阅读说明：本技术 一种三层核壳结构的复合微球及制备方法和应用其的复合型骨水泥 (Composite microsphere with three-layer core-shell structure, preparation method and composite bone cement using composite microsphere ) 是由 谢稼祥 于 2018-08-15 设计创作，主要内容包括：本发明涉及一种三层核壳结构的复合微球,所述核是甲基丙烯酸甲酯的均聚物(PMMA),中间层是甲基丙烯酸甲酯和羟基功能单体的共聚物(P(MMA-co-HMA)),壳是磷酸三钙(TCP)。所述复合微球的制备方法是先制备PMMA乳液,然后作为种子乳液,加入甲基丙烯酸甲酯和羟基功能单体的混合单体以及引发剂,继续进行乳液聚合,得到PMMA/P(MMA-co-HMA)乳液,然后磷酸三钙在乳胶粒表面进行沉积、包覆,得到一种PMMA/P(MMA-co-HMA)/TCP三层核壳结构的复合微球。所述复合微球粒径在0.02μm～200μm之间。将所述复合微球用于配制复合型骨水泥。(The invention relates to a composite microsphere with a three-layer core-shell structure, wherein the core is a homopolymer (PMMA) of methyl methacrylate, the middle layer is a copolymer (P (MMA-co-HMA)) of methyl methacrylate and a hydroxyl functional monomer, and the shell is tricalcium phosphate (TCP). The preparation method of the composite microsphere comprises the steps of firstly preparing PMMA emulsion, then taking the PMMA emulsion as seed emulsion, adding a mixed monomer of methyl methacrylate and a hydroxyl functional monomer and an initiator, continuing emulsion polymerization to obtain PMMA/P (MMA-co-HMA) emulsion, and then depositing and coating tricalcium phosphate on the surface of an emulsion particle to obtain the composite microsphere with the PMMA/P (MMA-co-HMA)/TCP three-layer core-shell structure. The particle size of the composite microsphere is between 0.02 and 200 mu m. The composite microspheres are used for preparing composite bone cement.)

1. The composite microsphere with a three-layer core-shell structure is characterized by being an organic-inorganic composite microsphere with a core/middle layer/shell three-layer structure, wherein the core is methyl methacrylate homopolymer, the middle layer is a copolymer of methyl methacrylate and hydroxyl functional monomers, and the shell is tricalcium phosphate.

2. The composite microsphere with a three-layer core-shell structure as claimed in claim 1, characterized in that the preparation method comprises the following steps:

(1) preparing a composite emulsifier, preparing a mixed monomer and preparing an initiator aqueous solution;

the compound emulsifier is an emulsifier compounded by an anionic surfactant and a nonionic surfactant in any proportion;

the mixed monomer comprises methyl methacrylate and a hydroxyl functional monomer, wherein the weight ratio of the methyl methacrylate to the hydroxyl functional monomer is 1: 0.02-0.2;

the hydroxyl functional monomer is one or any combination of hydroxymethyl acrylate, hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxybutyl acrylate, hydroxymethyl methacrylate, hydroxyethyl methacrylate, hydroxypropyl methacrylate and hydroxybutyl methacrylate;

the initiator is one of potassium persulfate, sodium persulfate and ammonium persulfate; the concentration of the initiator aqueous solution is 0.1-10%;

the initiator is a redox initiation system, the redox initiation system is composed of 1-2 parts of oxidant and 1 part of reducing agent, the oxidant is one of potassium persulfate, sodium persulfate and ammonium persulfate, and the reducing agent is one of water-soluble sulfite, bisulfite and ferrous salt; the initiator aqueous solution is formed by 0.1 to 10 percent of oxidant and 0.1 to 10 percent of reducer;

(2) adding 20-40 parts of methyl methacrylate, a composite emulsifier and a buffering agent into 40-70 parts of deionized water, heating to 30-90 ℃, stirring, emulsifying, filling nitrogen to remove oxygen, adding an initiator aqueous solution, dropwise adding within 0.5-2 h, controlling the temperature to 30-90 ℃ and reacting for 0.5-5 h to obtain PMMA emulsion;

the composite emulsifier accounts for 1-10% of the weight of the methyl methacrylate;

the initiator accounts for 0.06-1% of the weight of the methyl methacrylate;

the buffer is sodium bicarbonate, and the amount of the sodium bicarbonate accounts for 0.3 to 1.5 percent of the weight of the methyl methacrylate;

