阅读说明：本技术 一种含硫酸钙的聚醚醚酮微粒状骨填充材料及其制备方法 (calcium sulfate-containing polyetheretherketone particulate bone filling material and preparation method thereof ) 是由 章培标 纪庆明 焦自学 王宗良 孙烁 王鹏 于 2019-10-25 设计创作，主要内容包括：本发明提供了一种含硫酸钙的聚醚醚酮微粒状骨填充材料及其制备方法,方法包括：将聚醚醚酮粉、浓硫酸和CaSO<Sub>4</Sub>混合后静置,得到混合液；将混合液采用气流法制得微粒后沉降在乙醇-CaSO<Sub>4</Sub>饱和液中,再在乙醇-CaSO<Sub>4</Sub>饱和液中浸泡,过筛；将得到的粒径500～600μm的CaSO<Sub>4</Sub>-PEEK微粒和CaSO<Sub>4</Sub>饱和液水热处理,真空干燥,得到粒径400～500μm的含硫酸钙的聚醚醚酮微粒状骨填充材料。该方法采用CaSO<Sub>4</Sub>对聚醚醚酮粉进行共混,得到的共混材料具有较高的亲水性,有利于细胞增殖与黏附,促进细胞分化,提高生物矿化能力,增强材料的骨诱导性与生物活性,促进与组织的充分融合。还可充当微载体,搭载生长因子等。(The invention provides a calcium sulfate-containing polyetheretherketone particulate bone filling material and a preparation method thereof, wherein the method comprises the following steps: polyether ether ketone powder, concentrated sulfuric acid and CaSO 4 mixing and standing to obtain a mixed solution; the mixed solution is prepared into particles by adopting an air flow method and then is settled in ethanol-CaSO 4 in saturated solution, adding ethanol-CaSO 4 Soaking in saturated solution, and sieving; the obtained CaSO with the particle size of 500-600 mu m 4 -PEEK microparticles and CaSO 4 Carrying out hydrothermal treatment on the saturated liquid, and drying in vacuum to obtain the calcium sulfate-containing polyetheretherketone particulate bone filling material with the particle size of 400-500 mu m. The method adopts CaSO 4 The polyether ether ketone powder is blended to obtain a blended material which has high hydrophilicity, is beneficial to cell proliferation and adhesion, promotes cell differentiation and improves biomineralizationThe capability of enhancing the osteoinductive property and the biological activity of the material and promoting the full fusion with tissues. Can also be used as microcarrier for carrying growth factors.)

1. A preparation method of a calcium sulfate-containing polyetheretherketone particulate bone filling material comprises the following steps:

Polyether ether ketone powder, concentrated sulfuric acid and CaSO₄Mixing and standing to obtain a mixed solution;

Making the mixed solution into particles by adopting an air flow method, and settling the particles in ethanol-CaSO₄In saturated solution, and then in CaSO₄Soaking in saturated solution, and sieving to obtain CaSO with particle size of 500-600 μm₄-PEEK microparticles;

The CaSO with the particle size of 500-600 mu m₄-PEEK microparticles and CaSO₄Carrying out hydrothermal treatment on the saturated liquid, and drying in vacuum to obtain the calcium sulfate-containing polyetheretherketone particulate bone filling material with the particle size of 400-500 mu m.

2. the method according to claim 1, wherein the reaction mixture is heated to a temperature in the reaction mixtureThe polyether ether ketone powder, concentrated sulfuric acid and CaSO₄The standing after mixing specifically comprises:

Adding polyether ether ketone powder into concentrated sulfuric acid, stirring, and adding CaSO₄And (5) stirring the powder again, and standing to obtain a mixed solution.

3. The method according to claim 1, wherein the flow rate of the gas stream for producing the fine particles by the gas stream method is 6 to 7L/min.

4. The method of claim 1, wherein the reaction is performed in CaSO₄the soaking time in the saturated solution is 24h, and the soaking solution is changed every 8 h.

