WO2015067091A1 - 一种经过修饰的纳米羟基磷灰石及其制备方法和应用 - Google Patents

一种经过修饰的纳米羟基磷灰石及其制备方法和应用 Download PDF

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WO2015067091A1
WO2015067091A1 PCT/CN2014/085725 CN2014085725W WO2015067091A1 WO 2015067091 A1 WO2015067091 A1 WO 2015067091A1 CN 2014085725 W CN2014085725 W CN 2014085725W WO 2015067091 A1 WO2015067091 A1 WO 2015067091A1
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hydroxyapatite
bone cement
mma
mps
powder
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PCT/CN2014/085725
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English (en)
French (fr)
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蒋庆
全昌云
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中山大学
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Priority claimed from CN201310546044.XA external-priority patent/CN103553012A/zh
Priority claimed from CN201310712148.3A external-priority patent/CN103656739A/zh
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Publication of WO2015067091A1 publication Critical patent/WO2015067091A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B25/00—Phosphorus; Compounds thereof
    • C01B25/16—Oxyacids of phosphorus; Salts thereof
    • C01B25/26—Phosphates
    • C01B25/32—Phosphates of magnesium, calcium, strontium, or barium
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the present invention relates to the field of biological materials, and more particularly to a modified nano-hydroxyapatite and a preparation method and application thereof.
  • Bone cement is a kind of bone repair material that can be arbitrarily plasticized by self-curing. It has been widely used in clinical surgery this year. It is widely used in hip replacement surgery, plastic surgery and other fields. At present, bone cement on the market is mainly divided into two categories: calcium phosphate (CPC) bone cement. CPC bone cement has a large market of bone cement because of its excellent biocompatibility, but its poor mechanical properties make it impossible to be used. In the repair of load-bearing bone; traditional methacrylic acid (PMMA) bone cement has excellent mechanical properties, but because of its large difference with natural bone, its biocompatibility has great problems. The life of PMMA bone cement on the market is generally 8 years, so it has certain limitations in the use of clinical surgery.
  • CPC calcium phosphate
  • L-lacide L-LA was grafted to the surface of HA particles by chemical bonding by in-situ polymerization on the surface hydroxyl groups of nano-sized HA particles.
  • the modified HA due to the surface covering an organic molecule, may have an adverse effect on the calcium-phosphorus exposure, biomineralization and cell adhesion of the composite. Therefore, it is necessary to further study the effects of different graft ratios on the physical properties and biological properties of the composites, in order to achieve the improvement of the dispersibility and mechanical properties of the materials by graft modification, and to maintain or improve the biological activity of the materials. .
  • the present invention first provides a composite bone cement having a high hydroxyapatite content, comprising a powder portion and a liquid portion, the powder portion being modified by a surface of P(MMA-co-MPS). Hydroxyapatite and polymethyl methacrylate (PMMA); the liquid portion is methyl methacrylate containing an initiator and dimethyl terephthalate.
  • PMMA polymethyl methacrylate
  • the polymethyl methacrylate has a molecular weight of 800,000 to 900,000.
  • the weight ratio of hydroxyapatite and polymethyl methacrylate modified by P(MMA-co-MPS) surface in the powder portion is 1:1.5 to 2.0.
  • the initiator in the liquid portion is 0.8 to 1.2% by weight percent, and dimethyl terephthalate is 4 to 5%, the balance being methyl methacrylate.
  • the powder portion and the liquid portion are in a weight ratio of 1:2.5 to 2.9.
  • the initiator is benzoyl peroxide.
  • a method for preparing a modified nano-hydroxyapatite is provided in two steps:
  • MMA, AIBN, MPS, thioglycolic acid, and THF were added to the reaction flask while maintaining Ar gas, and Ar gas was turned off after half an hour.
  • the reaction was stirred at 60 to 70 ° C for 6 to 8 hours.
  • a mixed solution of ethanol/water is prepared, and the pH is adjusted to be acidic with glacial acetic acid, and an appropriate amount of the small molecule polymer obtained in the step (1) is added thereto to completely hydrolyze the small molecule polymer. Then, an appropriate amount of HA was added thereto, and the pH was adjusted to be alkaline with a NaOH solution to promote the condensation reaction. The obtained product was filtered and dried, and the dried powder was ultrasonically washed three times with tetrahydrofuran (THF), and then dried and stored.