(3) controlling the temperature within the range of 30-90 ℃, simultaneously dripping 10-20 parts of mixed monomer and initiator aqueous solution into the PMMA emulsion, finishing dripping within 0.5-2 h, preserving heat and reacting for 0.5-2 h under continuous stirring; cooling to room temperature, and performing multiple centrifugal separation and deionized water flushing circulation to obtain PMMA/P (MMA-co-HMA) core-shell structure microspheres;

the initiator accounts for 0.06-1% of the weight of the mixed monomer;

(4) adding 100 parts of deionized water, 10-60 parts of PMMA/P (MMA-co-HMA) core-shell structure microspheres and 20-100 parts of phosphoric acid into a reaction kettle in sequence, stirring until the mixture is dissolved, controlling the temperature at 30-50 ℃, slowly adding calcium hydroxide until the pH value in the system rises to be more than 8.0, stopping adding the calcium hydroxide until the adding amount of the calcium hydroxide reaches more than 1.2 times of the amount of the phosphoric acid, continuing to react for 0.5-2 h, cooling, filtering, washing and freeze-drying to obtain the PMMA/P (MMA-co-HMA)/TCP three-layer core-shell structure composite microspheres.

3. The composite microsphere of claim 1 or 2, wherein the particle size of the composite microsphere is 0.02 μm to 200 μm.

4. A composite bone cement is characterized by comprising a powder part and a liquid part, wherein the powder part is formed by uniformly mixing 65-75 parts of composite microspheres with a three-layer core-shell structure as claimed in claims 1-3, 0.1-3 parts of an initiator and 24-32 parts of barium sulfate, and the liquid part is formed by uniformly mixing 90-99.5 parts of methyl methacrylate, 0.5-10 parts of an accelerator and 60-200 ppm of hydroquinone;

the initiator is one of benzoyl peroxide and dilauroyl peroxide;

the accelerator is one of N, N-dimethyl-p-toluidine, N-dimethylaniline and N-methyl-N- (2-hydroxyethyl) -p-toluidine.

5. The composite bone cement of claim 4, wherein the powder portion and the liquid portion are respectively packaged in sterile containers after being subjected to sterile treatment, and are mixed according to the weight ratio of 1.5-4: 1 of the powder portion to the liquid portion before use.

Technical Field

The invention relates to an organic/inorganic composite microsphere with a three-layer core-shell structure. The core of the composite microsphere is methyl methacrylate homopolymer, the middle layer is a copolymer of methyl methacrylate and hydroxyl functional monomer, and the shell is tricalcium phosphate. Also relates to a preparation method of the composite microsphere and composite bone cement prepared by applying the composite microsphere.

Background

Bone cement is a biomaterial used to fill bone or implanted into a bone gap or cavity and having self-setting properties. The bone cement mainly comprises polymethyl methacrylate (PMMA) bone cement and calcium phosphate bone cement. The PMMA bone cement achieves good application effect clinically, but PMMA is biologically inert and cannot be combined with bone tissues. On the contrary, calcium phosphate bone cement has biocompatibility and biodegradability, is close to bone tissue in composition, and can promote osseointegration, cell adhesion and new bone formation.

The patent CN1821143 provides a preparation method of a calcium phosphate cement composite material, powder only containing hydroxyapatite and α -tricalcium phosphate is synthesized, the powder is mixed with sucrose crystals according to the weight ratio of 2: 1 to be used as a solid phase, meanwhile, acrylic acid-itaconic acid copolymer liquid is prepared to be used as a liquid phase, then, the solid phase and the liquid phase are weighed according to the weight ratio of 3: 1 to be mixed and filled into a mold for forming, human gene recombinant bone morphogenetic protein-2 is mixed in each mold in the process of blending the calcium phosphate cement, and the calcium phosphate cement material compounded with BMP-2 can be obtained.

