技术领域technical field
本发明涉及一种仿人骨材料的制备方法，属于生物医用材料技术运用领域。The invention relates to a preparation method of a human bone imitation material, which belongs to the technical application field of biomedical materials.
背景技术Background technique
众所周知，自然骨组织主要是由以HAP为主要成分的无机相和以胶原为主的有机相组成的。所以，仿制人骨的材料也应该以这两种材料为标准，选取尽可能与人骨成分结构相似的材料。在骨支架材料中，将羟基磷灰石与天然高分子材料相结合制备有机-无机复合材料，能够结合天然高分子材料与羟基磷灰石矿物的优点。天然高分子材料中，胶原是骨组织的主要有机物，而明胶是胶原蛋白经部分变性或化学处理水解得到的天然产物。它具有优良的物理化学性能，如亲水性强、能够形成凝胶、侧链基因反应活性高、便于化学改性等。由于这些优点，明胶被广泛应用于各种领域。同时，它具有很好的生物相容性和降解性且价格低廉、来源广泛，所以可用作组织工程支架。而羟基磷灰石无论在硬骨还是软骨中的应用都体现出良好的生物相容性，并且作为骨细胞外基质的主要的组成成分之一，具有良好的骨传导和骨结合性能及高的力学强度。然而，人工合成的羟基磷灰石的断裂韧性较低、脆性较大，韧性不足及力学性能差，使其在承重骨方面的应用方面受到限制。为了解决这些问题，近年来人们特别重视研究和开发各种羟基磷灰石复合材料，以改善羟基磷灰石生物材料的力学性能和生物学性能。It is well known that natural bone tissue is mainly composed of an inorganic phase mainly composed of HAP and an organic phase mainly composed of collagen. Therefore, materials for imitating human bones should also use these two materials as standards, and select materials that are as similar as possible to human bone composition and structure. In bone scaffold materials, organic-inorganic composite materials are prepared by combining hydroxyapatite and natural polymer materials, which can combine the advantages of natural polymer materials and hydroxyapatite minerals. Among natural polymer materials, collagen is the main organic matter of bone tissue, while gelatin is a natural product obtained by partial denaturation or chemical treatment of collagen. It has excellent physical and chemical properties, such as strong hydrophilicity, the ability to form gels, high side chain gene reactivity, and easy chemical modification. Due to these advantages, gelatin is widely used in various fields. At the same time, it has good biocompatibility and degradability, low price and wide sources, so it can be used as a tissue engineering scaffold. Hydroxyapatite has good biocompatibility whether it is applied in hard bone or cartilage, and as one of the main components of bone extracellular matrix, it has good osteoconduction and osseointegration properties and high mechanical properties. strength. However, synthetic hydroxyapatite has low fracture toughness, high brittleness, insufficient toughness and poor mechanical properties, which limit its application in load-bearing bone. In order to solve these problems, people have paid special attention to the research and development of various hydroxyapatite composite materials in recent years to improve the mechanical properties and biological properties of hydroxyapatite biomaterials.
对生物矿化的研究表明，在整个生物矿化过程中，界面分子识别过程起着至关重要的作用。在一定的条件下，有机基质通过自组装形成模板，该模板在为无机矿物提供结构框架的同时，通过与无机离子在界面上静电匹配、几何相似性和立体化学互补等来控制矿物的成核和生长，从而控制生物矿物材料的结构和性能。生物矿化方法可有效控制晶体的形貌及结构。Studies on biomineralization have shown that the interfacial molecular recognition process plays a crucial role throughout the biomineralization process. Under certain conditions, the organic matrix forms a template through self-assembly, which not only provides a structural framework for the inorganic mineral, but also controls the nucleation of the mineral through electrostatic matching, geometric similarity, and stereochemical complementarity with the inorganic ion on the interface. and growth, thereby controlling the structure and properties of biomineral materials. The biomineralization method can effectively control the morphology and structure of crystals.