  • THF tetrahydrofuran
  • MMA methyl methacrylate
  • AIBN azobisisobutyronitrile
  • MPS silane coupling agent
  • THF tetrahydrofuran
  • Ar argon
  • HA hydroxyapatite.
  • HA nanoparticles with amphiphilic polymer P (MMA-co-MPS) to prepare HA nanocomposite particles with different grafting rates.
  • the modified HA particles improved the interface with the matrix. Force and dispersion.
  • the suspended hydroxyl groups on the surface of HA are easily agglomerated in the form of hydrogen bonds.
  • the surface modification can prevent the re-agglomeration of HA in the matrix, improve the dispersion and stability of HA in the matrix, and improve the compatibility with the matrix.
  • the invention can improve the dispersibility and stability of HA in the bone cement compounding process, strengthen the interaction of HA with the matrix, and on the other hand, impart some new functions to the bone cement.
  • the powder portion of S1 and the liquid portion obtained by S2 are mixed and molded.
  • a composite bone cement having a high hydroxyapatite content as described above is provided for preparing an orthopedic plant Application in materials.
  • MMA methyl methacrylate
  • BPO dibenzoyl peroxide
  • PMMA polymethyl methacrylate
  • DMT dimethyl terephthalate
  • MPS silane coupling agent
  • THF tetrahydrofuran
  • PVA polyvinyl alcohol
  • the bone cement preparation method disclosed by the invention is an injectable bone cement, which is widely used.
  • the method for preparing bone cement disclosed by the invention has a high degree of surface modification of hydroxyapatite by P(MMA-co-MPS), thereby greatly improving the dispersibility of hydroxyapatite in bone cement, and has excellent Mechanical properties.
  • the content of hydroxyapatite in the bone cement solid powder is as high as 40%, which greatly improves the biocompatibility of the PMMA bone cement. Cytotoxicity test results showed that the bone cement was not toxic.
  • the modified nano-HA in the present invention has good dispersibility in MMA
  • the modified nano-HA synthesized by the invention has significant improvement in mechanical properties compared with the existing HA, and the method is simple and easy to operate; and has broad application prospects as orthopedic restoration and fixing materials.
  • the bone cement prepared by the nano-HA synthesized by the invention is convenient and quick to prepare, can be formed at room temperature, and the condition is mild.
  • Figure 1 is an infrared characterization of P(MMA-co-MPS)-HA.
  • thermogravimetric analysis diagram of P(MMA-co-MPS)-HA is a thermogravimetric analysis diagram of P(MMA-co-MPS)-HA.
  • Figure 3 is a graph showing the results of the compressive strength of the bone cement.
  • Fig. 4 is a graph showing the results of the bending strength of the bone cement.
  • Fig. 5 is a graph showing the results of the flexural modulus of the bone cement.
  • Figure 6 is a graph showing the results of cytotoxicity of bone cement.
  • the first step after dissolving 5 g of PMA (MMA-co-MPS) powder in 75 ml of acetone solution, adding a mixed solution of 90% ethanol/water and adjusting the pH of the solution to 3.5-4.0, after one hour of reaction, adding ultrasonic dispersion beforehand. A solution of 8 g of a hydroxyapatite suspension of 200 ml was adjusted and the pH of the whole system was adjusted to 9.0. The reaction was allowed to stand overnight, and the product was filtered, washed three times with tetrahydrofuran, and dried in vacuo to give P(MMA-co-MPS)-HA powder. The experimental infrared results are shown in Fig. 1.
  • the second step 0.4 g of the surface-modified hydroxyapatite powder obtained in the first step and 0.6 g of PMMA powder having a molecular weight of 850,000 were mixed and sterilized to obtain a powder portion of the bone cement.
  • the liquid portion of the bone cement consisted of 3 ml of MMA solution in which 0.03 g BPO and 14 ul DMT were dissolved.
  • the bone cement powder component was mixed with the liquid component, stirred and mixed, and after injection molding by a syringe, it was used as an experimental group bone cement.
  • the hydroxyapatite in the bone cement of the control group was an unmodified hydroxyapatite powder.
  • the experimental sample size was: a cylinder having a height of 12 mm and a diameter of 6 mm, and the experimental group bone cement was the bone cement described in Example 1.