Patent CN105315478 relates to a copolymer using nano calcium phosphate coated polymethyl methacrylate (PMMA) as substrate and its coating method. The method comprises the steps of synthesizing a copolymer microsphere with PMMA (polymethyl methacrylate) as a substrate containing a hydroxyl side group, enabling a calcium salt and phosphoric acid solution to react with the hydroxyl side group on the copolymer microsphere with PMMA as the substrate, and thickening a nano calcium phosphate coating on the polymer microsphere with PMMA as the substrate.

Patent CN103550823 relates to a preparation method of injectable composite bone cement, which utilizes amphiphilic polymer P (MMA-co-MPS) to couple and modify nano-hydroxyapatite, so that nano-hydroxyapatite is easier to disperse in MMA liquid phase, and the obtained bone cement has better mechanical properties.

Tricalcium phosphate has good biocompatibility, bioactivity and biodegradability, is an ideal human hard tissue repair and replacement material, and has been paid close attention to the field of biomedical engineering, β -tricalcium phosphate is generally used in medicine, and the form can be synthesized at low temperature.

The β -tricalcium phosphate is mainly composed of calcium and phosphorus, its composition is similar to the inorganic composition of bone matrix, and it is well combined with bone, and the animal or human body cell can grow, differentiate and reproduce on β -tricalcium phosphate material, and it is proved by lots of experimental researches that β -tricalcium phosphate has no adverse reaction, rejection reaction, acute toxic reaction, canceration and hypersusceptibility to bone marrow hemopoiesis function, so it can be widely used in the fields of joint and spine fusion, limb trauma, oral and maxillofacial surgery, cardiovascular surgery and filling up periodontal cavity, etc. with the continuous and deep research of β -tricalcium phosphate, its application form is diversified, and it has better performance in clinical medicine.

Disclosure of Invention

The invention provides a composite microsphere with a three-layer core-shell structure, wherein the core-shell structure comprises three layers of a core/a middle layer/a shell, the core is methyl methacrylate homopolymer (PMMA), the middle layer is a copolymer (P (MMA-co-HMA)) of methyl methacrylate and a hydroxyl functional monomer, and the shell is tricalcium phosphate (TCP). The intermediate layer may well bond the core and the shell together.

The composite microsphere is designed into a three-layer core-shell structure, and has the advantage that the middle layer can be very thin, so that the used hydroxyl functional monomer can be enriched on the surface of the core even if the used hydroxyl functional monomer is little, and the composite microsphere can also play a role in inducing tricalcium phosphate to deposit and coat on the surface.

On the other hand, the invention also provides a method for preparing the composite microsphere with the three-layer core-shell structure. Firstly synthesizing PMMA emulsion as seed emulsion, then dropwise adding a mixed monomer of MMA and a hydroxyl functional monomer, simultaneously dropwise adding an initiator solution, continuing emulsion polymerization to obtain PMMA/P (MMA-co-HMA) two-layer core-shell structure microspheres, then depositing and coating tricalcium phosphate on the surface of the PMMA/P two-layer core-shell structure microspheres, reacting calcium chloride with sodium tripolyphosphate, gathering and coating the calcium chloride and the sodium tripolyphosphate on the PMMA copolymer microspheres under the action of a template agent, and obtaining the PMMA/P (MMA-co-HMA)/TCP three-layer core-shell structure composite microspheres.

Furthermore, the invention provides composite bone cement applying the PMMA/P (MMA-co-HMA)/TCP three-layer core-shell structure composite microsphere.

The invention relates to a method for preparing PMMA/P (MMA-co-HMA)/TCP three-layer core-shell structure composite microspheres, which comprises the following steps:

(1) preparing composite emulsifier, preparing mixed monomer and preparing water solution of initiator.

The compound emulsifier is an emulsifier compounded by an anionic surfactant and a nonionic surfactant in any proportion.

The mixed monomer comprises methyl methacrylate and a hydroxyl functional monomer, wherein the weight ratio of the methyl methacrylate to the hydroxyl functional monomer is 1: 0.02-0.2.