从仿生学的角度来看，聚合物调控仿生矿化所制备的聚合物-羟基磷灰石复合材料在成分和结构上都类似于天然骨组织。之前已经讨论过了材料的选择，需要将有机明胶与羟基磷灰石相结合。并且论述过了通过有机基质如胶原是能够引导合成羟基磷灰石的，况且明胶材料是能够代替胶原作为生物矿化的有机大分子基体的。From the perspective of biomimetic, the polymer-hydroxyapatite composite prepared by polymer-regulated biomimetic mineralization is similar to natural bone tissue in composition and structure. The choice of materials has been discussed previously, requiring the combination of organic gelatin with hydroxyapatite. And it has been discussed that the synthesis of hydroxyapatite can be guided by organic matrix such as collagen, and gelatin material can replace collagen as the organic macromolecular matrix of biomineralization.
目前的天然高分子材料/羟基磷灰石复合材料的制备一般都是将羟基磷灰石粉末与高分子聚合物的水溶液相混合，由于此类粉末是不易溶于水的，这就导致了大部分的生物活性羟基磷灰石都被包埋在了聚合物的内部，在体外进行培养或是植入缺损部位无法与细胞有效地接触。并且聚合物大都具有一定的黏度，物理上的混合容易导致羟基磷灰石粉末的团聚，影响到了骨支架的结构。并且在接近生理条件的环境下，避免高温或者使用有机溶剂，通过聚合物在水溶液中控制无机矿物的仿生沉积是材料科学方面的一个重要的研究领域。The current preparation of natural polymer materials/hydroxyapatite composite materials is generally to mix the hydroxyapatite powder with the aqueous solution of the polymer, because this kind of powder is not easily soluble in water, which leads to large Part of the biologically active hydroxyapatite is embedded in the polymer, and cannot be effectively contacted with cells when cultured in vitro or implanted into a defect site. Moreover, most of the polymers have a certain viscosity, and physical mixing can easily lead to the agglomeration of hydroxyapatite powder, which affects the structure of the bone scaffold. And in an environment close to physiological conditions, avoiding high temperature or using organic solvents, controlling the biomimetic deposition of inorganic minerals in aqueous solution through polymers is an important research field in materials science.
发明内容Contents of the invention
本发明的目的在于提供一种仿人骨材料的制备方法，具体包括以下步骤：The object of the present invention is to provide a kind of preparation method of imitation human bone material, specifically comprise the following steps:
（1）配制质量百分比浓度为0.1%~0.3%的Ca(OH)2溶液，按200g/L~400g/L的比例在Ca(OH)2溶液中加入明胶颗粒，然后100ml/L~150ml/L的比例加入质量百分比浓度为1%-6%的丙三醇，待明胶颗粒完全溶于水中后，将溶胶放在室温下静置至黏度增加时倒入挤压容器中静置冷却，得到溶胶A；(1) Prepare a Ca(OH)2 solution with a mass percentage concentration of 0.1%~0.3%, add gelatin particles into the Ca(OH) 2solution at a ratio of 200g/L~400g/L, and then add 100ml/L~150ml/ Add glycerol with a mass percentage concentration of 1%-6% at a ratio of L, and after the gelatin particles are completely dissolved in water, put the sol at room temperature until the viscosity increases, pour it into a squeeze container and let it cool down, and obtain Sol A;
（2）将溶胶A进行挤压成型，然后放入无水乙醇中脱水，得到式样B；(2) Extrude sol A, then dehydrate in absolute ethanol to obtain pattern B;
（3）将式样B放入戊二醛溶液中交联，然后取出置于蒸馏水中清洗，然后在空气中干燥得到式样C；(3) Put pattern B into glutaraldehyde solution for cross-linking, then take it out and wash it in distilled water, and then dry it in air to obtain pattern C;
（4）将式样C放置在人体体液模拟液（SBF模拟体液）中，然后置于37.5℃的恒温培养箱中静置14-30天（即矿化时间），每2~4天换一次液，矿化结束的样品用去离子水清洗、干燥后得到仿人骨材料。(4) Place sample C in human body fluid simulation fluid (SBF simulated body fluid), and then place it in a constant temperature incubator at 37.5°C for 14-30 days (that is, mineralization time), and change the fluid every 2 to 4 days , the mineralized samples were washed with deionized water and dried to obtain human-like bone materials.