  • the compressive strength results measured by the universal material testing machine are shown in Fig. 3.
  • the compressive strength of the experimental group bone cement is significantly higher than that of the control group, and the compression performance of the experimental group bone cement reaches the standard of ISO5833.
  • the experimental sample size was: plate length 75 mm, width 10 mm, height 3.3 mm, and the experimental group bone cement was the bone cement described in Example 1.
  • the samples Prior to testing, the samples were immersed in a 37 ° C water bath for 72 ⁇ 1.0 hours.
  • the bending strength results measured on the universal material testing machine are shown in Fig. 4.
  • the bending strength of the cement containing the experimental group is higher than that of the control group, and the bending modulus results are shown in Fig. 5, and the results are similar to the bending strength.
  • the results of the bending properties indicate that the bending properties of the bone cement containing the copolymer hydroxyapatite are remarkably improved.
  • Cytotoxicity test (MTT) Experimental sample size: cylinder with a height of 6 mm and a diameter of 6 mm.
  • the experimental group bone cement was the bone cement described in Example 1.
  • Each bone cement sample was separately immersed in PBS for 24 hours, and then immersed in complete medium for 24 hours to obtain two groups of extracts.
  • the complete medium was used as a blank control group, and each sample was inoculated with 5000 human osteoblast cells (HFOB). Cell viability of each group was measured after 24 hours and 48 hours. The experimental results are shown in Fig. 6. Compared with the blank control group, the survival rate of each group was higher than 80%, indicating that the materials were not toxic.
  • the deionized water was mixed into a mixed solution, and the pH was adjusted to 3.5 to 4.0 with glacial acetic acid, and 0.5 g of P (MMA-co-MPS) was added thereto, and reacted at 50 ° C for 1 hour to completely hydrolyze the siloxane.
  • 100 ml of HA emulsion (16 g of HA powder dissolved in 400 ml of deionized water) was added thereto, and the pH was adjusted to 10 with 10% NaOH to promote the condensation reaction.
  • the obtained product was filtered, dried at 120 ° C, and the dried powder was ultrasonicated with tetrahydrofuran (THF) for 30 min, repeatedly washed three times with THF, and then dried at 120 ° C to obtain P(MMA-co-MPS)-HA.
  • THF tetrahydrofuran
  • the deionized water was mixed into a mixed solution, and the pH was adjusted to 3.5 to 4.0 with glacial acetic acid, and 1.5 g of P (MMA-co-MPS) was added thereto, and reacted at 50 ° C for 1 hour to completely hydrolyze the siloxane.
  • the deionized water was mixed into a mixed solution, and the pH was adjusted to 3.5 to 4.0 with glacial acetic acid, and then 2.5 g of P (MMA-co-MPS) was added thereto, and reacted at 50 ° C for 1 hour to completely hydrolyze the siloxane.
  • the obtained product was filtered, dried at 120 ° C, and the dried powder was ultrasonicated with tetrahydrofuran (THF) for 30 min, repeatedly washed three times with THF, and then dried at 120 ° C to obtain P(MMA-co-MPS)-HA.
  • THF tetrahydrofuran
  • L-HA and H-HA can form a uniform suspension in MMA solvent, especially H-HA can be uniformly dispersed, no agglomerates are observed; after standing for 5 min, HA is basically The sedimentation, while the surface-modified HA is mostly suspended in the solvent, only a small part of the phenomenon of sedimentation, which indicates that the surface-modified HA improves the dispersibility and stability in the MMA solvent.
  • the bending test sample size was a strip having a length of about 75 mm, a width of 10 mm, and a thickness of 3.3 mm.
  • the experimental sample should be immersed in a water bath of 37 ⁇ 1 ° C for 50 h ⁇ 2 h before the test.
  • the experimental sample was bent and loaded on a Sansi tensile machine at a loading rate of 5 mm/min for a three-point bending test with a span of 60 mm. It can be seen that the HA is uniformly dispersed in the PMMA matrix.

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Abstract

提供一种高羟基磷灰石含量的复合型骨水泥及其制备方法和用途，以及提高纳米羟基磷灰石在甲基丙烯酸甲酯中稳定性的方法和经过修饰的纳米羟基磷灰石的制备方法。该复合型骨水泥包括粉末部分和液体部分，粉末部分由经P(MMA-co-MPS)表面修饰的羟基磷灰石和聚甲基丙烯酸甲酯组成，液体部分为含有引发剂的对苯二甲酸二甲酯的甲基苯烯酸甲酯。提高了羟基磷灰石在骨水泥中的分散性和力学性能，是一种可注射型骨水泥。

Description

一种经过修饰的纳米羟基磷灰石及其制备方法和应用 技术领域
本发明涉及生物材料领域，更具体地，涉及一种经过修饰的纳米羟基磷灰石及其制备方法和应用。
背景技术
骨水泥是一类通过自行固化后任意塑性的骨修复材料，今年来已被广泛运用于临床外科手术中。在髋关节置换手术，整形美容等领域被广泛应用。目前市场上的骨水泥主要分为两类：磷酸钙(CPC)骨水泥，CPC骨水泥以其优异的生物相容性而占有了骨水泥大量的市场，但是力学性能差导致其不能被运用于承重骨的修复手术中；传统的甲基丙烯酸(PMMA)骨水泥具有优异的力学性能，但是却因其与自然骨的差异较大，导致其生物相容性存在很大的问题。市场上的PMMA骨水泥寿命一般为8年，故在临床手术的使用中有一定局限性。
中科院长春应化所近年来研究开发了多种方法对HA纳米粒子进行表面改性。首先，通过在纳米尺寸的HA粒子表面羟基上原位引发聚合的方法，将左旋丙交酯(L-LA)通过化学键的方式接枝到了HA粒子表面。
然而，在实验中发现修饰后的HA，由于表面覆盖一层有机分子，接枝率过高可能对复合材料的钙磷暴露、生物矿化和细胞粘附产生不利影响。因此，有必要进一步研究不同接枝率对复合材料的物理性能和生物学性能的影响，以期实现通过接枝改性既能改善材料的分散性和力学性能，又能保持或改善材料的生物活性。
发明内容
为克服这样的局限性，本发明先提供一种高羟基磷灰石含量的复合型骨水泥，包括粉末部分和液体部分，所述的粉末部分由经P(MMA-co-MPS)表面修饰的羟基磷灰石和聚甲基丙烯酸甲酯(PMMA)组成；所述的液体部分为含有引发剂和对苯二甲酸二甲酯的甲基苯烯酸甲酯。
所述的聚甲基丙烯酸甲酯的分子量为80万～90万。
粉末部分中的经P(MMA-co-MPS)表面修饰的羟基磷灰石和聚甲基丙烯酸甲酯的重量比为1:1.5～2.0。
按重量百分比计，液体部分中的引发剂为0.8～1.2％，对苯二甲酸二甲酯为 4～5％，余量为甲基苯烯酸甲酯。
所述的粉末部分和液体部分按重量比为1：2.5～2.9。
所述的引发剂为过氧化苯甲酰。
提供一种经过修饰的纳米羟基磷灰石的制备方法，分为两步：
(1)P(MMA-co-MPS)的合成
在保持通Ar气下将MMA、AIBN、MPS、巯基乙酸、THF加入反应瓶中，半小时后关掉Ar气。在60～70℃下搅拌反应6～8h。
(2)P(MMA-co-MPS)偶联修饰HA(P(MMA-co-MPS)-HA)的制备
配制乙醇/水的混合溶液，并用冰醋酸调节pH至酸性，再将适量的步骤(1)所得小分子聚合物加入其中，使小分子聚合物完全水解。然后取适量的HA加入其中，用]NaOH溶液调节pH至碱性来促进缩合反应。将所得的产物过滤干燥，将干燥的粉末用四氢呋喃(THF)超声洗涤3次，然后干燥保存备用。
MMA：甲基丙烯酸甲酯；AIBN：偶氮二异丁腈；MPS：硅烷偶联剂；THF：四氢呋喃；Ar：氩气；HA：羟基磷灰石。
我们采用两亲性聚合物P(MMA-co-MPS)对HA纳米粒子的表面进行改性，制备了不同接枝率的HA纳米复合粒子，改性后的HA粒子改善了与基体的界面结合力及分散性。
HA表面悬空羟基容易以氢键的形式发生团聚，可通过表面修饰的方法防止HA在基体中的再次团聚，改善HA在基体中的分散性和稳定性，改善其与基体的相容性。本发明通过对HA进行表面修饰，一方面可以改善HA在骨水泥调配过程中的分散性和稳定性，加强HA其与基体的相互作用，另一方面还可赋予骨水泥一些新的功能。
更进一步提供一种上述的高羟基磷灰石含量的复合型骨水泥的制备方法，包括以下步骤：
S1.将表面修饰后的羟基磷灰石粉末和聚甲基丙烯酸甲酯混合，消毒后，得骨水泥的粉末部分；
S2.将引发剂和对苯二甲酸二甲酯溶解于甲基苯烯酸甲酯中，得骨水泥的液体部分；
使用时，将S1所的粉末部分和S2所得的液体部分混合，成型即可。
更具体地，提供一种上述的高羟基磷灰石含量的复合型骨水泥在制备骨科植 入材料中的应用。
纳米羟基磷灰石的合成；
称取(CaNO3)2·4H2O和(NH4)2HPO4粉末溶解于水中，在超声搅拌的条件下，将(NH4)2HPO4溶液滴加到(CaNO3)2·4H2O溶液中，加入分散剂，调节pH，陈化，离心，水洗，即得。
高分子量PMMA的合成：
将聚乙烯醇溶于蒸馏水中，搅拌下充分溶解后，加入甲基丙烯酸甲酯(及过氧化二苯甲酰，升温至60～100℃，反应5～6h后，将所得的产物用蒸馏水洗3～5次，置于70～90℃烘箱中干燥4～8h，即得，将所得的高分子量PMMA碾磨成颗粒，待用。
其中，MMA：甲基丙烯酸甲酯；BPO：过氧化二苯甲酰；
PMMA：聚甲基丙烯酸甲酯；DMT：对苯二甲酸二甲酯；
MPS：硅烷偶联剂；THF：四氢呋喃；PVA：聚乙烯醇。
本发明的优点在于：
1、本发明公开的骨水泥制备方法，是一种可注射型骨水泥，应用广泛。
2、本发明公开的骨水泥制备方法，通过P(MMA-co-MPS)对羟基磷灰石进行高程度的表面修饰后，大大提高了羟基磷灰石在骨水泥中的分散性，具有优秀的力学性能。
3、本发明公开的骨水泥制备方法，羟基磷灰石在骨水泥固体粉末中的含量高达40％，大大提高了PMMA骨水泥的生物相容性。细胞毒性试验结果显示该骨水泥是没有毒性的。
4.本发明中改性的纳米HA在MMA中分散性良好；
5.本发明合成出的改性纳米HA相较于现有HA有力学性能有显著的提高且方法简单易行；作为骨科修复和固定材料有广阔的应用前景。
6.利用本发明合成的纳米HA调配的骨水泥制备方便快捷，可在室温下成型，条件温和。
附图说明
图1为P(MMA-co-MPS)-HA的红外表征图。
图2为P(MMA-co-MPS)-HA的热重分析图。
图3为骨水泥的压缩强度的结果图。
图4为骨水泥的弯曲强度的结果图。
图5为骨水泥的弯曲模量的结果图。
图6为骨水泥的细胞毒性的结果图。
具体实施方式
下面结合附图和具体实施例进一步详细说明本发明。除非特别说明，本发明采用的试剂、设备和方法为本技术领域常规市购的试剂、设备和常规使用的方法。实施案1
第一步，使用75ml丙酮溶液溶解5gP(MMA-co-MPS)粉末后，加入90％乙醇/水的混合溶液并调节溶液PH值至3.5-4.0，反应一个小时后，加入事先超声分散好的含有8g羟基磷灰石悬液200ml并调节整个体系的PH值至9.0，反应过夜，将产物过滤，用四氢呋喃超声清洗三次，真空干燥得到P(MMA-co-MPS)-HA粉末。实验红外结果如图1，从图中观察到，相对于羟基磷灰石(HA),P(MMA-co-MPS)-HA在1410～1460处的C-O反对称峰吸收峰出现裂峰的现象，说明CO32-进入羟基磷灰石的内部，P(MMA-co-MPS)成功修饰到羟基磷灰石的表面。实验热重分析结果如图2，羟基磷灰石(a)的质量随着温度的升高没有变化；经P(MMA-co-MPS)修饰后的羟基磷灰石(b)，其修饰程度高达50％。
第二步，将第一步中所得的表面修饰后的羟基磷灰石粉末0.4g与分子量为85万的PMMA粉末0.6g混合并经消毒后即得骨水泥的粉末部分。骨水泥的液体部分由溶解有0.03gBPO和14ulDMT的MMA溶液3ml组成。将骨水泥粉末组分与液体组分混合后搅拌混匀，经注射器注射成型后，作为实验组骨水泥。对照组骨水泥中羟基磷灰石为未经修饰的羟基磷灰石粉末。
实施案2
压缩性能实验样品尺寸为：高12mm，直径6mm的圆柱体，实验组骨水泥为实施例1所述的骨水泥。
使用万能材料试验机测得压缩强度结果如图3，实验组骨水泥的压缩强度明显高于对照组骨水泥，并且，实验组骨水泥的压缩性能达到ISO5833的标准。实施例3
弯曲性能实验样品尺寸为：长75mm，宽10mm，高3.3mm的板材，实验组骨水泥为实施例1所述的骨水泥。
测试前，样品于37℃的水浴中浸泡72±1.0小时。在万能材料试验机上测得弯曲强度结果如图4，含实验组骨水泥的弯曲强度高于对照组的强度，弯曲模量结果如图5，结果与弯曲强度类似。弯曲性能的结果说明含有共聚物羟基磷灰石的骨水泥的弯曲性能明显得到改善。
实施案4
细胞毒性测试(MTT)实验样品尺寸：高6mm，直径6mm的圆柱体，实验组骨水泥为实施例1所述的骨水泥。
各骨水泥样分别使用酒精，PBS浸泡24小时后，使用完全培养基浸泡24小时得到两组浸提液。以完全培养基为空白对照组，每个样品接种5000个人成骨细胞细胞(HFOB)。测得24小时和48小时后各组的细胞存活率。实验结果如图6，与空白对照组相比，各组细胞存活率均高于80％，说明材料均没有毒性。
实施例5
在Ar气氛围下将MMA27ml、AIBN0.11808g、MPS7.1424g、巯基乙酸249μl、THF60ml加入反应瓶中，半小时后关掉Ar气。在70℃下搅拌反应6h得到P(MMA-co-MPS)。将所得的产物，用乙醚重沉淀2～3次，真空干燥得到样品，磨成粉末，密封保存，备用。
实施例6
配制乙醇/水(v/v＝9:1)的混合溶液110ml,其中V乙醇90ml，V水10ml。去离子水配成混合溶液，并用冰醋酸调节pH值3.5～4.0,再将0.5g的P(MMA-co-MPS)加入其中，50℃反应1h，使硅氧烷完全水解。取100mlHA乳液(16gHA粉末溶于400ml去离子水中)加入其中，用10％NaOH调节PH至10来促进缩合反应。将所得的产物过滤，120℃干燥，将干燥的粉末用四氢呋喃(THF)超声30min，反复用THF超声洗3遍，然后120℃干燥，得到P(MMA-co-MPS)-HA。
实施例7
配制乙醇/水(v/v＝9:1)的混合溶液100ml,其中V乙醇90ml，V水10ml。去离子水配成混合溶液，并用冰醋酸调节pH值3.5～4.0,再将1.5g的P(MMA-co-MPS)加入其中，50℃反应1h，使硅氧烷完全水解。取100ml的HA加入其中，用10％NaOH调节PH＝10来促进缩合反应。将所得的产物过滤，120 ℃干燥，将干燥的粉末用四氢呋喃(THF)超声30min，反复用THF超声洗3遍，然后120℃干燥，得到P(MMA-co-MPS)-HA。
实施例8
配制乙醇/水(v/v＝9:1)的混合溶液100ml,其中V乙醇90ml，V水10ml。去离子水配成混合溶液，并用冰醋酸调节pH值3.5～4.0,再将2.5g的P(MMA-co-MPS)加入其中，50℃反应1h，使硅氧烷完全水解。取100ml的HA加入其中，用10％NaOH调节PH＝10来促进缩合反应。将所得的产物过滤，120℃干燥，将干燥的粉末用四氢呋喃(THF)超声30min，反复用THF超声洗3遍，然后120℃干燥，得到P(MMA-co-MPS)-HA。
实施例9
将实施例5、实施例7、实施例8中的HA、0.5gP(MMA-co-MPS)修饰的HA，和2.5g修饰的P(MMA-co-MPS)-HA分别溶于MMA中。超声后静置1min时，L-HA和H-HA在MMA溶剂中可形成均一的悬浮液，尤其H-HA能够均匀的分散，没有观察到沉降的团聚体；在静置5min后，HA基本沉降，而经过表面修饰的HA大部分都悬浮在溶剂中，只有少部分沉降的现象，该现象表明经过表面修饰后的HA，改善了在MMA溶剂中的分散性和稳定性。以上分析得到：HA在MMA溶剂中的稳定性及分散性由强到弱的排列顺序为H-HA>L-HA>HA。说明HA经P(MMA-co-MPS)表面修饰后，提高了HA在MMA溶剂中的分散性和稳定性，改善HA与PMMA基体材料的相容性。
弯曲实验样品尺寸为长约75mm，宽10mm，厚3.3mm的板条。实验样品试验前应浸泡在37±1℃的水浴中50h±2h。将弯曲实验样品，在三思拉力机上以5mm/min的加载速率加载，进行三点弯曲实验，跨距60mm。可以看到HA均匀的分散在PMMA基体中。

Claims (10)

  1. 一种高羟基磷灰石含量的复合型骨水泥，包括粉末部分和液体部分，其特征在于，所述的粉末部分由经P(MMA-co-MPS)表面修饰的羟基磷灰石和聚甲基丙烯酸甲酯组成；所述的液体部分为含有引发剂和对苯二甲酸二甲酯的甲基苯烯酸甲酯。
  2. 根据权利要求1所述的复合型骨水泥，其特征在于，所述的聚甲基丙烯酸甲酯的分子量为80万～90万。
  3. 根据权利要求1所述的复合型骨水泥，其特征在于，粉末部分中的经P(MMA-co-MPS)表面修饰的羟基磷灰石和聚甲基丙烯酸甲酯的重量比为1:1.5～2.0。
  4. 根据权利要求1所述的复合型骨水泥，其特征在于，按重量百分比计，液体部分中的引发剂为0.8～1.2％，对苯二甲酸二甲酯为4～5％，余量为甲基苯烯酸甲酯。
  5. 根据权利要求1所述的复合型骨水泥，其特征在于，所述的粉末部分和液体部分按重量比为1：2.5～2.9。
  6. 根据权利要求1所述的复合型骨水泥，其特征在于，所述的引发剂为过氧化苯甲酰。
  7. 一种根据权利要求1所述的高羟基磷灰石含量的复合型骨水泥的制备方法，其特征在于，包括以下步骤：
    S1.将表面修饰后的羟基磷灰石粉末和聚甲基丙烯酸甲酯混合，消毒后，得骨水泥的粉末部分；
    S2.将引发剂和对苯二甲酸二甲酯溶解于甲基苯烯酸甲酯中，得骨水泥的液体部分；
    使用时，将S1所的粉末部分和S2所得的液体部分混合，成型即可。
  8. 一种根据权利要求1所述的高羟基磷灰石含量的复合型骨水泥在制备骨科植入材料中的应用。
  9. 一种提高纳米羟基磷灰石在甲基丙烯酸甲酯中稳定性的方法，其特征在于，在羟基磷灰石上用P(MMA-co-MPS)进行修饰。
  10. 一种经过修饰的纳米羟基磷灰石的制备方法，其特征在于，
    S1.P(MMA-co-MPS)的合成；
    在惰性气体下，将甲基丙烯酸甲酯、偶氮二异丁腈、硅烷偶联剂和四氢呋喃加入容器中，在60～70℃搅拌反应6～8小时，即得P(MMA-co-MPS)；
    S2.P(MMA-co-MPS)-HA的制备；
    将乙醇/水的混合溶液用冰醋酸调节至酸性，将步骤S1所述的P(MMA-co-MPS)加入其中，加入纳米羟基磷灰石，调节至碱性，将产物过滤干燥，再用四氢呋喃超声洗涤，即得。
PCT/CN2014/085725 2013-11-07 2014-09-02 一种经过修饰的纳米羟基磷灰石及其制备方法和应用 WO2015067091A1 (zh)

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