The hydroxyl functional monomer is one or any combination of hydroxymethyl acrylate, hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxybutyl acrylate, hydroxymethyl methacrylate, hydroxyethyl methacrylate, hydroxypropyl methacrylate and hydroxybutyl methacrylate;

the initiator is one of potassium persulfate, sodium persulfate and ammonium persulfate; the concentration of the initiator aqueous solution is 0.1-10%.

The initiator is a redox initiation system, the redox initiation system is composed of 1-2 parts of oxidant and 1 part of reducing agent, the oxidant is one of potassium persulfate, sodium persulfate and ammonium persulfate, and the reducing agent is one of water-soluble sulfite, bisulfite and ferrous salt; the initiator aqueous solution is 0.1-10% of oxidant concentration and 0.1-10% of reducer concentration.

(2) Adding 20 to 40 parts of methyl methacrylate, a composite emulsifier and a buffering agent into 40 to 70 parts of deionized water, heating to 30 to 90 ℃, stirring, emulsifying, filling nitrogen to remove oxygen, adding an initiator aqueous solution, dropwise adding within 0.5 to 2 hours, controlling the temperature between 30 and 90 ℃ and reacting for 0.5 to 5 hours to obtain the PMMA emulsion.

The composite emulsifier accounts for 1-10% of the weight of the methyl methacrylate.

The buffer is sodium bicarbonate, and the amount of the sodium bicarbonate accounts for 0.3-1.5% of the weight of the methyl methacrylate.

The initiator accounts for 0.06-1% of the weight of the methyl methacrylate.

(3) Controlling the temperature within the range of 30-90 ℃, simultaneously dripping 10-20 parts of mixed monomer and initiator aqueous solution into the PMMA emulsion, finishing dripping within 0.5-2 h, preserving heat and reacting for 0.5-2 h under continuous stirring; and cooling to room temperature, and performing multiple centrifugal separation and deionized water flushing cycles to obtain the PMMA/P (MMA-co-HMA) core-shell structure microspheres.

The initiator accounts for 0.06-1% of the weight of the mixed monomer.

(4) Adding 100 parts of deionized water, 1-20 parts of PMMA/P (MMA-co-HMA) core-shell structure microspheres and 1-40 parts of phosphoric acid into a reaction kettle in sequence, stirring until the mixture is dissolved, controlling the temperature to be 30-50 ℃, slowly adding calcium hydroxide until the pH value in the system rises to be more than 8.0, stopping adding the calcium hydroxide until the adding amount of the calcium hydroxide reaches more than 1.2 times of the amount of the phosphoric acid, cooling, filtering, washing and freeze-drying to obtain the PMMA/P (MMA-co-HMA)/TCP three-layer core-shell structure composite microspheres.

The PMMA/P (MMA-co-HMA)/TCP composite microsphere has the grain diameter of 0.02-200 mu m.

The preparation method has the advantages of simple process, mild reaction conditions and easy production.

The PMMA/P (MMA-co-HMA)/TCP composite microspheres are used for preparing the composite bone cement. The bone cement consists of a powder part and a liquid part, wherein the powder part is formed by uniformly mixing 65-75 parts of PMMA/P (MMA-co-HMA)/TCP composite microspheres, 0.1-3 parts of initiator and 24-32 parts of barium sulfate, and the liquid part is formed by uniformly mixing 90-99.5 parts of methyl methacrylate, 0.5-10 parts of accelerator and 60-200 ppm of hydroquinone.

The initiator is one of benzoyl peroxide and dilauroyl peroxide.

The accelerator is one of N, N-dimethyl-p-toluidine, N-dimethylaniline and N-methyl-N- (2-hydroxyethyl) -p-toluidine.

And respectively packaging the powder part and the liquid part after aseptic treatment in an aseptic container, and mixing the powder part and the liquid part according to the weight ratio of 1.5-4: 1 before use. The powder part and the liquid part are simply mixed and shaken uniformly before use, and the mixture is easy to modulate; the powder has a microsphere structure, so that the bone cement has good fluidity and is easy to be uniformly dispersed in liquid.

The prepared bone cement has good bioactivity, osteoconductivity, biocompatibility and mechanical properties, and can be widely used as a bone substitute and repair material and a bone defect filling material.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION