WO2019218433A1 - 石墨烯与羟基磷灰石复合仿生骨材料及其制备方法 - Google Patents

石墨烯与羟基磷灰石复合仿生骨材料及其制备方法 Download PDF

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WO2019218433A1
WO2019218433A1 PCT/CN2018/094081 CN2018094081W WO2019218433A1 WO 2019218433 A1 WO2019218433 A1 WO 2019218433A1 CN 2018094081 W CN2018094081 W CN 2018094081W WO 2019218433 A1 WO2019218433 A1 WO 2019218433A1
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graphene
hydroxyapatite
solution
bone material
black
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PCT/CN2018/094081
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French (fr)
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邢士超
王鹏君
吕秋兰
于腾波
马学晓
陈泽庆
刘秀
徐大星
王广涛
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青岛大学附属医院
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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
    • A61L27/02—Inorganic materials
    • A61L27/12—Phosphorus-containing materials, e.g. apatite
    • 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
    • A61L27/02—Inorganic materials
    • A61L27/08—Carbon ; Graphite
    • 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
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • 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
    • 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
    • A61L2430/12—Materials or treatment for tissue regeneration for dental implants or prostheses

Definitions

  • the invention relates to the field of medical biomimetic materials, in particular to a method for preparing medical bone materials.
  • HA Hydroxyapatite
  • PO4 OH
  • a specific gravity 3.16 g/cm 3
  • Mohs hardness 5.
  • natural apatite The minerals are similar.
  • HA is the main inorganic component of human bone tissue and teeth. It is about 96% in enamel and can account for more than 69% in bone.
  • traditional metal stainless steel, titanium alloy
  • ceramic alumina, silicon nitride
  • HA can be used as an inducing factor in the field of oral health to achieve desensitization of teeth to whiten the effect. Because HA particles have good biocompatibility with enamel and high affinity, it can effectively prevent the loss of calcium ions, solve the problem of enamel demineralization, and fundamentally prevent dental caries. Toothpaste containing HA material can reduce dental plaque in the patient's mouth, promote the healing of gingivitis, and have a good preventive effect on rickets and periodontal disease.
  • HA also has a strong adsorption effect on biomacromolecules, and it is safe and effective as a drug carrier, and is not dissolved by gastrointestinal fluids, and can be degraded or absorbed after being released from the drug or all discharged with feces.
  • Other studies have shown that it has different degrees of inhibition on the growth of various cancer cells such as liver cancer, gastric cancer and osteosarcoma. Based on the above characteristics, it is widely used in diseases prevention, biomedical, targeted drugs, environmental protection and other industries.
  • the fracture toughness of natural bone is 2 ⁇ 12MPa ⁇ m 0.5
  • the fracture toughness of HA is less than 1MPa ⁇ m 0.5
  • the bionic bone material formed cannot meet the dual requirements of strength and toughness at the same time. It is necessary to ensure the reliable service of HA and expand its application. For the range, it is necessary to toughen it to improve its fracture toughness.
  • Graphene is a honeycomb two-dimensional planar material formed by carbon atom by sp 2 hybridization. It has high physical strength, high specific surface area and low density of physical and chemical properties. Its elastic modulus reaches 1TPa and its breaking strength. It is 42N/m, 100 times higher than steel, and its areal density is only 0.77mg/m 2 , which is an ideal high-strength material; it is resistant to acid and alkali and has good stability. In recent years, graphene materials have been found to promote stem cell osteogenic differentiation and increase the proliferation rate of osteoblasts, and have great application prospects in bone tissue repair engineering. However, its solubility is poor, resulting in a complex process with HA, which greatly affects the composite and application with HA.
  • Chinese Patent Application No. CN103435031A discloses a method for preparing water-soluble graphene (HG), it does not disclose how to apply it to a bionic bone material.
  • Chinese Patent Application No. CN102492082A discloses a method for preparing a medical artificial bone material, which uses flake graphite as a raw material, obtains graphene oxide by Hummers oxidation method, and acylates acrylic acid to disperse graphene oxide in acid-chlorinated acrylic acid.
  • the solution is added to the reaction vessel, and then the catalyst pyridine is added, and the reaction is carried out at 70 to 100 ° C for 3 to 5 hours under the protection of N 2 to obtain an esterified product; methyl methacrylate is added to the obtained esterified product, and the temperature is raised.
  • the initiator is added, the polymerization reaction is carried out for 5 to 10 hours, and cooled to room temperature to obtain a gray solid, which is a material for medical artificial bones; the initiator is cyclohexanone peroxide and methyl ethyl ketone peroxide One of them.
  • the preparation method disclosed in the patent requires limitation of reaction conditions such as an initiator, a catalyst, and a nitrogen gas, and the reaction steps are cumbersome and the reagent requirements are complicated.
  • Chinese Patent Application No. CN105816916A discloses a medical artificial bone material and a preparation method thereof, which comprises 20 to 50 parts of graphene oxide, 20 to 75 parts of 3,3-phenylacryloyl chloride, and 50 to 50% of methacrylic acid.
  • 100 parts, 0.5-2 parts of catalyst and 0.5-2 parts of initiator firstly disperse graphene oxide in 3-phenylacryloyl chloride solution by weight ratio, add to the reaction vessel, and then add catalyst under argon protection
  • the reaction is heated; then methyl methacrylate is added to the reaction vessel, an initiator is added, and the reaction is heated. After the reaction is completed, the mixture is cooled to room temperature to obtain a medical artificial bone material.
