所属技术领域Technical field
本发明涉及无机材料表面改性技术，特别涉及人工器官材料钛表面的生物化改性方法。The invention relates to the surface modification technology of inorganic materials, in particular to the biochemical modification method of the titanium surface of artificial organ materials.
背景技术Background technique
钛(Ti)及钛合金材料因其良好的生物相容性已广泛应用于医疗器械领域，如骨材料、牙种植体、外周血管支架等。但对于一些特殊应用的领域，如作为心血管植入材料用于冠心病的治疗，其安全性和生物相容性还远未达到临床要求。其中，Ti材料血液相容性差、细胞相容性不足以及对于血管内膜增生和炎症反应等并无显著抑制作用是制约其应用的主要方面。Titanium (Ti) and titanium alloy materials have been widely used in the field of medical devices due to their good biocompatibility, such as bone materials, dental implants, peripheral vascular stents, etc. However, for some special application fields, such as the treatment of coronary heart disease as a cardiovascular implant material, its safety and biocompatibility are far from meeting the clinical requirements. Among them, poor hemocompatibility, insufficient cytocompatibility and no significant inhibitory effect on vascular intimal hyperplasia and inflammatory response of Ti materials are the main aspects restricting its application.
通过对材料表面进行生物化改性，构建合理的生物微环境，赋予材料良好的抗凝血能力和诱导内皮再生能力是改善其生物相容性的有效方法。层粘连蛋白(Ln)是血管内皮基底膜中所特有的非胶原糖蛋白，能有效促进血管内皮细胞的粘附、迁移和增殖。间质细胞衍生因子-1α(SDF-1α)是一种对骨髓CXCR4+干细胞及内皮祖细胞(EPCs)具有强烈趋化作用的趋化因子，同时也具有刺激内皮细胞生长，诱导内皮祖细胞向内皮细胞分化的功能。肝素(Hep)是一种广泛使用的抗凝血药物，临床也常用于免疫炎症反应的预防和治疗。此外，Hep能够结合多种功能蛋白，如Ln和SDF-1α，肝素与蛋白质的相互作用可以增强蛋白质的生物学活性，延长其作用时间。By biochemically modifying the surface of the material, constructing a reasonable biological microenvironment, endowing the material with good anticoagulant ability and inducing endothelial regeneration ability are effective methods to improve its biocompatibility. Laminin (Ln) is a unique non-collagen glycoprotein in the vascular endothelial basement membrane, which can effectively promote the adhesion, migration and proliferation of vascular endothelial cells. Mesenchymal cell-derived factor-1α (SDF-1α) is a chemokine that has a strong chemotactic effect on bone marrow CXCR4+ stem cells and endothelial progenitor cells (EPCs). function of cell differentiation. Heparin (Hep) is a widely used anticoagulant drug, and it is also commonly used clinically for the prevention and treatment of immune inflammatory reactions. In addition, Hep can bind a variety of functional proteins, such as Ln and SDF-1α, and the interaction between heparin and protein can enhance the biological activity of the protein and prolong its action time.
多聚赖氨酸(PLL)是一种富含氨基的氨基酸聚合物，在中性环境下呈强正电性，通过静电作用可牢固结合于碱热活化后呈负电性的Ti表面，并在表面引入大量具有反应活性的氨基。通过EDC/NHSMES偶联剂的作用，可将Ln/Hep复合物共价固定于氨基化的Ti表面。利用Hep特异性结合SDF-1α的特点，可在共固定Ln/Hep的表面进一步引入SDF-1α。Polylysine (PLL) is an amino acid polymer rich in amino groups, which is strongly positively charged in a neutral environment, and can be firmly bound to the negatively charged Ti surface after alkali thermal activation through electrostatic interaction, and is A large number of reactive amino groups are introduced into the surface. Through the action of EDC/NHSMES coupling agent, the Ln/Hep complex can be covalently immobilized on the aminated Ti surface. Taking advantage of the characteristic of Hep specifically binding to SDF-1α, SDF-1α can be further introduced on the surface of co-immobilized Ln/Hep.
这种Ln/Hep/SDF-1α多功能层能显著提高在材料表面的血液相容性，同时诱导骨髓和血液来源的内皮祖细胞在材料表面粘附增殖，促进血管内皮细胞的再生，刺激损伤修复。而目前尚无将Ln/Hep/SDF-1α生物微环境用于Ti材料表面生物化改性的相关报道。This Ln/Hep/SDF-1α multifunctional layer can significantly improve the blood compatibility on the surface of the material, and at the same time induce the adhesion and proliferation of bone marrow and blood-derived endothelial progenitor cells on the surface of the material, promote the regeneration of vascular endothelial cells, and stimulate the damage repair. However, there is no report on the use of Ln/Hep/SDF-1α biological microenvironment for Ti material surface biochemical modification.
发明内容Contents of the invention
本发明的目的在于提供一种在Ti材料表面构建Ln/Hep/SDF-1α抗凝及诱导内皮化多功能层的方法，通过该方法对Ti材料表面进行生物化改性可有效提高材料的血液相容性和诱导内皮再生能力。The object of the present invention is to provide a method for constructing a Ln/Hep/SDF-1α anticoagulant and endothelialized multifunctional layer on the surface of Ti material, by which biochemical modification on the surface of Ti material can effectively improve the hemostatic effect of the material. Compatibility and ability to induce endothelial regeneration.
本发明实现以上目的采用的技术方案是，一种在钛表面构建Ln/Hep/SDF-1α生物微环境的方法，其步骤包含：The technical solution adopted by the present invention to achieve the above object is a method for constructing a Ln/Hep/SDF-1α biological microenvironment on a titanium surface, the steps of which include:
A、碱热活化纯钛经表面抛光和清洗处理后，浸入浓度为1～5mol/L的NaOH溶液中，在60～90℃条件下反应8～16小时，单蒸水超声清洗后，浸入双蒸水中，60～90℃条件下反应8～16小时，单蒸水超声清洗后，37℃烘干；A. Alkaline heat activated pure titanium is polished and cleaned on the surface, immersed in NaOH solution with a concentration of 1-5mol/L, reacted at 60-90°C for 8-16 hours, ultrasonically cleaned with single distilled water, immersed in double React in distilled water at 60-90°C for 8-16 hours, after ultrasonic cleaning with single-distilled water, dry at 37°C;
B、表面氨基化将A步骤中碱热活化的样品浸泡于0.5～3mg/ml的多聚赖氨酸(PLL，MW150～300KDa)溶液中，在4℃条件下静置反应8～24小时，然后用磷酸盐缓冲液(PBS)清洗样品，保存待用；B. Surface amination Soak the sample activated by alkali heat in step A in 0.5-3mg/ml polylysine (PLL, MW150-300KDa) solution, and let it stand at 4°C for 8-24 hours. Then wash the sample with phosphate buffered saline (PBS), and save it for later use;
C、层粘连蛋白/肝素的共固定首先将浓度为30～300μg/ml的层粘连蛋白溶液与浓度为3～10mg/ml的肝素钠溶液等体积共混，37℃条件下静置孵育1～3小时；配置摩尔比为2:1:1的EDC/NHS/MES(0.05mol)缓冲液，以1:10的体积比加入至层粘连蛋白/肝素的混合液中，室温下静置1～5分钟；然后将B步骤中涂覆有PLL的钛片浸泡于上述层粘连蛋白/肝素钠混合液中，37℃条件下静置反应3～6小时；最后用PBS漂洗样品，保存待用；C. Co-immobilization of laminin/heparin First, the laminin solution with a concentration of 30-300 μg/ml and the sodium heparin solution with a concentration of 3-10 mg/ml are mixed in equal volumes, and incubated at 37°C for 1- 3 hours; prepare the EDC/NHS/MES (0.05mol) buffer solution with a molar ratio of 2:1:1, add it to the laminin/heparin mixture at a volume ratio of 1:10, and let it stand at room temperature for 1~ 5 minutes; then soak the titanium sheet coated with PLL in step B in the above-mentioned laminin/heparin sodium mixture, and let it stand for a reaction at 37°C for 3-6 hours; finally rinse the sample with PBS and save it for later use;
D、SDF-1α的装载将C步骤获得的样品浸入50～500ng/ml的SDF-1α溶液中，在4℃条件下静置反应8～24小时，PBS漂洗后即得目标物。D. Loading of SDF-1α Immerse the sample obtained in step C into 50-500 ng/ml SDF-1α solution, let it stand at 4°C for 8-24 hours, and rinse with PBS to obtain the target object.
参见说明书附图1，本发明的反应过程与机理分为两个部分，第一部分为氨基化Ti表面的获得。首先通过碱热活化在Ti表面引入大量的羟基，使表面呈强负电性；其次在pH＝7.4的PBS体系中，正电性的PLL分子通过静电作用牢固吸附于碱活化Ti表面，从而在表面引入丰富的氨基用于后续生物分子的固定。第二部分为Ln/Hep/SDF-1α在Ti表面的固定。首先将Ln与Hep溶液共混，利用Hep与Ln相互作用的特性使两种生物分子充分结合，然后使用EDC/NHS/MES偶联剂活化Ln/Hep复合物中的羧基，并于氨基化Ti表面的伯氨基发生脱水缩合反应，从而使Ln/Hep共价固定于Ti表面，最后利用Hep与SDF-1α能发生结构域上的结合的特性，将SDF-1α装载于固定Ln/Hep的Ti表面。Referring to accompanying drawing 1 of the description, the reaction process and mechanism of the present invention are divided into two parts, the first part is the obtaining of aminated Ti surface. First, a large number of hydroxyl groups are introduced into the surface of Ti through alkali-thermal activation, making the surface strongly negatively charged; secondly, in the PBS system with pH = 7.4, the positively charged PLL molecules are firmly adsorbed on the surface of alkali-activated Ti through electrostatic interaction, so that the surface Introduce abundant amino groups for subsequent immobilization of biomolecules. The second part is the immobilization of Ln/Hep/SDF-1α on Ti surface. Firstly, the Ln and Hep solution are blended, and the two biomolecules are fully combined by using the interaction characteristics of Hep and Ln, and then the carboxyl group in the Ln/Hep complex is activated by EDC/NHS/MES coupling agent, and the aminated Ti The primary amino group on the surface undergoes a dehydration condensation reaction, so that Ln/Hep is covalently immobilized on the Ti surface. Finally, using the property of Hep and SDF-1α to bind to the structural domain, SDF-1α is loaded on the Ti surface on which Ln/Hep is immobilized. surface.
与现有技术相比，本发明的有益效果是：Compared with prior art, the beneficial effect of the present invention is:
一、创造性的选择出多功能层的构建方式，并在一定的生物分子浓度比例下，利用Hep与Ln和SDF-1α的特异性结合作用，以及EDC/NHS/MES偶联剂的交联作用，在Ti表面构建出Ln/Hep/SDF-1α生物微环境。通过该种方法，可以有效抑制共价固定过程中生物分子的活性损失。此外，碱热活化后样品表面的特殊微孔化形貌以及共价固定的方式能有效提高Ln和Hep在材料表面的稳定性，延长SDF-1α的释放时间，增强其诱导损伤内皮修复的效果。1. Creatively choose the construction method of the multifunctional layer, and use the specific binding effect of Hep to Ln and SDF-1α under a certain concentration ratio of biomolecules, as well as the cross-linking effect of EDC/NHS/MES coupling agent , to build a Ln/Hep/SDF-1α biological microenvironment on the Ti surface. Through this method, the activity loss of biomolecules during covalent immobilization can be effectively suppressed. In addition, the special microporous morphology of the sample surface after alkali-thermal activation and the way of covalent immobilization can effectively improve the stability of Ln and Hep on the surface of the material, prolong the release time of SDF-1α, and enhance its effect of inducing damaged endothelial repair .
二、生物微环境的构建工艺及固定方法均简单易操作，无需昂贵复杂的设备，工艺成本较低，可控制性强，效果显著。2. The construction process and fixation method of the biological microenvironment are simple and easy to operate, without the need for expensive and complicated equipment, the process cost is low, the controllability is strong, and the effect is remarkable.
三、Ti表面的活化及所有生物分子的固定均采用浸泡方式进行，可保证材料各个部分能均匀的固定上生物分子，有利于实现各种结构复杂的心血管植入器械如血管支架、血栓滤器等表面的抗凝/诱导内皮再生功能化修饰，适用范围广。3. The activation of the Ti surface and the immobilization of all biomolecules are carried out by soaking, which can ensure that all parts of the material can be uniformly immobilized with biomolecules, which is conducive to the realization of various complex cardiovascular implant devices such as vascular stents and thrombus filters. The anticoagulant/endothelial regeneration-inducing functional modification of the isosurface has a wide range of applications.
附图说明Description of drawings
下面结合附图和实施例对本发明的方法作进一步详细的说明。The method of the present invention will be further described in detail below in conjunction with the accompanying drawings and embodiments.
图1为本发明方法中Ti表面Ln/Hep/SDF-1α生物微环境构建的各步骤示意图。Fig. 1 is a schematic diagram of each step in the construction of the Ln/Hep/SDF-1α biological microenvironment on the Ti surface in the method of the present invention.
图2为样品表面血小板粘附的扫描电镜图。(A)Ti；(B)固定Ln/Hep/SDF-1α的Ti。Figure 2 is a scanning electron microscope image of platelet adhesion on the sample surface. (A) Ti; (B) Ti immobilized Ln/Hep/SDF-1α.
图3为样品表面内皮细胞培养3天后荧光染色结果。(A)Ti；(B)固定Ln/Hep/SDF-1α的Ti。Figure 3 is the results of fluorescent staining of the endothelial cells on the surface of the sample after 3 days of culture. (A) Ti; (B) Ti immobilized Ln/Hep/SDF-1α.
图4为样品表面内皮祖细胞培养2小时和3天后荧光染色结果。(A1)Ti-2小时；(A2)Ti-3天；(B1)Ln/Hep/SDF-1α-2小时；(B2)Ln/Hep/SDF-1α-3天Figure 4 shows the results of fluorescent staining of endothelial progenitor cells on the surface of the sample after 2 hours and 3 days of culture. (A1) Ti-2 hours; (A2) Ti-3 days; (B1) Ln/Hep/SDF-1α-2 hours; (B2) Ln/Hep/SDF-1α-3 days
图5为(A)碱热处理后样品表面形貌扫描电镜图；(B)QCM表征共价固定的Ln/Hep功能层的稳定性；(C)SDF-1α的释放动力学检测结果。Figure 5 is (A) SEM image of the surface morphology of the sample after alkali heat treatment; (B) QCM to characterize the stability of the covalently immobilized Ln/Hep functional layer; (C) SDF-1α release kinetics detection results.
