (eg, NHS-PEG-NHS) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).

[0059] Preferably, in this embodiment, the mass ratio of acrylic acid (AA) monomer, methyl methacrylate (MMA) monomer and drug powder is 10:89:1, and the particle size of the modified PMMA microspheres is 20 μm to 50 μm.

[0060] It should be noted that, through the operation of S20, the modified PMMA microspheres prepared in this embodiment include PMMA spheres and drug powder coated outside the PMMA spheres.

[0061] The modified PMMA microspheres are applied to bone cement, in which the modified PMMA microspheres are evenly distributed. Some drug particles are combined with other components in the bone cement, and then form a network distribution together with some drug particles grown in the modified PMMA microspheres. As a result, when the bone cement is used, after the drug particles on the surface of the bone cement are dissolved and released, the remaining drugs in the network distribution inside the bone cement will also be slowly dissolved and released, thereby achieving the slow release of the drug particles in the bone cement, which makes the bone cement have a long-lasting effect (anti-infection).

[0062] Preferably, in S20, deionized water, emulsifier, acrylic acid monomer, and methyl methacrylate monomer are first mixed (the ratio of water phase to oil phase is controlled to be 1:1 to 3:1), and then deoxygenated (deoxygenation can be performed by blowing nitrogen) to remove dissolved oxygen in the system to prevent oxidative inhibition of the polymerization reaction. Then, the dispersion is added to the emulsion system under stirring (slowly added by constant pressure dropwise addition), and then the first initiator is added to start the polymerization reaction. A cross-linking agent is added in the later stage of the polymerization reaction to fix the drug powder coated outside the PMMA ball and form a protective coating.

[0063] More preferably, in another embodiment, S20 is: deionized water, an emulsifier, a first acrylic acid monomer and a first methyl methacrylate monomer are mixed (the ratio of the aqueous phase to the oil phase is controlled to be 1:1 to 3:1), and the dissolved oxygen is removed (deoxygenation can be performed by blowing nitrogen) to obtain an emulsion system, and the dispersion is added to the emulsion system under stirring (slowly added by constant pressure dropwise addition), and stirring is continued until a stable emulsion is formed; then the first initiator is added to start the polymerization reaction to obtain semi-finished microspheres, the semi-finished microspheres including a PMMA core obtained by the reaction and a part of the drug powder coated outside the PMMA core obtained by the reaction; then the second acrylic acid monomer and the second methyl methacrylate monomer are added, and the reaction is continued so that the PMMA obtained by the reaction is coated on the outside of the semi-finished microspheres to form a PMMA layer, and another part of the drug powder is coated outside the PMMA layer; finally, a cross-linking agent is added in the later stage of the reaction to fix the other part of the drug powder coated outside the PMMA layer and form a protective coating.

[0064] Among them, the acrylic acid monomer consists of a first acrylic acid monomer and a second acrylic acid monomer, the methyl methacrylate monomer consists of a first methyl methacrylate monomer and a second methyl methacrylate monomer, the mass ratio of the first acrylic acid monomer to the second acrylic acid monomer is 1-2:0-2, and the mass ratio of the first methyl methacrylate monomer to the second methyl methacrylate monomer is 3-7:3-7.

[0065] The mass ratio of the first acrylic acid monomer to the second acrylic acid monomer is 1-2:0-2, that is, the acrylic acid monomer can be added once or twice without affecting the introduction of the drug particles during the reaction.

[0066] Specifically, as a hydrophobic monomer, MMA is more likely to combine with hydrophobic modified drug particles (such as particles modified with silane coupling agents or PEG derivatives) during the polymerization process to form a uniform drug coating layer. AA (acrylic acid) is usually used as a hydrophilic monomer, mainly to adjust the surface properties of the polymer (such as hydrophilicity or functionalization) or introduce cross-linking points, and is not suitable as a main monomer to be added in batches to achieve a coating effect.

[0067] It should be noted that, in this embodiment, the prepared modified PMMA microspheres include a PMMA core, an intermediate layer composed of a portion of drug powder and a PMMA layer, and an outer layer formed by another portion of drug powder.

[0068] It should be pointed out that, in this embodiment, the second acrylic acid monomer and the second methyl methacrylate monomer added for the second time can be added once or multiple times, and the specific adding method is set according to the actual situation.