5. The preparation method according to claim 1, wherein the temperature of the hydrothermal treatment is 170-190 ℃; the time of the hydrothermal treatment is 7-9 h.

6. The method according to claim 1, wherein CaSO is contained in the particulate bone filler of polyetheretherketone containing calcium sulfate having a particle size of 400 to 500 μm₄The mass content of (A) is 10-60%.

7. Particulate calcium sulphate-containing polyetheretherketone bone filler material obtainable by a process according to any one of claims 1 to 6.

8. Particulate bone filler material of polyetheretherketone containing calcium sulphate obtained by a process according to any one of claims 1 to 6 or a particulate bone filler material of polyetheretherketone containing calcium sulphate according to claim 7 for use in bone repair materials.

Technical Field

The invention belongs to the technical field of bone repair materials, and particularly relates to a calcium sulfate-containing polyetheretherketone particulate bone filling material and a preparation method thereof.

Background

In the orthopedic field, bone defects caused by various reasons such as severe trauma, bone tumors, osteomyelitis and the like are very common, especially large-area and irregular bone defects. What kind of material and way to perform the bone grafting operation is the hot spot of the current research. Currently, the bone repair materials commonly used in clinic include autologous bones, allogeneic bones, metal prostheses, polymer synthetic materials and the like. Although autogenous bone is an ideal bone defect repairing material, the bone taking process increases the trauma and pain of patients, the bone source is limited, the shaping is not easy, and the requirement of large-section bone transplantation is difficult to meet; allogeneic bone may transmit diseases and cause postoperative complications due to immunological rejection; the metal prosthesis is easy to loosen, break, and has poor histocompatibility and inflammatory reaction; the polymer synthetic material has the problems that the degradation rate is not matched with the osteogenesis rate, degradation byproducts change the surrounding microenvironment to influence bone repair and the like, and the clinical application is limited to different degrees.

Polyetheretherketone (PEEK) is a synthetic wholly aromatic semi-crystalline polymer with many excellent properties: high strength, toughness and rigidity, good oxidation resistance and fatigue resistance, and certain biocompatibility, so the PEEK can be applied to a plurality of fields, such as: medical treatment, aerospace, automobile manufacturing, chemical manufacturing, precision instrument manufacturing and other high-tech fields. However, the polyetheretherketone material is a biologically inert material, and needs to be modified to improve the bioactivity thereof, so that the polyetheretherketone material has wider application.

disclosure of Invention

In view of the above, the present invention aims to provide a calcium sulfate-containing polyetheretherketone particulate bone filler and a method for preparing the same, wherein the bone filler prepared by the method has excellent hydrophilicity.

the invention provides a preparation method of a polyether-ether-ketone particulate bone filling material containing calcium sulfate, which comprises the following steps:

Polyether ether ketone powder, concentrated sulfuric acid and CaSO₄Mixing and standing to obtain a mixed solution;

Making the mixed solution into particles by adopting an air flow method, and settling the particles in ethanol-CaSO₄In saturated solution, and then in CaSO₄Soaking in saturated solution, and sieving to obtain CaSO with particle size of 500-600 μm₄-PEEK microparticles;

The CaSO with the particle size of 500-600 mu m₄-PEEK microparticles and CaSO₄Carrying out hydrothermal treatment on the saturated liquid, and drying in vacuum to obtain the calcium sulfate-containing polyetheretherketone particulate bone filling material with the particle size of 400-500 mu m.

Preferably, the polyether ether ketone powder, concentrated sulfuric acid and CaSO₄The standing after mixing specifically comprises:

Adding polyether ether ketone powder into concentrated sulfuric acid, stirring, and adding CaSO₄And (5) stirring the powder again, and standing to obtain a mixed solution.

Preferably, the flow velocity of the air flow for preparing the particles by the air flow method is 6-7L/min.

Preferably, said in CaSO₄The soaking time in the saturated solution is 24h, and the soaking solution is changed every 8 h.

Preferably, the temperature of the hydrothermal treatment is 170-190 ℃; the time of the hydrothermal treatment is 7-9 h.