优选的，本发明步骤（1）中静置至黏度增加的时间为10~30 min。Preferably, the time for standing until the viscosity increases in step (1) of the present invention is 10-30 min.
优选的，本发明步骤（3）中的清洗过程为：取出式样置于蒸馏水中浸泡2-6次，每次10-30min。Preferably, the cleaning process in step (3) of the present invention is: take out the samples and soak them in distilled water for 2-6 times, each time for 10-30 minutes.
优选的，本发明步骤（3）中戊二醛溶液的质量百分比浓度为1-10wt%，交联时间为6-24 h。Preferably, the mass percent concentration of the glutaraldehyde solution in step (3) of the present invention is 1-10 wt%, and the crosslinking time is 6-24 h.
优选的，本发明步骤（3）中干燥的温度为40-60℃。Preferably, the drying temperature in step (3) of the present invention is 40-60°C.
本发明制备得到的仿人骨材料具有规则直通孔，孔径分布在300-450μm。孔隙率在50%-95%范围内。该多孔支架轴向抗压强度达到12-14MPa，横向抗压强度达到7-9 MPa。The humanoid bone material prepared by the invention has regular through-holes, and the pore size distribution is 300-450 μm. The porosity is in the range of 50%-95%. The axial compressive strength of the porous support reaches 12-14 MPa, and the transverse compressive strength reaches 7-9 MPa.
本发明的有益效果：Beneficial effects of the present invention:
（1）本发明采用挤压成型法制备出以明胶为原料的多孔支架材料，该材料能满足骨组织工程要求的孔洞结构和孔隙大小，能够提供一个组织生长的三维支架结构。(1) The present invention adopts an extrusion molding method to prepare a porous scaffold material using gelatin as a raw material. The material can meet the pore structure and pore size required by bone tissue engineering, and can provide a three-dimensional scaffold structure for tissue growth.
（2）本发明采用体外仿生矿化的方法，构建出与人体生理环境相似的条件，并模拟人骨在体内的矿化，尝试在明胶的基体表面原位合成与自然骨中的生物矿物质相接近的羟基磷灰石晶体，构建仿骨有机-无机复合材料。(2) The present invention adopts the method of in vitro biomimetic mineralization, constructs conditions similar to the human physiological environment, and simulates the mineralization of human bone in vivo, and tries to synthesize biomineral phases on the surface of the gelatin matrix in situ with natural bone Approaching hydroxyapatite crystals to construct bone-mimetic organic-inorganic composites.
附图说明Description of drawings
图1是实施例2中制备的明胶多孔支架的SEM图片。FIG. 1 is a SEM picture of the gelatin porous scaffold prepared in Example 2.
具体实施方式detailed description
下面结合附图和具体实施例对本发明作进一步详细说明，但本发明的保护范围并不限于所述内容。The present invention will be described in further detail below in conjunction with the accompanying drawings and specific embodiments, but the protection scope of the present invention is not limited to the content described.
本发明所述人体体液模拟液（SBF模拟体液）由常规方法及常规原料配制得到。本发明实施例中所述SBF模拟体液由以下方法配制得到：量取800ml的去离子水作为缓冲液，并放在水浴锅中加热到35℃-37℃，通过搅拌器不断搅拌溶液，并用PH计不断测量实时的PH值，当PH达到6.5-7.5时依次加入8g NaCl粉末、0.35g NaHCO3粉末、0.2g KCl粉末、0.2gK2HPO4*3H2O粉末、0.3g MgCl2*6H2O粉末，1.0mol/ml的 HCl 30ml，0.3g CaCl2粉末，0.1gNa2SO4粉末；再分批少量加入6g TRIS（CH2OH）3CNH2粉末，用HCl溶液使PH稳定在7.0左右，直到TRIS（CH2OH）3CNH2粉末全部加完为止；最后定容到1000ml定量瓶中，待溶液温度降到室温后滴加去离子水到刻度线即得到人体体液模拟液。The human body fluid simulated fluid (SBF simulated body fluid) described in the present invention is prepared by conventional methods and conventional raw materials. The SBF simulated body fluid described in the embodiment of the present invention is prepared by the following method: Measure 800ml of deionized water as a buffer solution, put it in a water bath and heat it to 35°C-37°C, stir the solution continuously with a stirrer, and use pH The meter continuously measures the real-time pH value, and when the pH reaches 6.5-7.5, add 8g NaCl powder, 0.35g NaHCO3 powder, 0.2g KCl powder, 0.2g K2 HPO4 *3H2 O powder, 0.3g MgCl2 *6H2 O powder, 1.0mol/ml HCl 30ml, 0.3g CaCl2 powder, 0.1g Na2 SO4 powder; then add 6g TRIS(CH2 OH)3 CNH2 powder in batches, and use HCl solution to stabilize the pH at about 7.0 , until all the TRIS (CH2 OH)3 CNH2 powders are added; finally set the volume to a 1000ml quantitative bottle, and after the temperature of the solution drops to room temperature, add deionized water to the scale line to obtain a human body fluid simulation liquid.
实施例1Example 1
本实施所述的一种原位合成仿人骨材料及其制备方法具体步骤包括：A kind of in-situ synthesis humanoid bone material described in this implementation and the specific steps of its preparation method include:
（1）将0.01g Ca（OH）2加入到10ml蒸馏水中，置于磁力搅拌器上加热至40℃左右，再向上述溶液中加入2g的明胶颗粒，加入浓度为2%丙三醇1ml作为润滑剂，恒温搅拌。待明胶颗粒完全溶于水中后，将溶胶放在室温下静置（10min）至黏度有明显增加的时候倒入30ml的针管中静置冷却，得到溶胶A。(1) Add 0.01g Ca(OH)2 to 10ml distilled water, place it on a magnetic stirrer and heat it to about 40°C, then add 2g of gelatin particles to the above solution, and add 1ml of 2% glycerol as Lubricant, constant temperature stirring. After the gelatin particles are completely dissolved in water, let the sol stand at room temperature (10min) until the viscosity increases significantly, pour it into a 30ml needle tube and let it cool down to obtain Sol A.
（2）将溶胶A进行挤压成型，每挤出3cm长的支架后用细铁丝切下，并将切下的样品直接放入无水乙醇中脱水，得到式样B。(2) Extrude sol A, cut out each 3cm-long bracket with a thin iron wire, and put the cut samples directly into absolute ethanol for dehydration to obtain pattern B.
（3）将式样B切割成3x3的小支架，将小支架放入浓度为10%的戊二醛溶液中交联6h后，取出置于蒸馏水中浸泡6次，每次10min，清洗完后放在滤纸上空气干燥，得到式样C。(3) Cut pattern B into small 3x3 stents, put the small stents into a 10% glutaraldehyde solution for cross-linking for 6 hours, take them out and soak them in distilled water for 6 times, each time for 10 minutes, and put them away after cleaning. Air dry on filter paper to obtain Form C.
（4）将式样C放置在50ml的塑料离心管中，每支离心管添加30ml的SBF模拟体液，然后置于37.5℃的恒温培养箱中静置30天，每三天换一次液，对矿化结束的样品用去离子水小心清洗，置于60℃的干燥箱中干燥，得到最终支架材料。(4) Place pattern C in a 50ml plastic centrifuge tube, add 30ml of SBF simulated body fluid to each centrifuge tube, and then place it in a constant temperature incubator at 37.5°C for 30 days. The finished samples were carefully washed with deionized water, and dried in a drying oven at 60°C to obtain the final scaffold material.
本实施例通过对该明胶支架的轴向抗压强度和横向抗压强度进行测定，表明轴向抗压强度和横向抗压强度分别为11.52MPa，7.56 MPa；对其孔隙率进行测定，表明孔隙率为75%。In this embodiment, by measuring the axial compressive strength and transverse compressive strength of the gelatin stent, it is shown that the axial compressive strength and transverse compressive strength are 11.52MPa and 7.56 MPa respectively; The rate is 75%.
实施例2Example 2
本实施所述的一种原位合成仿人骨材料及其制备方法具体步骤包括：A kind of in-situ synthesis humanoid bone material described in this implementation and the specific steps of its preparation method include:
（1）将0.02g Ca（OH）2加入到10ml蒸馏水中，置于磁力搅拌器上加热至40℃左右，再向上述溶液中加入3.5g的明胶颗粒，加入浓度为4%丙三醇1ml作为润滑剂，恒温搅拌。待明胶颗粒完全溶于水中后，将溶胶放在室温下静置（20min）至黏度有明显增加的时候倒入30ml的针管中静置冷却，得到溶胶A。(1) Add 0.02g Ca(OH)2 to 10ml of distilled water, place it on a magnetic stirrer and heat it to about 40°C, then add 3.5g of gelatin particles to the above solution, and add 1ml of 4% glycerol As a lubricant, stir at constant temperature. After the gelatin particles are completely dissolved in water, let the sol stand at room temperature (20min) until the viscosity increases significantly, pour it into a 30ml needle tube and let it cool down to obtain Sol A.
（2）将溶胶A进行挤压成型，每挤出3cm长的支架后用细铁丝切下，并将切下的样品直接放入无水乙醇中脱水，得到式样B。(2) Extrude sol A, cut out each 3cm-long bracket with a thin iron wire, and put the cut samples directly into absolute ethanol for dehydration to obtain pattern B.
（3）将式样B切割成3x3的小支架，将小支架放入浓度为5%的戊二醛溶液中交联12h后，取出置于蒸馏水中浸泡3次，每次20min，清洗完后放在滤纸上空气干燥，得到式样C。(3) Cut pattern B into small 3x3 stents, place the small stents in a 5% glutaraldehyde solution for cross-linking for 12 hours, take them out and soak them in distilled water for 3 times, each time for 20 minutes, and put them away after cleaning. Air dry on filter paper to obtain Form C.
（4）将式样C放置在50ml的塑料离心管中，每支离心管添加30ml的SBF模拟体液，然后置于37.5℃的恒温培养箱中静置25天，每三天换一次液，对矿化结束的样品用去离子水小心清洗，置于40℃的干燥箱中干燥，得到最终支架材料。(4) Place pattern C in a 50ml plastic centrifuge tube, add 30ml of SBF simulated body fluid to each centrifuge tube, then place it in a constant temperature incubator at 37.5°C for 25 days, change the liquid every three days, and The finished samples were carefully washed with deionized water, and dried in a drying oven at 40°C to obtain the final scaffold material.
本实施例通过对该明胶支架的轴向抗压强度和横向抗压强度进行测定，表明轴向抗压强度和横向抗压强度分别为13.50MPa，8.5 MPa。对其孔隙率进行测定，表明孔隙率为85%。本实施例中制备的明胶支架的SEM图片如图1所示，由图可看出，该多孔支架具有规则直通孔的孔洞结构，孔径为300-450um。In this embodiment, the axial compressive strength and transverse compressive strength of the gelatin stent are measured, which show that the axial compressive strength and transverse compressive strength are 13.50 MPa and 8.5 MPa, respectively. Its porosity was measured, showing that the porosity was 85%. The SEM picture of the gelatin scaffold prepared in this example is shown in FIG. 1 . It can be seen from the figure that the porous scaffold has a pore structure with regular through holes, and the pore diameter is 300-450um.
实施例3Example 3
本实施所述的一种原位合成仿人骨材料及其制备方法具体步骤包括：A kind of in-situ synthesis humanoid bone material described in this implementation and the specific steps of its preparation method include:
（1）将0.03g Ca（OH）2加入到10ml蒸馏水中，置于磁力搅拌器上加热至40℃左右，再向上述溶液中加入4g的明胶颗粒，加入5%丙三醇1ml作为润滑剂，恒温搅拌。待明胶颗粒完全溶于水中后，将溶胶放在室温下静置（30min）至黏度有明显增加的时候倒入30ml的针管中静置冷却，得到溶胶A。(1) Add 0.03g Ca(OH)2 to 10ml distilled water, place it on a magnetic stirrer and heat it to about 40°C, then add 4g of gelatin particles to the above solution, and add 1ml of 5% glycerol as a lubricant , stirring at constant temperature. After the gelatin particles are completely dissolved in water, let the sol stand at room temperature (30min) until the viscosity increases significantly, pour it into a 30ml needle tube and let it cool down to obtain Sol A.
（2）将溶胶A进行挤压成型，每挤出3cm长的支架后用细铁丝切下，并将切下的样品直接放入无水乙醇中脱水，得到式样B。(2) Extrude sol A, cut out each 3cm-long bracket with a thin iron wire, and put the cut samples directly into absolute ethanol for dehydration to obtain pattern B.
（3）将式样B切割成3x3的小支架，将小支架放入浓度为1%的戊二醛溶液中交联24h后，取出置于蒸馏水中浸泡5次，每次30min，清洗完后放在滤纸上空气干燥，得到式样C。(3) Cut pattern B into small 3x3 stents, put the small stents into a 1% glutaraldehyde solution for cross-linking for 24 hours, take them out and soak them in distilled water for 5 times, each time for 30 minutes, and put them away after cleaning. Air dry on filter paper to obtain Form C.
（4）将式样C放置在50ml的塑料离心管中，每支离心管添加30ml的SBF模拟体液，然后置于37.5℃的恒温培养箱中静置14天，每三天换一次液，对矿化结束的样品用去离子水小心清洗，置于30℃的干燥箱中干燥，得到最终支架材料。(4) Place pattern C in a 50ml plastic centrifuge tube, add 30ml of SBF simulated body fluid to each centrifuge tube, then place it in a constant temperature incubator at 37.5°C for 14 days, change the liquid every three days, and The finished samples were carefully washed with deionized water, and dried in a drying oven at 30°C to obtain the final scaffold material.
本实施例通过对该明胶支架的轴向抗压强度和横向抗压强度进行测定，表明轴向抗压强度和横向抗压强度分别为14.50MPa，9.47 MPa。对其孔隙率进行测定，表明孔隙率为90%。In this embodiment, the axial compressive strength and transverse compressive strength of the gelatin stent are measured, which show that the axial compressive strength and transverse compressive strength are 14.50 MPa and 9.47 MPa, respectively. Its porosity was measured, showing that the porosity was 90%.
根据国家标准GB/T14233.3-2005，采用选用293T细胞（转染腺病毒E1A基因的人肾上皮细胞）、CCK-8法对实施例1制备的多孔磷酸钙/明胶复合支架材料进行细胞毒性测试，实验结果如表1所示。结合国家标准GB/T14233.3-2005相关规定，细胞毒性结果表明，支架浓度在0.1-0.2g/ml时，细胞增殖度均在145-165之间，细胞毒性为0级。由此说明实施例1所制备的多孔磷酸钙/明胶复合支架材料无细胞毒性。According to the national standard GB/T14233.3-2005, 293T cells (human kidney epithelial cells transfected with adenovirus E1A gene) and CCK-8 method were used to perform cytotoxicity on the porous calcium phosphate/gelatin composite scaffold material prepared in Example 1. The test results are shown in Table 1. Combined with the relevant provisions of the national standard GB/T14233.3-2005, the cytotoxicity results show that when the scaffold concentration is 0.1-0.2g/ml, the cell proliferation degree is between 145-165, and the cytotoxicity is 0 grade. This shows that the porous calcium phosphate/gelatin composite scaffold material prepared in Example 1 has no cytotoxicity.
表1明胶支架的细胞增殖度Table 1 Cell proliferation degree of gelatin scaffold
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