[0069] In this embodiment, acrylic acid monomer and methyl methacrylate are divided into two parts and added to the polymerization reaction successively (secondary addition). The addition of the second acrylic acid monomer and the second methyl methacrylate during the polymerization reaction allows some drug particles to penetrate into the middle area of ​​the prepared modified PMMA microspheres. Such modified PMMA microspheres are applied to bone cement, and each modified PMMA microsphere forms a node of a drug particle, so that the drug particles in the bone cement can form a larger network structure with a wider coverage, thereby further improving the sustained release performance of the drug in the bone cement.

[0070] S30, separating, washing and drying the reaction product to obtain the desired modified PMMA microspheres.

[0071] Preferably, in this embodiment, the reaction product can be separated by centrifugation or ultrafiltration to remove unreacted monomers and impurities.

[0072] Preferably, in this embodiment, the reaction product may be cleaned once or twice with 50% to 70% by volume ethanol or isopropanol solution to remove the emulsifier and other impurities remaining on the surface.

[0073] Preferably, in this embodiment, the reaction product can be dried by vacuum drying at 40°C to 50°C or by rapid freezing and sublimation drying at -40°C.

[0074] In S30, by using mild conditions (such as ethanol solution washing and freeze drying) during the washing and drying process, drug loss or degradation can be avoided and drug activity can be protected.

[0075] In addition, the protective coating formed by the cross-linking agent on the surface of the drug particles, combined with the non-aqueous cleaning in S30, can minimize impurities while improving the durability of the drug particle coating.

[0076] The preparation method of the modified PMMA microspheres of the present invention introduces drug particles into a polymerization reaction process, and in the prepared modified PMMA microspheres, the drug particles are uniformly loaded and stably coated on the surface of the PMMA microspheres.

[0077] In the bone cement including the above-mentioned modified PMMA, the modified PMMA microspheres are uniformly distributed in the bone cement, and some drug particles are combined with other components in the bone cement, and then together with some drug particles grown in the modified PMMA microspheres, form a network distribution. As a result, when the bone cement is used, after the drug particles on the surface of the bone cement are dissolved and released, the remaining drugs in the network distribution inside the bone cement will also be slowly dissolved and released, thereby achieving the slow release of the drug particles in the bone cement, so that the bone cement has a long-term effect (anti-infection).

[0078] Combined with the test examples, compared with the traditional drug-doped bone cement, the sustained-release performance of the drug in the bone cement of the present invention is better.

[0079] In addition, the dispersion uniformity of drug particles in the bone cement including the above-mentioned modified PMMA microspheres is also greatly improved.

[0080] More preferably, in the present invention, acrylic acid monomer and methyl methacrylate are divided into two parts and then added to the polymerization reaction successively (secondary addition). The addition of the second acrylic acid monomer and the second methyl methacrylate during the polymerization reaction allows some drug particles to penetrate into the middle region of the prepared modified PMMA microspheres. In the bone cement including such modified PMMA microspheres, each modified PMMA microsphere forms a node of a drug particle, so that the drug particles in the bone cement can form a larger network structure with a wider coverage, thereby further improving the sustained release performance of the drug in the bone cement.

[0081] Combined with the test examples, the modified PMMA microspheres prepared by secondary addition were applied to bone cement, which can significantly improve the sustained release performance of drugs in bone cement.

[0082] The present invention also discloses an embodiment of the modified PMMA microspheres prepared by the above-mentioned preparation method of the modified PMMA microspheres.

[0083] The present invention also discloses a method for preparing bone cement according to an embodiment, comprising the following steps:

[0084] 3wt% to 10wt% of the modified PMMA microspheres, 70wt% to 85wt% of PMMA prepolymer powder, 5wt% to 10wt% of a developer and 1wt% to 3wt% of a second initiator are uniformly mixed to obtain a mixed powder; the mixed powder is uniformly mixed with a curing liquid at a solid-liquid ratio of 1.5g / mL to 2.5g / mL, and the uniformly mixed mixture is cured and formed at 17°C to 25°C to obtain the required PMMA bone cement.

[0085] The mixing operation can transfer part of the drug powder of the modified PMMA microspheres to other components, so that the surfaces of the PMMA prepolymer powder, developer and initiator are uniformly modified with the drug powder to further enhance the drug release ability of the bone cement.

[0086] Preferably, in this embodiment, the developer is selected from at least one of zirconium oxide, barium sulfate and titanium oxide.

[0087] More preferably, the particle size of zirconium oxide may be 10 nm to 50 nm, in which case the radiation barrier property of bone cement can be significantly improved without affecting the drug release behavior.

[0088] Preferably, in this embodiment, the second initiator is at least one selected from benzoyl peroxide (BPO), tri-n-butylborane (TBB) and an azo compound.

[0089] Preferably, in this embodiment, the curing liquid is composed of methyl methacrylate and N,N-dimethyl-p-toluidine in a mass ratio of 80 to 100:5.

[0090] Combined with the test examples, the drug release time of the bone cement of the present invention in PBS (phosphate buffer) is 20 to 30 days, and its compressive strength is not less than 70 MPa, which meets the standard requirements of medical implants.

[0091] Combined with the test examples, compared with the traditional drug-doped bone cement, the sustained-release performance of the drug in the bone cement of the present invention is better.

[0092] In addition, the dispersion uniformity of drug particles in the bone cement including the above-mentioned modified PMMA microspheres is also greatly improved.

[0093] Combined with the test examples, more preferably, in the present invention, the modified PMMA microspheres prepared by secondary addition are applied to bone cement, which can significantly improve the sustained release performance of the drug in the bone cement.

[0094] The present invention also discloses a bone cement prepared by the above-mentioned method for preparing bone cement in one embodiment.

[0095] The following are specific embodiments.

[0096] In a specific embodiment, gentamicin sulfate (Sigma-Aldrich; Catalog No.: G3632; purity: ≥99%), vancomycin (Cayman Chemical; Catalog No.: 11052; purity: ≥98%), tigecycline (Cayman Chemical; Catalog No.: 10003074; purity: ≥98%), silane coupling agent KH570 (Alfa Aesar; Catalog No.: H50707; purity: ≥98%), polyethylene glycol diacrylate (PEGDA) (Sigma-Aldrich; Catalog No.: 455008; molecular weight range: 700 to 1,000 Da), SDS (Sigma-Aldrich; Catalog No.: L3771; purity: ≥99%), MMA monomer (Sigma-Aldrich; Catalog No.: M55909; purity: ≥99%), AA monomer (Alfa Aesar; Catalog No.: A18642; purity: ≥99%), PMMA prepolymer powder (Evonik; particle size: 20-40μm), PMMA spheres (Cospheric LLC; particle size: 40-80μm), zirconium oxide (Tosoh Corporation; particle size: 5-10μm), benzoyl peroxide (TCI Chemicals; Catalog No.: B0346; purity: ≥98%), DMPT (TCI Chemicals; Catalog No.: D1932; purity: ≥98%), potassium persulfate (KPS) (Alfa Aesar; Catalog No.: A15830; purity: ≥98%), NHS-PEG-NHS (Nanocs; molecular weight: 5,000Da; Catalog No.: PEG-NHS-5000).

[0097] Example 1

[0098] 1. Preparation of modified PMMA microspheres

[0099] Gentamycin sulfate was dissolved in deionized water to prepare a 0.5wt% aqueous solution; KH570 (5% of gentamicin sulfate by mass) was added and stirred at room temperature for 30 minutes. A drug powder with a particle size of 1μm to 5μm was prepared by spray drying, and 5g of the drug powder was dispersed in 50mL of a 0.5wt% SDS solution to form a stable drug powder dispersion.

[0100] Add 100 mL of deionized water, 1.5 g of SDS, 5 g of MMA monomer and 0.5 g of AA monomer into a three-necked flask and adjust the water-oil ratio to 2:1; purge with nitrogen for 10 minutes to deoxygenate; slowly drop the drug powder dispersion into the emulsion system and stir to form a stable emulsion; add 0.2 g of potassium persulfate (KPS) and stir the reaction at 70°C for 3 h.

[0101] The remaining 5 g of MMA monomer was added in three times, with an interval of 30 minutes between each addition to ensure uniform coating of the drug particles; 0.2 g of NHS-PEG-NHS was added in the late stage of polymerization for surface immobilization.

[0102] The product was separated by centrifugation to remove unreacted monomers and impurities; the product was washed twice with 60% ethanol to remove impurities and emulsifiers; and vacuum dried at 40° C. for 6 h to obtain modified PMMA microspheres with a particle size of 20 μm to 50 μm.