Preferably, CaSO is contained in the calcium sulfate-containing polyetheretherketone particulate bone filling material with the particle size of 400-500 mu m₄The mass content of (A) is 10-60%.

The invention provides a polyether-ether-ketone particulate bone filling material containing calcium sulfate, which is prepared by the preparation method of the technical scheme.

The invention provides a polyether-ether-ketone particulate bone filling material containing calcium sulfate prepared by the preparation method in the technical scheme or an application of the polyether-ether-ketone particulate bone filling material containing calcium sulfate in a bone repair material in the technical scheme.

The invention provides a preparation method of a polyether-ether-ketone particulate bone filling material containing calcium sulfate, which comprises the following steps: mixing polyether ether ketone powder and concentrated sulfuric acidAnd CaSO₄Mixing and standing to obtain a mixed solution; making the mixed solution into particles by adopting an air flow method, and settling the particles in ethanol-CaSO₄In saturated solution, adding ethanol-CaSO₄Soaking in saturated solution, and sieving to obtain CaSO with particle size of 500-600 μm₄-PEEK microparticles; the CaSO with the particle size of 500-600 mu m₄-PEEK microparticles and CaSO₄Carrying out hydrothermal treatment on the saturated liquid, and drying in vacuum to obtain the calcium sulfate-containing polyetheretherketone particulate bone filling material with the particle size of 400-500 mu m. The method provided by the invention adopts CaSO₄The polyether-ether-ketone powder is blended to obtain a blended material which has high hydrophilicity, is beneficial to cell proliferation and adhesion, promotes cell differentiation, improves the biomineralization capacity, enhances the bone inductivity and the bioactivity of the material, promotes the full fusion with tissues, has a honeycomb-like hole structure in the section display of the polyether-ether-ketone particulate bone filling material, is similar to cancellous bone, accelerates the healing process of large-area bone defect tissues and realizes the pre-organization process. Meanwhile, the particle can also be used as a microcarrier for carrying growth factors and the like.

Drawings

FIG. 1 shows CaSO with a diameter of 500-600 μm prepared in example 1 of the present invention₄-scanning electron microscopy test patterns before and after hydrothermal treatment of PEEK particles;

FIG. 2 shows CaSO with a particle size of 400-500 μm prepared in example 3 of the present invention₄The shapes and the section diagrams of the PEEK particles and the PEEK particles prepared by the comparative example;

FIG. 3 shows CaSO with a particle size of 400-500 μm prepared in examples 1-5 of the present invention₄the infrared spectrogram of PEEK particles with topological appearance prepared by the PEEK particles and the comparative example;

FIG. 4 shows CaSO prepared in examples 1 to 5 of the present invention₄PEEK micro-particles and PEEK with topological morphology prepared by a comparative example have a water contact angle test chart;

FIG. 5 shows CaSO with a particle size of 400-500 μm prepared in example 4 of the present invention₄PEEK particles mineralization 4-week topography and elemental analysis (EDX) spectra of topological topography prepared by/PEEK particles and comparative example;

FIG. 6 shows Ca of 400 to 500 μm particle size prepared in examples 1 to 4 of the present inventionSO₄CCK cell proliferation test results for PEEK microparticles, smooth PEEK prepared in comparative example, and topological PEEK;

FIG. 7 shows CaSO with a particle size of 400-500 μm prepared in example 4 of the present invention₄Morphology of cell adhesion for 7 days for PEEK microparticles/PEEK microparticles and PEEK microparticles with topology prepared in comparative example.

Detailed Description

The invention provides a preparation method of a polyether-ether-ketone particulate bone filling material containing calcium sulfate, which comprises the following steps:

Polyether ether ketone powder, concentrated sulfuric acid and CaSO₄Mixing and standing to obtain a mixed solution;

Making the mixed solution into particles by adopting an air flow method, and settling the particles in ethanol-CaSO₄In saturated solution, adding ethanol-CaSO₄Soaking in saturated solution, and sieving to obtain CaSO with particle size of 500-600 μm₄-PEEK microparticles;

The CaSO with the particle size of 500-600 mu m₄-PEEK microparticles and CaSO₄Carrying out hydrothermal treatment on the saturated liquid, and drying in vacuum to obtain the calcium sulfate-containing polyetheretherketone particulate bone filling material with the particle size of 400-500 mu m.

The method provided by the invention adopts CaSO₄the polyether ether ketone powder is blended to obtain a blended material which has higher hydrophilicity, is beneficial to cell proliferation and adhesion, promotes cell differentiation, improves the biomineralization capability, enhances the osteoinductive property and the biological activity of the material, promotes the full fusion with tissues, and contains CaSO₄The section of the PEEK particles shows that the interior of the section has a honeycomb-like hole structure, which is similar to cancellous bone, so that the healing process of large-area bone defect tissues is accelerated, and the pre-organization process is realized. Meanwhile, the particle can also be used as a microcarrier for carrying growth factors and the like.

The invention is used for polyether ether ketone powder and CaSO₄And the source of concentrated sulfuric acid is not particularly limited, and commercially available products thereof may be used.

According to the invention, PEEK powder is preferably added into concentrated sulfuric acid; the mass concentration of the concentrated sulfuric acid is preferably 95-98%. In the invention, the volume ratio of the mass of the PEEK powder to concentrated sulfuric acid is preferably (1.7-1.9) g, (28-33) mL, more preferably (1.75-1.85) g, (29-32) mL; in a specific embodiment, the volume ratio of the PEEK powder to concentrated sulfuric acid is 1.8g:30 mL.

The mixed PEEK powder and concentrated sulfuric acid are heated in a water bath manner; the temperature of the water bath heating is preferably 25 ℃. The PEEK powder and concentrated sulfuric acid are mechanically stirred until the PEEK powder is completely dissolved, and then CaSO is added₄(ii) a Adding CaSO₄Then mechanically stirring again until CaSO₄After being dispersed evenly, the mixture is kept stand to obtain mixed liquid. The mechanical stirring time is preferably 55-65 min, and more preferably 60 min; the time for the mechanical stirring again is preferably 55-65 min, and more preferably 60 min. The CaSO₄The mass fraction in the mixed solution is preferably 5-65%, and more preferably 10-60%; in a specific embodiment, CaSO₄The mass fraction in the mixed solution is 10%, 20%, 30%, 40%, 50% or 60%.

after the mixed solution is obtained, the mixed solution is prepared into particles by adopting an air flow method and then is settled in ethanol-CaSO₄In saturated solution, adding ethanol-CaSO₄Soaking in saturated solution, and sieving to obtain particulate bone filler containing calcium sulfate and polyetheretherketone with particle size of 500-600 μm (CaSO with particle size of 500-600 μm)₄PEEK microparticles. The invention preferably puts the mixed solution into the syringe; the volume of the syringe is 50 mL; the diameter of the Teflon needle head of the syringe is 25-27G; in particular embodiments, the Teflon needle has a diameter of 25G, 26G or 27G. The invention adopts ethanol-CaSO₄Taking saturated liquid as sedimentation liquid; ethanol-CaSO₄The volume of the saturated solution is 1000 mL; the ethanol-CaSO₄The saturated liquid is CaSO₄Saturating in ethanol to obtain saturated solution; the mass concentration of the ethanol is preferably 28-32%, and more preferably 30%.

The invention preferably carries out sedimentation under ice bath condition; during sedimentation, the height of the needle from the liquid level of the sedimentation liquid is preferably 13-15 cm, more preferably 13.5-14.5 cm, and most preferably 14 cm. The air flow velocity of the particles prepared by the air flow method is preferably 6-7L/min; the gas used in the gas flow method is preferably nitrogen.