  • the preparation method disclosed in the patent also requires limitation of reaction conditions such as an initiator, a catalyst, and a nitrogen gas, and the reaction product is liable to cause other impurity ions.
  • the object of the present invention is to provide a composite bionic bone of graphene and hydroxyapatite which has simple preparation process, uniform composition, hydrophilicity of hydroxyapatite regulation, excellent biocompatibility and promotion of osteoblast proliferation. Method of preparation of materials.
  • the invention prepares a graphene/hydroxyapatite bionic bone material by hydrothermal method for water-soluble graphene and hydroxyapatite.
  • the present invention provides a method for preparing a composite biomimetic bone material of graphene and hydroxyapatite, comprising: (1) a molar ratio of a calcium hydroxide aqueous solution to a phosphorus source solution according to a Ca/P ratio of 1.67. After mixing and forming hydroxyapatite, a stoichiometric ratio of 2.5% to 25% of the water-soluble graphene of the synthesized hydroxyapatite is added, and a uniform black solution is obtained after 5 to 10 minutes of ultrasonication; (2) the step ( 1) The black solution is added to the polar solution and mixed uniformly.
  • the volume ratio of the black solution to the polar solution is 2:3 to 1:5, and the reaction is carried out at 180 degrees Celsius to 220 degrees Celsius for 12 to 36 hours, and then cooled to At room temperature, a mixed solution is obtained; (3) the mixture obtained in the step (2) is centrifugally washed with deionized water to be neutral to obtain a black crude product; and (4) the black crude product obtained in the step (3) is ultrasonically dispersed. Pre-freezing in deionized water for 12 hours gave a graphene/hydroxyapatite bionic bone material.
  • the phosphorus source solution in the step (1) is a calcium dihydrogen phosphate solution, a calcium hydrogen phosphate solution, or a phosphoric acid solution.
  • the concentration of the phosphorus source solution in the step (1) is from 0.012 to 0.06 mol/liter.
  • the concentration of the aqueous calcium hydroxide solution in the step (1) is 0.02 to 0.1 mol/liter.
  • the water-soluble graphene added in the step (1) is 5% to 20% by mass of the stoichiometrically synthesized hydroxyapatite.
  • the polar solution water in step (2) a mixture of N,N-dimethylformamide and dimethyl sulfoxide, wherein water, N,N-dimethylformamide and dimethyl
  • the volume ratio of sulfoxide is 1:1:1 to 2:3:5.
  • the black solution and the polar solution are reacted in a blast drying oven at 180 degrees Celsius to 220 degrees Celsius.
  • pre-freezing is performed in a low temperature medical refrigerator at -70 degrees Celsius to -50 degrees Celsius.
  • the mass ratio of the black crude product to the deionized water in the step (4) is 1:1 to 1:10.
  • the hydrophilic/water-soluble graphene (HG) employed in the present invention can be obtained by a method disclosed in, for example, Chinese Patent Application No. CN103435031A, CN102145882A or CN107857254A, or by other commercial sources.
  • the beneficial effects of the invention are as follows: (1) In the present invention, the phosphorus source and the calcium source are both main constituent components of hydroxyapatite, and no other impurity ions are introduced, thereby avoiding ion doping or vacancy occurrence, Improving the purity and crystallinity of hydroxyapatite; (2) In the present invention, the self-assembly and compounding of water-soluble graphene and hydroxyapatite is realized by a hydrothermal method in a polar solvent, and the preparation method is simple and feasible, and is easy to operate and Control, low cost and no environmental pollution; (3), the graphene/hydroxyapatite bone material prepared by the invention not only retains the hydrophilicity of graphene, but also has excellent biological phase of hydroxyapatite.
  • the hydrophilic property of the material can be controlled by changing the content of graphene, and the use of adding a surfactant is omitted; (4) the composition of the graphene/hydroxyapatite bone material prepared by the invention The crystal structure of the composition is complete, the distribution is uniform, and the product quality is high; (5), the invention can obtain the medical bone material without interference ions, and can be widely applied to the construction of bone and teeth.
  • 1 is a Raman spectrum of a pure hydroxyapatite material and a graphene/hydroxyapatite bionic bone material of the present invention.
  • FIG. 2 is an XRD pattern of a pure hydroxyapatite material and a graphene/hydroxyapatite bionic bone material of the present invention.
  • 3 is a Fourier infrared spectrum of a pure hydroxyapatite material and a graphene/hydroxyapatite bionic bone material of the present invention.
  • Example 4 is an SEM image of a graphene/hydroxyapatite bionic bone material obtained in Example 1 of the present invention.
  • Figure 5 is an SEM image of a graphene/hydroxyapatite bionic bone material obtained in Example 2 of the present invention.
  • Figure 6 is a SEM image of a graphene/hydroxyapatite bionic bone material obtained in Example 3 of the present invention.
  • Figure 7 is a SEM image of a graphene/hydroxyapatite bionic bone material obtained in Example 4 of the present invention.
  • Figure 8 is a SEM image of a graphene/hydroxyapatite bionic bone material obtained in Example 5 of the present invention.
  • Figure 9 is a SEM image of the graphene/hydroxyapatite bionic bone material obtained in Example 6 of the present invention.
  • Figure 10 is a chart showing the energy spectrum of a graphene/hydroxyapatite bionic bone material obtained in Example 3 of the present invention.
  • Figure 11 is a TEM image of a graphene/hydroxyapatite bionic bone material obtained in Example 1 of the present invention.
  • Figure 12 is a TEM image of a graphene/hydroxyapatite bionic bone material obtained in Example 5 of the present invention.
  • Figure 13 is a TEM image of a graphene/hydroxyapatite bionic bone material obtained in Example 6 of the present invention.
  • Figure 14 is a HRTEM image of the graphene/hydroxyapatite bionic bone material obtained in Example 1 of the present invention.
  • Figure 15 is a HRTEM image of the graphene/hydroxyapatite bionic bone material obtained in Example 3 of the present invention.
  • Figure 16 is a HRTEM image of a graphene/hydroxyapatite bionic bone material obtained in Example 7 of the present invention.
  • Figure 17 is a graph showing the relationship between cell proliferation and concentration of graphene/hydroxyapatite bionic bone material obtained in Example 7 of the present invention.
  • Figure 18 is a graph showing the relationship between cell proliferation and time of a graphene/hydroxyapatite bionic bone material obtained in Example 7 of the present invention.
  • a represents pure hydroxyapatite material without graphene synthesized by this method
  • b, c, and d represent Examples 1, 5, and 7, respectively.
  • a method for preparing a graphene-hydroxyapatite composite bionic bone material comprising the steps of:
  • Step (1) mixing the calcium hydroxide aqueous solution and the phosphorus source solution according to a Ca/P molar ratio of 1.67 to form hydroxyapatite, and adding a stoichiometrically synthesized hydroxyapatite mass of 2.5%-25% of water solubility. Graphene, after 5 to 10 minutes of ultrasound, a uniform black solution is obtained;
  • Step (2) adding the black solution in the step (1) to the polar solution and mixing uniformly, wherein the volume ratio of the black solution to the polar solution is 2:3 to 1:5, and the reaction is carried out at 180 degrees Celsius to 220 degrees Celsius. After 36 hours, cooled to room temperature to obtain a mixed solution;
  • the mixture obtained in the step (2) is centrifugally washed with deionized water to neutrality to obtain a black crude product
  • the volume ratio of the black solution to the polar solution is 2:3. After being cooled to room temperature, the resulting mixture was centrifuged with deionized water to neutrality to give a crude black product.
  • the black crude product and deionized water were ultrasonically dispersed at a mass ratio of 1:1 and pre-frozen at -60 ° C for 12 hours, and lyophilized to obtain a black solid, which is a non-interfering ion graphene/hydroxyapatite bone material.
  • the resulting mixture was centrifuged with deionized water to neutrality to give a crude black product.
  • the black crude product and deionized water were ultrasonically dispersed at a mass ratio of 1:2 and pre-frozen at -70 ° C for 12 hours, and lyophilized to obtain a black solid, which is an interference-free ion graphene/hydroxyapatite bone material.
  • the resulting mixture was centrifuged with deionized water to neutrality to give a crude black product.
  • the black crude product and deionized water were ultrasonically dispersed at a mass ratio of 1:5 and pre-frozen at -50 ° C for 12 hours, and lyophilized to obtain a black solid, which is an interference-free ion graphene/hydroxyapatite bone material.
  • the resulting mixture was centrifuged with deionized water to neutrality to give a crude black product.
  • the black crude product and deionized water were ultrasonically dispersed at a mass ratio of 1:10 and pre-frozen at -60 ° C for 12 hours, and lyophilized to obtain a black solid, which is an interference-free ion graphene/hydroxyapatite bone material.
  • the resulting mixture was centrifuged with deionized water to neutrality to give a crude black product.
  • the black crude product and deionized water were ultrasonically dispersed at a mass ratio of 1:1 and pre-frozen at -65 ° C for 12 hours, and lyophilized to obtain a black solid, which is an interference-free ion graphene/hydroxyapatite bone material.
  • the resulting mixture was centrifuged with deionized water to neutrality to give a crude black product.
  • the black crude product and deionized water were ultrasonically dispersed at a mass ratio of 1:8 and pre-frozen at -60 ° C for 12 hours, and lyophilized to obtain a black solid, which was an interference-free ion graphene/hydroxyapatite bone material.
  • the black crude product and deionized water were ultrasonically dispersed at a mass ratio of 1:2 and pre-frozen at -60 ° C for 12 hours, and lyophilized to obtain a black solid, which is a non-interfering ion graphene/hydroxyapatite bone material.
  • the obtained graphene/hydroxyapatite bone material was prepared and tested accordingly.
  • the sample a in the Raman spectrum of Fig. 1 showed only at 432 cm -1 , 587 cm -1 , 964 cm -1 , and 1048 cm -1 .
  • Characteristic peak of hydroxyapatite In addition to the characteristic peak of hydroxyapatite, the sample bd showed strong graphene peaks at 1350 and 1578 cm -1 , indicating that the sample bd has both graphene and hydroxyapatite structures.
  • the sample ad in the XRD of Fig. 2 shows characteristic diffraction peaks of hydroxyapatite at 6.78°, 25.88°, 31.78°, 32.20°, 32.94°, 34.08°, 39.84°, 46.78°, and 49.50°, which is in accordance with the standard.
  • the hydroxyapatite PDF card matches. This result indicates that the obtained material has good crystallinity and no crystal defects, and even the presence of graphene does not affect its crystal structure.
  • the infrared spectrum of Figure 3 shows that the absorption peaks characteristic of hydroxyapatite are 1022 cm -1 , 962 cm -1 , 600 cm -1 , and 560 cm -1 , which correspond to the stretching vibration and bending vibration of the phosphate group in hydroxyapatite. . 3570 cm -1 is a stretching vibration of its hydroxyl group. This indicates the presence of hydroxyapatite in the material.
  • Figures 4-9 are SEM images of graphene/hydroxyapatite bionic bone materials. The figure shows that the rod-shaped hydroxyapatite is uniformly dispersed in the graphene of the sheet structure.
  • Figure 10 is an energy spectrum of a graphene/hydroxyapatite bionic bone material.
  • the figure shows that the material has Ca, P, O, C, S elements.
  • the Ca, P, O and graphene-specific elements C and S of hydroxyapatite were found in this material, which proved that the graphene/hydroxyapatite bionic bone material was successfully compounded.
  • Figures 11-13 are TEM images of graphene/hydroxyapatite bionic bone materials. The figure shows that the rod-like or spherical hydroxyapatite is uniformly supported in the sheet-like tissue-like graphene.
  • FIGS. 14-16 are HRTEM images of graphene/hydroxyapatite bionic bone materials.
  • the figure shows the crystal structure of graphene polycrystalline structure and hydroxyapatite.
  • the lattice spacing of hydroxyapatite was 0.342 nm, which matched the (002) crystal plane.
  • Figure 17 is a graph showing the relationship between cell proliferation and concentration of graphene/hydroxyapatite bionic bone material. The figure shows that under the same concentration conditions, the cell proliferation effect increases with the increase of graphene content. Graphene does not damage cells and has good biocompatibility.
  • Figure 18 is a graph showing the relationship between cell proliferation and time of graphene/hydroxyapatite bionic bone material. The figure shows that the material has the best culture time and graphene dosage for cell proliferation.

Abstract

一种石墨烯与羟基磷灰石复合仿生骨材料及其制备方法，该方法包括：将氢氧化钙水溶液与磷源溶液按照Ca/P摩尔比为1.67比例混合生成羟基磷灰石后，加入化学计量比合成的羟基磷灰石质量2.5%-25%的水溶性石墨烯，超声5分钟后得到均匀的黑色溶液；将黑色溶液加入至极性溶液中，于200摄氏度反应12-36小时，冷却至室温，得到混合液；将混合液用去离子水离心洗涤至中性，得到黑色粗产品，以及将黑色粗产品超声分散于去离子水中，并进行预冷冻，得到石墨烯/羟基磷灰石仿生骨材料。

Description

石墨烯与羟基磷灰石复合仿生骨材料及其制备方法 技术领域
本发明涉及医学仿生材料的领域，特别是涉及一种医用骨材料的制备方法。
背景技术
羟基磷灰石(Hydroxyapatite，HA)为六方晶系的白色粉末，化学组成为Ca 10(PO4) 6(OH) 2，比重为3.16克/立方厘米，莫氏硬度为5，与天然磷灰石矿物相近。HA是人体骨骼组织和牙齿的主要无机成分，其在牙釉质中含量约为96％，其在骨骼中也能占到69％以上。相对于传统的金属(不锈钢、钛合金)和陶瓷(氧化铝、氮化硅)类骨替代材料，HA生物活性陶瓷不仅抗腐蚀性强，能与骨形成骨性结合界面，结合强度高，稳定性好，而且还具有诱导骨细胞生长的作用，逐步参与代谢，是完全可以在生物体内降解的一类生物材料，因此消除了安全隐患。另外，HA在口腔保健领域中可作为一种诱导因子，实现对牙齿脱敏以美白作用。由于HA粒子与牙釉质生物相容性好，亲和性高，可以有效阻止钙离子流失，解决牙釉质脱矿问题，从根本上预防龋齿病。含有HA材料的牙膏，能减少患者口腔的牙菌斑，促进牙龈炎愈合，对龋病、牙周病有较好的防治作用。此外，HA还对生物大分子具有较强的吸附作用，将其作为药物载体，安全有效，且不为胃肠液所溶解，在释放药物后可降解吸收或全部随粪便排出。另有研究表明，其对肝癌、胃癌、骨肉瘤等多种癌细胞的生长具有不同程度的抑制作用。基于上述特点，其在疾病预防、生物医疗、靶向药物、环境保护等行业均具有广泛应用。
虽然HA及其复合材料的研究和在组织工程中的应用均取得了较快的发展，但仍然存在很多问题，如HA的脆性较高，降低了其在临床应用的可靠性与服役时间。自然骨的断裂韧性为2～12MPa·m 0.5，而HA的断裂韧性不到1MPa·m 0.5，其形成的仿生骨材料不能同时满足强度和韧性的双重要求，要确保HA可靠服役并扩展其应用范围，就需要对其 进行增韧以提高其断裂韧性。
石墨烯是一种由碳原子以sp 2杂化方式形成的蜂窝状的二维平面材料，具有高机械强度、高比表面积、低密度的物理化学特性，其弹性模量达到1TPa，抗断强度为42N/m，比钢高100倍，而其面密度仅为0.77mg/m 2，是理想的高强度材料；同时它耐酸碱、具有良好的稳定性。近年来，石墨烯材料被发现可促进干细胞成骨分化，提高成骨细胞的增殖速度，在骨组织修复工程中具有极大的应用前景。但是，其溶解性较差，造成其与HA复合工艺复杂，极大影响了与HA的复合及应用。尽管中国专利申请CN103435031A公开了一种水溶性石墨烯(HG)的制备方法，但其并未揭示如何应用于仿生骨材料。
如中国专利申请CN102492082A公开了一种医用人造骨骼用材料的制备方法，其以鳞片石墨为原料，采用Hummers氧化法制得氧化石墨烯，并酰氯化丙烯酸，将氧化石墨烯分散于酰氯化后的丙烯酸溶液中，加入反应釜中，再加入催化剂吡啶，在N 2保护下，于70～100℃下反应3～5小时，得到酯化产物；将甲基丙烯酸甲酯加入所得酯化产物中，升温至100～200℃，加入引发剂，聚合反应5～10小时，冷却至室温，得灰色固体，即为制得的医用人造骨骼用材料；所述引发剂为过氧化环己酮和过氧化甲乙酮中的一种。然而，该专利公开的制备方法需要引发剂、催化剂及氮气保护等反应条件的限定，反应操作步骤繁琐，试剂要求复杂。
又如中国专利申请CN105816916A公开了一种医用人造骨骼用材料及其制备方法，该材料包括氧化石墨烯20～50份、3，3-苯基丙烯酰氯20～75份、异丁烯酸甲酯50～100份、催化剂0.5～2份和引发剂0.5～2份，首先按重量份比将氧化石墨烯分散于3-苯基丙烯酰氯溶液中，加入反应釜中，然后加入催化剂，在氩气保护下，加热反应；然后将异丁烯酸甲酯加入到反应釜中，加入引发剂，加热反应，反应完后冷却至室温，即可制得医用人造骨骼用材料。然而专利公开的制备方法同样需要引发剂、催化剂及氮气保护等反应条件的限定，反应产物容易出现其他杂质离子。
由此可见，提供一种易于操作控制、可将羟基磷灰石与石墨烯进行有效结合的仿生骨材料的制备方法成为业内急需解决的问题。
发明内容
本发明的目的在于提出一种制备工艺简单、复合均匀、兼具有调控羟基磷灰石亲水性、优异生物相容性，可促进成骨细胞增殖的石墨烯与羟基磷灰石复合仿生骨材料的制备方法。
本发明将水溶性石墨烯和羟基磷灰石通过水热法制备得到一种石墨烯/羟基磷灰石仿生骨材料。
为了实现上述目的，本发明提供了一种石墨烯与羟基磷灰石复合仿生骨材料的制备方法，其包括：(1)、将氢氧化钙水溶液与磷源溶液按照Ca/P摩尔比为1.67比例混合生成羟基磷灰石后，加入化学计量比合成的羟基磷灰石质量2.5％～25％的水溶性石墨烯，超声5～10分钟后得到均匀的黑色溶液；(2)、将步骤(1)中的黑色溶液加入至极性溶液中混合均匀，其中，黑色溶液与极性溶液的体积比2:3～1:5，于180摄氏度～220摄氏度的条件下反应12～36小时，冷却至室温，得到混合液；(3)、将步骤(2)得到的混合液用去离子水离心洗涤至中性，得到黑色粗产品；以及(4)将步骤(3)得到的黑色粗产品超声分散于去离子水中，预冷冻12小时，得到石墨烯/羟基磷灰石仿生骨材料。
可选择地，步骤(1)中的磷源溶液为磷酸二氢钙溶液、磷酸氢钙溶液、或磷酸溶液。
可选择地，步骤(1)中的磷源溶液的浓度为0.012～0.06摩尔/升。
可选择地，步骤(1)中的氢氧化钙水溶液的浓度为0.02～0.1摩尔/升。
可选择地，步骤(1)中加入的水溶性石墨烯质量为化学计量比合成的羟基磷灰石质量的5％-20％。
可选择地，步骤(2)中的极性溶液水、N,N-二甲基甲酰胺及二甲基亚砜的混合物，其中，水、N,N-二甲基甲酰胺及二甲基亚砜的体积比为1:1:1～2:3:5。
可选择地，在步骤(2)中，黑色溶液和极性溶液在鼓风干燥箱中于180摄氏度～220摄氏度的条件下反应。
可选择地，在步骤(4)中，在低温医用冰箱中于-70摄氏度～-50摄氏度的条件下进行预冷冻。
可选择地，步骤(4)中黑色粗产品与去离子水的质量比为1:1～1:10。
可选择地，本发明采用的亲水性/水溶性石墨烯(HG)可通过如中国专利申请CN103435031A、CN102145882A或CN107857254A等公开的方法制得，亦可通过其它商业渠道获得。
本发明的有益效果是：(1)、本发明中磷源和钙源均为羟基磷灰石的主要组成成分，无其他杂质离子的引入，避免了离子掺杂或缺位现象的产生，可以提升羟基磷灰石的纯度和结晶度；(2)、本发明中用水热法在极性溶剂中实现了水溶性石墨烯与羟基磷灰石的自组装复合，制备方法简单可行，易于操作和控制，成本低及无环境污染；(3)、本发明所制备的石墨烯/羟基磷灰石骨材料既保留了石墨烯亲水性的特点，同时也具备了羟基磷灰石的优异生物相容性等优点，可通过改变石墨烯的含量调控该材料的亲水性能，省去了添加表面活性剂的使用；(4)、本发明制备的石墨烯/羟基磷灰石骨材料中各组成成分的晶体结构完整，分布均匀，产品质量高；(5)、本发明可获得无干扰离子的医用骨材料，可广泛应用于骨和牙齿的构建中。
附图说明
图1为纯羟基磷灰石材料及本发明的石墨烯/羟基磷灰石仿生骨材料的Raman光谱图。
图2为纯羟基磷灰石材料及本发明的石墨烯/羟基磷灰石仿生骨材料的XRD图。
图3为纯羟基磷灰石材料及本发明的石墨烯/羟基磷灰石仿生骨材料的傅里叶红外光谱图。
图4为本发明实施例1中所得到的石墨烯/羟基磷灰石仿生骨材料的SEM图。
图5为本发明实施例2中所得到的石墨烯/羟基磷灰石仿生骨材料的SEM图。
图6为本发明实施例3中所得到的石墨烯/羟基磷灰石仿生骨材料的SEM图。
图7为本发明实施例4中所得到的石墨烯/羟基磷灰石仿生骨材料的SEM图。
图8为本发明实施例5中所得到的石墨烯/羟基磷灰石仿生骨材料的SEM图。
图9为本发明实施例6中所得到的石墨烯/羟基磷灰石仿生骨材料的SEM图。
图10为本发明实施例3中所得到的石墨烯/羟基磷灰石仿生骨材料的能谱图。
图11为本发明实施例1中所得到的石墨烯/羟基磷灰石仿生骨材料的TEM图。
图12为本发明实施例5中所得到的石墨烯/羟基磷灰石仿生骨材料的TEM图。
图13为本发明实施例6中所得到的石墨烯/羟基磷灰石仿生骨材料的TEM图。
图14为本发明实施例1中所得到的石墨烯/羟基磷灰石仿生骨材料的HRTEM图。
图15为本发明实施例3中所得到的石墨烯/羟基磷灰石仿生骨材料的HRTEM图。
图16为本发明实施例7中所得到的石墨烯/羟基磷灰石仿生骨材料的HRTEM图。
图17为本发明实施例7中所得到的石墨烯/羟基磷灰石仿生骨材料的细胞增殖作用与浓度的关系图。
图18为本发明实施例7中所得到的石墨烯/羟基磷灰石仿生骨材料的细胞增殖作用与时间的关系图。
图1、图2、图3、图17及图18中：a代表为用该方法合成的未添加石墨烯的纯羟基磷灰石材料；b、c、d分别代表实施例1、5和7所得的石墨烯/羟基磷灰石骨材料。
具体实施方式
根据本发明的一种非限制性实施方式，提供了一种石墨烯与羟基磷灰石复合仿生骨材料的制备方法，该方法包括以下步骤：
步骤(1)：将氢氧化钙水溶液与磷源溶液按照Ca/P摩尔比为1.67比例混合生成羟基磷灰石后，加入化学计量比合成的羟基磷灰石质量2.5％-25％的水溶性石墨烯，超声5～10分钟后得到均匀的黑色溶液；
步骤(2)：将步骤(1)中的黑色溶液加入至极性溶液中混合均匀，其中，黑色溶液与极性溶液的体积比2:3～1:5，于180摄氏度～220摄氏度反应12～36小时，冷却至室温，得到混合液；
(3)：将步骤(2)得到的混合液用去离子水离心洗涤至中性，得到黑色粗产品；
(4)：将步骤(3)得到的黑色粗产品超声分散于去离子水中，预冷冻12小时，得到石墨烯/羟基磷灰石仿生骨材料。
下面结合具体实施例对本发明作出进一步详细阐述，但实施例不应理解为对本发明保护范围的限制。
实施例1
将0.014mol/L氢氧化钙和0.006mol/L磷酸二氢钙按照Ca/P摩尔比为1.67比例混合，加入化学计量比合成的羟基磷灰石质量的2.5％的亲水性石墨烯(HG)，超声5min后得到均匀的黑色溶液。将上述混合溶液加入极性溶液中，其中，黑色溶液与极性溶液的体积比为2：3，极性溶液为体积比为1:1:1的水、N,N-二甲基甲酰胺(DMF)、以及二甲基亚砜(DMSO)的混合液。在鼓风干燥箱中于200℃反应12小时。黑色溶液与极性溶液的体积比为2：3。待降至室温后，将得到的混合液用去离子水离心洗涤至中性，得到黑色粗产品。将黑色粗产品与去离子水按质量比1:1超声分散并于-60℃预冷冻12小时，进行冷冻干燥后得到黑色固体，即为无干扰离子石墨烯/羟基磷灰石骨材料。
实施例2
将0.02mol/L氢氧化钙和0.012mol/L磷酸氢钙按照Ca/P摩尔比为 1.67比例混合，加入化学计量比合成的羟基磷灰石质量的10％的亲水性石墨烯(HG)，超声8min后得到均匀的黑色溶液。将上述混合溶液加入极性溶液中，其中，黑色溶液与极性溶液的体积比为1：5，极性溶液为体积比为2:3:5的水、N,N-二甲基甲酰胺(DMF)、以及二甲基亚砜(DMSO)的的混合液。在鼓风干燥箱中于180℃反应36小时。待降至室温后，将得到的混合液用去离子水离心洗涤至中性，得到黑色粗产品。将黑色粗产品与去离子水按质量比1:2超声分散并于-70℃预冷冻12小时，进行冷冻干燥后得到黑色固体，即为无干扰离子石墨烯/羟基磷灰石骨材料。
实施例3
将0.02mol/L氢氧化钙和0.012mol/L磷酸按照Ca/P摩尔比为1.67比例混合，加入化学计量比合成的羟基磷灰石质量的25％的亲水性石墨烯(HG)，超声10min后得到均匀的黑色溶液。将上述混合溶液加入极性溶液中，其中，黑色溶液与极性溶液的体积比为1：3，极性溶液为体积比为1:1:2的水、N,N-二甲基甲酰胺(DMF)、以及二甲基亚砜(DMSO)的混合液。在鼓风干燥箱中于220℃反应24小时h。待降至室温后，将得到的混合液用去离子水离心洗涤至中性，得到黑色粗产品。将黑色粗产品与去离子水按质量比1:5超声分散并于-50℃预冷冻12小时，进行冷冻干燥后得到黑色固体，即为无干扰离子石墨烯/羟基磷灰石骨材料。
实施例4
将0.07mol/L氢氧化钙和0.03mol/L磷酸二氢钙按照Ca/P摩尔比为1.67比例混合，加入化学计量比合成的羟基磷灰石质量的5％的亲水性石墨烯(HG)，超声6min后得到均匀的黑色溶液。将上述混合溶液加入极性溶液中，其中，黑色溶液与极性溶液的体积比为1：4，极性溶液为体积比为1:1.5:2的水、N,N-二甲基甲酰胺(DMF)、以及二甲基亚砜(DMSO)的混合液。在鼓风干燥箱中于190℃反应30小时。待降至室温后，将得到的混合液用去离子水离心洗涤至中性，得到黑色粗产品。将黑色粗产品与去离子水按质量比1:10超声分散并于-60℃预冷冻12小时，进行冷冻干燥后得到黑色固体，即为无干扰离子石墨烯/羟基磷灰石骨材料。
实施例5
将0.04mol/L氢氧化钙和0.06mol/L磷酸氢钙按照Ca/P摩尔比 为1.67比例混合，加入化学计量比合成的羟基磷灰石质量的20％的亲水性石墨烯(HG)，超声8min后得到均匀的黑色溶液。将上述混合溶液加入极性溶液中，其中，黑色溶液与极性溶液的体积比为1：5，极性溶液为体积比为1:1:1的水、N,N-二甲基甲酰胺(DMF)、以及二甲基亚砜(DMSO)的混合液。在鼓风干燥箱中于210℃反应24小时。待降至室温后，将得到的混合液用去离子水离心洗涤至中性，得到黑色粗产品。将黑色粗产品与去离子水按质量比1:1超声分散并于-65℃预冷冻12小时，进行冷冻干燥后得到黑色固体，即为无干扰离子石墨烯/羟基磷灰石骨材料。
实施例6
将0.10mol/L氢氧化钙和0.06mol/L磷酸按照Ca/P摩尔比为1.67比例混合，加入化学计量比合成的羟基磷灰石质量的15％的亲水性石墨烯(HG)，超声10min后得到均匀的黑色溶液。将上述混合溶液加入极性溶液中，其中，黑色溶液与极性溶液的体积比为2：3，极性溶液为体积比为2:3:5的水、N,N-二甲基甲酰胺(DMF)、以及二甲基亚砜(DMSO)的混合液。在鼓风干燥箱中于200℃反应18小时。待降至室温后，将得到的混合液用去离子水离心洗涤至中性，得到黑色粗产品。将黑色粗产品与去离子水按质量比1:8超声分散并于-60℃预冷冻12小时，进行冷冻干燥后得到黑色固体，即为无干扰离子石墨烯/羟基磷灰石骨材料。
实施例7
将0.0583mol/L氢氧化钙和0.025mol/L磷酸二氢钙按照Ca/P摩尔比为1.67比例混合，加入化学计量比合成的羟基磷灰石质量的10％的亲水性石墨烯(HG)，超声5min后得到均匀的黑色溶液。将上述混合溶液加入极性溶液中，其中，黑色溶液与极性溶液的体积比为1：3.5，极性溶液为体积比为2:3:5的水、N,N-二甲基甲酰胺(DMF)、以及二甲基亚砜(DMSO)的混合液。在鼓风干燥箱中于200℃反应30小时。将黑色粗产品与去离子水按质量比1:2超声分散并于-60℃预冷冻12小时，进行冷冻干燥后得到黑色固体，即为无干扰离子石墨烯/羟基磷灰石骨材料。
制备得到的石墨烯/羟基磷灰石骨材料，进行相应的检测，如图1 所示，图1Raman光谱中样品a仅在432cm -1、587cm -1、964cm -1、以及1048cm -1显示出羟基磷灰石的特征峰。而样品b-d除显示了羟基磷灰石的特征峰外，还在1350和1578cm -1显示出较强的石墨烯特征峰，表明样品b-d中同时具备石墨烯和羟基磷灰石的结构。
图2的XRD中样品a-d均在6.78°、25.88°、31.78°、32.20°、32.94°、34.08°、39.84°、46.78°、以及49.50°显示出羟基磷灰石的特征衍射峰，这与标准羟基磷灰石的PDF卡片相吻合。这个结果表明所得材料具有较好的结晶度，无晶体缺陷，即使石墨烯的存在也不会对其晶体结构造成影响。
图3的红外光谱显示出羟基磷灰石所特有的吸收峰为1022cm -1、962cm -1、600cm -1、以及560cm -1，对应着羟基磷灰石中磷酸基团的伸缩振动和弯曲振动。3570cm -1为其羟基基团的伸缩振动。这表明，该材料中羟基磷灰石的存在。
图4-图9为石墨烯/羟基磷灰石仿生骨材料的SEM图。该图显示出棒状的羟基磷灰石均匀分散在片层结构的石墨烯中。
图10为石墨烯/羟基磷灰石仿生骨材料的能谱图。该图显示出该材料中具有Ca、P、O、C、S元素。羟基磷灰石的Ca、P、O以及石墨烯特有的元素C和S均在该材料中发现，证明石墨烯/羟基磷灰石仿生骨材料复合成功。
图11-图13为石墨烯/羟基磷灰石仿生骨材料的TEM图。该图显示棒状或球状的羟基磷灰石均匀负载在片层薄纱状的石墨烯中。
图14-图16为石墨烯/羟基磷灰石仿生骨材料的HRTEM图。该图显示出石墨烯多晶结构和羟基磷灰石的晶体结构。通过计算得到，羟基磷灰石的晶格间距为0.342nm，与(002)晶面匹配。
图17为石墨烯/羟基磷灰石仿生骨材料的细胞增殖作用与浓度的关系图。该图表明在同一浓度条件下，该材料随着石墨烯含量的增加，细胞增殖作用增加。石墨烯未损伤细胞，具有较好的生物相容性。
图18为石墨烯/羟基磷灰石仿生骨材料的细胞增殖作用与时间的关系图。该图表明该材料对细胞的增殖作用有最佳的培养时间和石墨烯用量。
尽管在此已详细描述本发明的优选实施方式，但要理解的是本发明并不局限于这里详细描述和示出的具体结构和步骤，在不偏离本发明的实质和范围的情况下可由本领域的技术人员实现其它的变型和变体。此外，本发明中的剂量、比例或浓度等参数可以根据具体使用条件在本发明所公开的范围内适当选取。

Claims (10)

  1. 一种石墨烯与羟基磷灰石复合仿生骨材料的制备方法，其特征在于，包括：
    (1)、将氢氧化钙水溶液与磷源溶液按照Ca/P摩尔比为1.67比例混合生成羟基磷灰石后，加入化学计量比合成的羟基磷灰石质量
    2.5％～25％的水溶性石墨烯，超声5～10分钟后得到均匀的黑色溶液；
    (2)、将步骤(1)中的黑色溶液加入至极性溶液中混合均匀，其中，黑色溶液与极性溶液的体积比2:3～1:5，于180摄氏度～220摄氏度的条件下反应12～36小时，冷却至室温，得到混合液；
    (3)、将步骤(2)得到的混合液用去离子水离心洗涤至中性，得到黑色粗产品；以及
    (4)将步骤(3)得到的黑色粗产品超声分散于去离子水中，预冷冻12小时，得到石墨烯/羟基磷灰石仿生骨材料。
  2. 如权利要求1所述的石墨烯与羟基磷灰石复合仿生骨材料的制备方法，其特征在于，步骤(1)中的磷源溶液为磷酸二氢钙溶液、磷酸氢钙溶液、或磷酸溶液。
  3. 如权利要求2所述的石墨烯与羟基磷灰石复合仿生骨材料的制备方法，其特征在于，步骤(1)中的磷源溶液的浓度为0.012～0.06摩尔/升。
  4. 如权利要求3所述的石墨烯与羟基磷灰石复合仿生骨材料的制备方法，其特征在于，步骤(1)中的氢氧化钙水溶液的浓度为0.02～0.1摩尔/升。
  5. 如权利要求3所述的石墨烯与羟基磷灰石复合仿生骨材料的制备方法，其特征在于，步骤(1)中加入的水溶性石墨烯质量为化学计量比合成的羟基磷灰石质量的5％～20％。
  6. 如权利要求1所述的石墨烯与羟基磷灰石复合仿生骨材料的制备方法，其特征在于，步骤(2)中的极性溶液为水、N,N-二甲基甲酰胺及二甲基亚砜的混合物，其中，水、N,N-二甲基甲酰胺及二甲基亚砜的体积比为1～2:1～3:1～5。
  7. 如权利要求1所述的石墨烯与羟基磷灰石复合仿生骨材料的制备方法，其特征在于，在步骤(2)中，黑色溶液和极性溶液在鼓风干燥箱中于180摄氏度～220摄氏度的条件下反应。
  8. 如权利要求1所述的石墨烯与羟基磷灰石复合仿生骨材料的制备方法，其特征在于，在步骤(4)中，在低温医用冰箱中于-70摄氏度～-50摄氏度的条件下进行预冷冻。
  9. 如权利要求1所述的石墨烯与羟基磷灰石复合仿生骨材料的制备方法，其特征在于，步骤(4)中黑色粗产品与去离子水的质量比为1:1～1:10。
  10. 一种石墨烯与羟基磷灰石复合仿生骨材料，其特征在于，所述石墨烯与羟基磷灰石复合仿生骨材料通过如权利要求1～9中任一项所述的方法制备而成。
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