[0103] 2. Preparation of bone cement

[0104] Place 3g of modified PMMA microspheres, 81g of PMMA prepolymer powder, 5g of zirconium oxide, and 1g of benzoyl peroxide (BPO) in a mechanical stirrer and stir for 15 minutes to ensure uniform dispersion to obtain a mixed powder. Mix MMA monomer with DMPT (98:2 mass ratio) to prepare a curing liquid. Mix 10g of the mixed powder with 5mL of the curing liquid and stir evenly to form a bone cement slurry. Pour the bone cement slurry into multiple molds and cure at 25°C for 24 hours to obtain 4 bone cements of 75mm long × 10mm wide × 3.3mm thick.

[0105] Example 2

[0106] 1. Preparation of modified PMMA microspheres

[0107] Vancomycin was dissolved in deionized water to prepare a 0.2wt% solution; 1,6-hexanedialdehyde (2% of the drug mass) was added and stirred at room temperature for 1h. Freeze-dried to obtain drug powder with a particle size of 1μm to 5μm, 3g of drug powder was dispersed in 100mL of 0.3wt% SDS solution, and ultrasonicated to form a stable drug powder dispersion.

[0108] Add 100 mL of deionized water, 1.5 g of SDS, 5 g of MMA monomer and 0.25 g of AA monomer into a three-necked flask and adjust the water-oil ratio to 2:1; purge with nitrogen for 10 minutes to deoxygenate; slowly drop the drug powder dispersion into the emulsion system and stir to form a stable emulsion; add 0.2 g of AIBN and polymerize at 65°C for 4 hours.

[0109] The remaining 5 g of MMA monomer and 0.25 g of AA were added in three portions, with an interval of 30 minutes between each addition to ensure uniform coating of the drug particles; 0.15 g of EDC was added in the later stage of polymerization to fix the drug particles.

[0110] The product was separated by centrifugation, washed with 70% isopropanol to remove impurities; and sublimation dried after freezing at -40°C to obtain modified PMMA microspheres with a particle size of 20 μm to 50 μm.

[0111] 2. Preparation of bone cement

[0112] Place 3g of modified PMMA microspheres, 81g of PMMA prepolymer powder, 5g of zirconium oxide, and 1g of benzoyl peroxide (BPO) in a mechanical stirrer and stir for 15 minutes to ensure uniform dispersion to obtain a mixed powder. Mix MMA monomer with DMPT (98:2 mass ratio) to prepare a curing liquid. Mix 10g of the mixed powder with 4.2mL of the curing liquid and stir evenly to form a bone cement slurry. Pour the bone cement slurry into multiple molds and cure at 25°C for 24 hours to obtain 4 bone cements of 75mm long × 10mm wide × 3.3mm thick.

[0113] Example 3

[0114] 1. Preparation of modified PMMA microspheres

[0115] Dissolve tigecycline in deionized water to prepare a 0.3 wt% solution. Add polyethylene glycol diacrylate (PEGDA, 3% of the drug mass) and stir at room temperature for 0.5 h. Spray dry to obtain drug particles with a particle size of 1 μm to 5 μm, then disperse 4 g of drug powder in 80 mL of 0.8 wt% SDS aqueous solution to form a stable dispersion.

[0116] Add 120 mL of deionized water, 2 g of SDS, 6 g of MMA and 0.34 g of AA monomer into a three-necked flask and adjust the water-oil ratio to 2:1; purge with nitrogen for 10 minutes to deoxygenate; slowly drop the drug powder dispersion into the emulsion system and stir to form a stable emulsion; add 0.3 g of potassium persulfate initiator and polymerize at 70°C for 3 h.

[0117] The remaining 5 g of MMA monomer and 0.66 g of AA monomer were added in three times, with an interval of 30 minutes each time to ensure uniform coating of the drug particles; 0.25 g of NHS-PEG-NHS was added in the late stage of polymerization for immobilization.

[0118] The product was separated by centrifugation to remove unreacted monomers and impurities; the product was washed twice with 70% ethanol to remove impurities and emulsifiers; and vacuum dried at 50° C. for 5 hours to obtain modified PMMA microspheres with a particle size of 20 μm to 50 μm.

[0119] 2. Preparation of bone cement

[0120] Place 3g of modified PMMA microspheres, 81g of PMMA prepolymer powder, 5g of zirconium oxide, and 1g of benzoyl peroxide (BPO) in a mechanical stirrer and stir for 15 minutes to ensure uniform dispersion to obtain a mixed powder. Mix MMA monomer with DMPT (98:2 mass ratio) to prepare a curing liquid. Mix 10g of the mixed powder with 4.5mL of the curing liquid and stir evenly to form a bone cement slurry. Pour the bone cement slurry into multiple molds and cure at 25°C for 24 hours to obtain 4 bone cements of 75mm long × 10mm wide × 3.3mm thick.

[0121] Example 4

[0122] 1. Preparation of modified PMMA microspheres

[0123] Dissolve gentamicin sulfate in deionized water to prepare a 0.5wt% aqueous solution; add KH570 (5% of gentamicin sulfate by mass) and stir at room temperature for 30 minutes. Prepare the modified particles into 1μm to 5μm drug powder by spray drying, and then disperse 6g of drug powder in 60mL 0.5% SDS solution to form a stable dispersion.

[0124] Add 100 mL of deionized water, 1.5 g of SDS, 10 g of MMA and 0.5 g of AA monomer into a three-necked flask and adjust the water-oil ratio to 2:1; purge with nitrogen for 10 minutes to deoxygenate; slowly add the drug powder to the emulsion system and stir to form a stable emulsion; add 0.2 g of potassium persulfate (KPS) and 0.2 g of NHS-PEG-NHS, and stir the reaction at 70°C for 3 h.

[0125] The product was separated by centrifugation to remove unreacted monomers and impurities; the product was washed twice with 60% ethanol to remove impurities and emulsifiers; and vacuum dried at 40° C. for 6 h to obtain modified PMMA microspheres with a particle size of 20 μm to 50 μm.

[0126] 2. Preparation of bone cement

[0127] Place 3g of modified PMMA microspheres, 81g of PMMA prepolymer powder, 5g of zirconium oxide, and 1g of benzoyl peroxide (BPO) in a mechanical stirrer and stir for 15 minutes to ensure uniform dispersion to obtain a mixed powder. Mix MMA monomer with DMPT (98:2 mass ratio) to prepare a curing liquid. Mix 10g of the mixed powder with 4.3mL of the curing liquid and stir evenly to form a bone cement slurry. Pour the bone cement slurry into multiple molds and cure at 25°C for 24 hours to obtain 4 bone cements of 75mm long × 10mm wide × 3.3mm thick.

[0128] Comparative Example 1

[0129] 84g of PMMA balls, 5g of zirconium oxide, and 1g of BPO were mixed to form uniform PMMA powder. MMA liquid (MMA:DMPT=95:5) was prepared and mixed at a ratio of 2.5g of powder to 1mL of liquid, and stirred to form bone cement slurry. The bone cement slurry was poured into multiple molds and cured at 25°C for 24 hours to obtain 4 bone cements of 75mm length×10mm width×3.3mm thickness.

[0130] Comparative Example 2

[0131] 82g of PMMA balls, 5g of zirconium oxide, 1g of BPO, and 2g of gentamicin sulfate were mixed to form uniform PMMA powder. MMA liquid (mass ratio MMA:DMPT = 95:5) was prepared, and the powder and liquid were mixed at a ratio of 2.5g:1mL, and the bone cement slurry was evenly stirred to form a bone cement slurry, which was poured into multiple molds and cured at 25°C for 24 hours to obtain 4 bone cements of 75mm long × 10mm wide × 3.3mm thick.

[0132] Test Case

[0133] 1. Dispersion uniformity test

[0134] (1) Sample preparation: Take 0.1 g of the modified PMMA microspheres of Examples 1 to 4 and the PMMA powder prepared in Comparative Examples 1 to 2, respectively, and disperse the samples in 10 mL of deionized water using an ultrasonic disperser to ensure complete dispersion, and remove undispersed particles and impurities through a filter (0.45 μm).

[0135] (2) Preparation of standard solutions: A series of drug standard solutions with concentration gradients (0.1 μg / mL, 0.5 μg / mL, 1 μg / mL, 5 μg / mL, 10 μg / mL) were prepared for use as the standard curve for ion chromatography quantitative analysis.

[0136] (3) Sample testing: The samples were injected into a chromatograph (ion chromatograph model: Dionex ICS-600; chromatographic column: IonPac AS22 anion exchange column; detector: conductivity detector). Each sample was tested three times and the peak area of ​​the main drug peak was recorded.

[0137] (4) Compare the contents of samples from different parts and calculate the particle uniformity index (uniformity coefficient). The above test results are shown in Table 1 below.

[0138] Table 1: Uniformity data of PMMA balls in Examples 1 to 4 and Comparative Examples 1 to 2

[0139]

[0140] Combined with Table 1, we can see that:

[0141] 1. The modified samples (Examples 1-4) have more uniform distribution of drug particles, with a deviation of less than 5% and a uniformity coefficient close to 1. The unmodified samples (Comparative Examples 1-2) have uneven distribution, with a deviation of up to 20%-25% and a lower uniformity coefficient, indicating poor particle dispersibility.

[0142] 2. The uniformity data of each embodiment are similar, and the deviation is controlled within 5%, indicating that the particle dispersibility can be significantly improved under different modification conditions.

[0143] 3. The modification process significantly improves the distribution uniformity of drug particles, providing a reliable guarantee for improving the performance of bone cement.

[0144] 2. Sustained release performance test: Reference standard: ISO 10993 standard.

[0145] (1) Preparation: ① Sample preparation: Take the cubic bone cement samples prepared in Examples 1 to 4 and Comparative Examples 1 to 2, and record the sample surface area and volume. ② PBS solution preparation: Prepare a phosphate buffer solution (PBS) with a pH of 7.4 and place it in a constant temperature oscillator at 37°C to simulate the human body environment.

[0146] (2) Immersion experiment: ① Immerse the bone cement sample in 20 mL of PBS solution to ensure that the sample is completely immersed. ② At the specified time points (such as 1 day, 3 days, 7 days, 14 days, 21 days, and 30 days), take out 1 mL of the leaching solution and replenish it with an equal amount of fresh PBS to maintain the liquid volume.

[0147] (3) Concentration detection: ① Use ultraviolet spectrophotometry (UV-Vis) to detect the concentration of gentamicin sulfate in the extract and calculate the cumulative release amount.

[0148] 3. Mechanical properties test: Reference standard: ISO 5833:2002 "Bone cement for surgery".

[0149] 3.1 Compressive strength

[0150] (1) Compressive strength sample preparation: Use the methods of Examples 1 to 4 and Comparative Examples 1 to 2 to prepare cylindrical samples with a diameter of 6 mm and a height of 12 mm, respectively, and ensure that the sample surface is flat and free of defects.

[0151] (2) Test conditions: Use an electronic universal testing machine equipped with a suitable indenter. Set the compression speed to 1 mm / min and record the maximum load (F) when the sample breaks.

[0152] Calculation formula: σ = F / A, where σ is the compressive strength (MPa), F is the maximum load (N), and A is the cross-sectional area of ​​the sample (mm 2 ).

[0153] 3.2 Bending strength

[0154] (1) Flexural strength sample preparation: Prepare a strip sample with the size of 75 mm long × 10 mm wide × 3.3 mm thick, and ensure that the surface is flat.

[0155] (2) Test conditions: Use an electronic universal testing machine with a three-point bending device, set the support distance to 60 mm, load at a rate of 1 mm / min, and record the maximum load (F) when the sample breaks.

[0156] Calculation formula: σ f =3FL / (2bd 2 ) where σf is the ultimate strength (MPa), F is the maximum load (N), L is the support distance (mm), and b and d are the sample width and thickness (mm), respectively.

[0157] 4. Biocompatibility test: Reference standard: ISO 10993-5 "In vitro cytotoxicity test".

[0158] (1) Cell culture: MC3T3-E1 osteoblasts (purchased from Qisai Biotechnology) were selected and seeded in 96-well plates, with 100 μL of cell suspension per well (cell concentration was 1×10 cells / mL) and cultured at 37°C and 5% CO for 24 hours.

[0159] (2) Extraction solution preparation: According to ISO 10993-12 standard, the bone cement samples were placed in culture medium and extracted for 24 hours (the ratio of the extract volume to the sample surface area was 3 mL / cm 2 ).

[0160] (3) Cell treatment: The extract was diluted at a certain ratio (e.g., 1×, 2×, 4× dilution), added to a 96-well plate, and cultured for 24 hours.

[0161] (4) Cell activity detection: Use CCK-8 reagent (or MTS reagent), add 10 μL of reagent to each well, incubate for 1-4 hours, and use an enzyme reader to detect the absorbance value at 450 nm.

[0162] (5) Toxicity assessment: The cell survival rate was calculated based on the absorbance value. A survival rate > 75% indicated no cytotoxicity.

[0163] The above test results are shown in Table 2 below.