Settling in ethanol-CaSO₄Microparticles obtained in a saturated liquidThen CaSO₄Soaking in saturated solution. The CaSO₄The saturated liquid is water saturated liquid of calcium sulfate. In CaSO₄The soaking time in the saturated solution is preferably 24h, and the soaking solution is changed every 8 h. Soaking, sieving, and sieving to obtain CaSO with particle size of 500-600 μm₄-PEEK microparticles.

Obtaining CaSO with the particle size of 500-600 mu m₄After PEEK particles are adopted, the CaSO with the particle size of 500-600 mu m is added₄-PEEK microparticles and CaSO₄Carrying out hydrothermal treatment on the saturated liquid, and drying in vacuum to obtain the calcium sulfate-containing polyetheretherketone particulate bone filling material with the particle size of 400-500 mu m.

CaSO with the particle size of 500-600 mu m is preferably selected₄Placing PEEK particles in a reaction kettle to neutralize CaSO₄Mixing saturated solutions; the volume of the reaction kettle is 50 mL; added CaSO₄The volume of the saturated solution was 30 mL. In order to make the CaSO with the particle size of 500-600 mu m₄The PEEK particles are reduced in volume and subjected to a hydrothermal treatment. The temperature of the hydrothermal treatment is preferably 170-190 ℃, and more preferably 175-185 ℃; the time of the hydrothermal treatment is preferably 7-9 h, and more preferably 7.5-8.5 h; in the specific embodiment, the temperature of the hydrothermal treatment is 180 ℃ and the time is 8 h.

In the invention, CaSO is contained in the calcium sulfate-containing polyetheretherketone particulate bone filling material with the particle size of 400-500 mu m₄The mass content of (A) is preferably 10 to 60%.

The invention provides a polyether-ether-ketone particulate bone filling material containing calcium sulfate, which is prepared by the preparation method of the technical scheme.

The section of the polyether-ether-ketone particulate bone filling material containing calcium sulfate provided by the invention shows that the interior of the section has a honeycomb-like hole structure, is similar to cancellous bone, promotes the sufficient fusion with tissues, accelerates the bone healing process and realizes the pre-organization process. The special size of the particles enables the particles to have special functions such as bone filling function which are not possessed by other materials, and even the particles can be implanted into the body in a minimally invasive mode such as injection and the like, so that the surgical injury and the surgical time are reduced; meanwhile, the particle can also be used as a microcarrier for carrying growth factors and the like.

The invention provides a polyether-ether-ketone particulate bone filling material containing calcium sulfate prepared by the preparation method in the technical scheme or an application of the polyether-ether-ketone particulate bone filling material containing calcium sulfate in a bone repair material in the technical scheme.

In order to further illustrate the present invention, the particulate bone filler material of polyetheretherketone containing calcium sulphate, a process for its preparation and its use according to the present invention are described in detail below with reference to the examples, which should not be construed as limiting the scope of the present invention.

Comparative example: preparation of PEEK microparticles

Weighing 1.8G of PEEK powder, adding the PEEK powder into 30mL of concentrated sulfuric acid, placing the concentrated sulfuric acid into a water bath kettle at 25 ℃, mechanically stirring for one hour, standing after the PEEK powder is completely dissolved, adding the liquid into a 50mL needle cylinder, wherein the diameters of Teflon needle heads are respectively 27G, preparing 1000mL of 30% ethanol solution as a sedimentation liquid, carrying out ice bath, and preparing PEEK particles by adopting an air flow method, wherein the height of the needle head from the liquid level of the sedimentation liquid is 14cm, and the air flow velocity is 6-7L/min. And (3) after obtaining the PEEK particles, soaking the PEEK particles for 24h in water once, changing the soaking solution for 1 time every 8h, and filtering the PEEK particles by using a screen to obtain the PEEK particles with the diameter of 500-600 microns and smooth surfaces. And transferring the PEEK microspheres with smooth surfaces into a 50mL reaction kettle, adding 30mL deionized water, heating at 180 ℃ for 8h, cooling to room temperature, and then carrying out vacuum drying to obtain the PEEK microspheres with special topological surfaces.