[0164] Table 2: Test results

[0165]

[0166] Combined with Table 2, we can see that:

[0167] 1. Sustained release performance: Examples 1 to 4 all showed good sustained release properties, meeting the design goal of 30-day slow release. Comparative Example 1 had too low release because it did not contain drugs; Comparative Example 2 had low release because the drugs were wrapped inside by the polymer and there was no channel for sustained release of the drugs. In addition, Examples 1 to 3 all showed significantly higher sustained release performance than Example 4.

[0168] 2. Mechanical properties: Examples 1 to 4 all meet the strength requirements of ISO 5833 surgical bone cement (compressive strength ≥ 70 MPa, flexural strength ≥ 50 MPa). The strength index of Comparative Example 1 is biased, and the bending resistance is reduced due to the addition of drugs.

[0169] 3. Biocompatibility: The example group showed excellent biocompatibility (cell survival rate>75%). The comparative example had a low cell survival rate, which may be due to the fact that comparative example 1 did not contain drugs and comparative example 2 did not release drugs continuously, resulting in unsuitability for cell growth.

[0170] 4. Analysis of advantages and disadvantages: Examples 1 to 3 have excellent comprehensive performance, especially Example 1 has the best mechanical strength and sustained release performance.

[0171] The sustained-release performance and biocompatibility of the comparative example are relatively poor, and cannot meet the requirement of sustained efficacy of bone repair materials.

[0172] In the description of the embodiments of the present invention, it should be noted that the terms "center", "longitudinal", "lateral", "up", "down", "front", "back", "left", "right", "vertical", "horizontal", "top", "bottom", "inside", "outside" and the like indicate positions or positional relationships based on the positions or positional relationships shown in the accompanying drawings, and are only for the convenience of describing the embodiments of the present invention and simplifying the description, and do not indicate or imply that the devices or elements referred to must have a specific orientation, be constructed and operate in a specific orientation, and therefore cannot be understood as limitations on the embodiments of the present invention. In addition, the terms "first", "second", and "third" are used for descriptive purposes only and cannot be understood as indicating or implying relative importance.

[0173] In the description of the embodiments of the present invention, it should be noted that, unless otherwise clearly specified and limited, the terms "connected" and "connection" should be understood in a broad sense, for example, it can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection or an electrical connection; it can be a direct connection or an indirect connection through an intermediate medium. For ordinary technicians in this field, the specific meanings of the above terms in the embodiments of the present invention can be understood according to specific circumstances.

[0174] In the embodiments of the present invention, unless otherwise clearly specified and limited, the first feature being "above" or "below" the second feature may mean that the first and second features are in direct contact, or the first and second features are in indirect contact through an intermediate medium. Moreover, the first feature being "above", "above" and "above" the second feature may mean that the first feature is directly above or obliquely above the second feature, or simply means that the first feature is higher in level than the second feature. The first feature being "below", "below" and "below" the second feature may mean that the first feature is directly below or obliquely below the second feature, or simply means that the first feature is lower in level than the second feature.

[0175] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the embodiment of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0176] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing modified PMMA microspheres, characterized in that: The steps include: Providing drug powder, and dispersing the drug powder into an emulsion to obtain a dispersion; Deionized water, an emulsifier, an acrylic acid monomer, a methyl methacrylate monomer, the dispersion, a first initiator and a crosslinking agent are mixed, and the mixture is reacted at 60° C. to 80° C. so that the drug powder is coated on the outside of the PMMA core obtained by the reaction, wherein the ratio of the deionized water, the emulsifier, the acrylic acid monomer, the methyl methacrylate monomer, the drug powder, the first initiator and the crosslinking agent is 100 mL to 120 mL: 0.5 g to 2.0 g: 0.5 g to 1 g: 10 g to 20 g: 1 g to 5 g: 0.1 g to 0.5 g: 0.05 g to 0.3 g; The reaction product is separated, cleaned and dried to obtain the desired modified PMMA microspheres.

2. The method for preparing modified PMMA microspheres according to claim 1, characterized in that: The operation of providing the drug powder is as follows: dissolving the drug in deionized water to prepare a drug solution of 0.1 w / v% to 1 w / v%; performing surface modification on the drug solution to achieve hydrophobic modification of the drug surface to form a preliminary hydrophobic coating; and preparing the drug powder with a particle size of 1 μm to 5 μm from the surface-modified drug solution through spray drying or freeze drying technology.

3. The method for preparing modified PMMA microspheres according to claim 2, characterized in that: The operation of surface modification treatment of the drug solution is: at least one of electrostatic spraying, chemical coupling and dispersant treatment; The electrostatic spraying is to form a uniform charge distribution on the surface of the drug to enhance the binding force of the drug; The chemical coupling is: adding a coupling agent to the drug solution to form a hydrophobic modification on the drug surface, wherein the coupling agent is a silane coupling agent or a functional coupling agent with a carboxyl group, and the mass ratio of the coupling agent to the drug is 1-5:100-200; The dispersant treatment is: adding a dispersant with hydrophilic / hydrophobic properties to the drug solution so that the dispersant covers the drug to enhance the dispersibility and interface binding properties of the drug, wherein the mass ratio of the dispersant to the drug is 1-10:100-200; The drug is selected from at least one of gentamicin, vancomycin, tigecycline, cefuroxime, rifampicin, clindamycin, tobramycin, erythromycin and colistin sulfate.

4. The method for preparing modified PMMA microspheres according to any one of claims 1 to 3, characterized in that: The operation of mixing deionized water, emulsifier, acrylic acid monomer, methyl methacrylate monomer, the dispersion, the first initiator and the crosslinking agent, and fully reacting so that the drug powder is coated on the PMMA core obtained by the reaction is as follows: The deionized water, the emulsifier, the first acrylic acid monomer and the first methyl methacrylate monomer are mixed, and dissolved oxygen is removed to obtain an emulsion system, and the dispersion is added to the emulsion system under stirring, and stirring is continued until a stable emulsion is formed; then the first initiator is added to start the polymerization reaction to obtain semi-finished microspheres, wherein the semi-finished microspheres include a PMMA core obtained by the reaction and a portion of the drug powder coated on the outside of the PMMA core obtained by the reaction; then the second acrylic acid monomer and the second methyl methacrylate monomer are added, and the reaction is continued so that the PMMA obtained by the reaction is coated on the outside of the semi-finished microspheres to form a PMMA layer, and so that another part of the drug powder is coated outside the PMMA layer; finally, the cross-linking agent is added to fix the other part of the drug powder coated outside the PMMA layer and form a protective coating, wherein the acrylic acid monomer consists of the first acrylic acid monomer and the second acrylic acid monomer, the methyl methacrylate monomer consists of the first methyl methacrylate monomer and the second methyl methacrylate monomer, the mass ratio of the first acrylic acid monomer to the second acrylic acid monomer is 1-2:0-2, and the mass ratio of the first methyl methacrylate monomer to the second methyl methacrylate monomer is 3-7:3-7.

5. The method for preparing modified PMMA microspheres according to claim 4, characterized in that: The emulsion is a solution of the emulsifier having a concentration of 0.5 wt% to 2 wt%, and the concentration of the drug powder in the dispersion is 0.1 w / v% to 1 w / v%; The emulsifier is selected from at least one of sodium lauryl sulfate, polyvinyl pyrrolidone and polysorbate 80; The first initiator is selected from at least one of potassium persulfate and azobisisobutyronitrile; The cross-linking agent is selected from at least one of polyethylene glycol derivatives and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.

6. The method for preparing modified PMMA microspheres according to claim 4, characterized in that: The mass ratio of the acrylic acid monomer, the methyl methacrylate monomer and the drug powder is 10:89:1, and the particle size of the modified PMMA microspheres is 20 μm to 50 μm.

7. A modified PMMA microsphere, characterized in that: The modified PMMA microspheres are prepared by the preparation method of any one of claims 1 to 6.

8. A method for preparing bone cement, characterized in that: The steps include: 3 wt % to 10 wt % of the modified PMMA microspheres as claimed in claim 7, 70 wt % to 85 wt % of PMMA prepolymer powder, 5 wt % to 10 wt % of a developer and 1 wt % to 3 wt % of a second initiator are uniformly mixed to obtain a mixed powder; The mixed powder and the solidifying liquid are mixed evenly at a solid-liquid ratio of 1.5 g / mL to 2.5 g / mL, and the evenly mixed mixture is solidified at 17° C. to 25° C. to obtain the required PMMA bone cement.

9. The method for preparing bone cement according to claim 8, characterized in that: The developer is selected from at least one of zirconium oxide, barium sulfate and titanium oxide; The second initiator is selected from at least one of benzoyl peroxide, tri-n-butylborane and an azo compound; The curing liquid consists of methyl methacrylate and N,N-dimethyl-p-toluidine in a mass ratio of 80-100:

5.

10. A bone cement, characterized in that: The bone cement is prepared by the method for preparing the bone cement according to any one of claims 8 to 9.

Images