具体实施方式detailed description
实施例一Embodiment one
参见图1，本发明的第一种具体实施方式是，一种在钛表面构建Ln/Hep/SDF-1α抗凝及诱导内皮化多功能层的方法，其步骤为：Referring to Fig. 1, the first kind of embodiment of the present invention is, a kind of method for constructing Ln/Hep/SDF-1α anticoagulation and inducing endothelialization multifunctional layer on titanium surface, its steps are:
A、碱热活化纯钛经表面抛光和清洗处理后，浸入浓度为5mol/L的NaOH溶液中，在60℃条件下反应8小时，单蒸水超声清洗后，浸入双蒸水中，90℃条件下反应16小时，单蒸水超声清洗后，37℃烘干；A. Alkaline heat activated pure titanium is surface polished and cleaned, immersed in NaOH solution with a concentration of 5mol/L, and reacted at 60°C for 8 hours, after ultrasonic cleaning with single distilled water, immersed in double distilled water, at 90°C React for 16 hours under high temperature, after ultrasonic cleaning with single distilled water, dry at 37°C;
B、表面氨基化将A步骤中碱热活化的样品浸泡于3mg/ml的多聚赖氨酸(PLL，MW150～300KDa)溶液中，在4℃条件下静置反应8小时，然后用磷酸盐缓冲液(PBS)清洗样品，保存待用；B. Surface amination Soak the sample activated by alkali heat in step A in 3mg/ml polylysine (PLL, MW150～300KDa) solution, let it stand for 8 hours at 4°C, and then wash it with phosphate Buffer solution (PBS) washes the sample and saves it for later use;
C、层粘连蛋白/肝素的共固定首先将浓度为300μg/ml的层粘连蛋白溶液与浓度为10mg/ml的肝素钠溶液等体积共混，37℃条件下静置孵育3小时；配置摩尔比为2:1:1的EDC/NHS/MES(0.05mol)缓冲液，以1:10的体积比加入至层粘连蛋白/肝素的混合液中，室温下静置5分钟；然后将B步骤中涂覆有PLL的钛片浸泡于上述层粘连蛋白/肝素钠混合液中，37℃条件下静置反应3小时；最后用PBS漂洗样品，保存待用；C. Co-immobilization of laminin/heparin First, mix the laminin solution with a concentration of 300 μg/ml and the sodium heparin solution with a concentration of 10 mg/ml in equal volumes, and incubate at 37°C for 3 hours; configure the molar ratio 2:1:1 EDC/NHS/MES (0.05mol) buffer solution, added to the laminin/heparin mixture at a volume ratio of 1:10, and allowed to stand at room temperature for 5 minutes; then in step B The titanium sheet coated with PLL was soaked in the above-mentioned laminin/heparin sodium mixture, and left to react at 37°C for 3 hours; finally, the sample was rinsed with PBS and stored for later use;
D、SDF-1α的装载将C步骤获得的样品浸入500ng/ml的SDF-1α溶液中，在4℃条件下静置反应24小时，PBS漂洗后即得。D. Loading of SDF-1α Immerse the sample obtained in step C into 500ng/ml SDF-1α solution, let it stand for reaction at 4°C for 24 hours, rinse with PBS.
实施例二Embodiment two
一种在钛表面构建Ln/Hep/SDF-1α生物微环境的方法，其步骤为：A method for constructing Ln/Hep/SDF-1α biological microenvironment on titanium surface, the steps are:
A、碱热活化纯钛经表面抛光和清洗处理后，浸入浓度为1mol/L的NaOH溶液中，在90℃条件下反应16小时，单蒸水超声清洗后，浸入双蒸水中，60℃条件下反应8小时，单蒸水超声清洗后，37℃烘干；A. Alkaline heat activated pure titanium is surface polished and cleaned, immersed in NaOH solution with a concentration of 1mol/L, and reacted at 90°C for 16 hours. After ultrasonic cleaning with single distilled water, immersed in double distilled water, at 60°C React for 8 hours, after ultrasonic cleaning with single distilled water, dry at 37°C;
B、表面氨基化将A步骤中碱热活化的样品浸泡于0.5mg/ml的多聚赖氨酸(PLL，MW150～300KDa)溶液中，在4℃条件下静置反应24小时，然后用磷酸盐缓冲液(PBS)清洗样品，保存待用；B. Surface amination Soak the sample activated by alkali heat in step A in 0.5mg/ml polylysine (PLL, MW150～300KDa) solution, let it stand at 4°C for 24 hours, and then wash it with phosphoric acid Wash the sample with salt buffer solution (PBS) and save it for later use;
C、层粘连蛋白/肝素的共固定首先将浓度为30μg/ml的层粘连蛋白溶液与浓度为3mg/ml的肝素钠溶液等体积共混，37℃条件下静置孵育1小时；配置摩尔比为2:1:1的EDC/NHS/MES(0.05mol)缓冲液，以1:10的体积比加入至层粘连蛋白/肝素的混合液中，室温下静置1分钟；然后将B步骤中涂覆有PLL的钛片浸泡于上述层粘连蛋白/肝素钠混合液中，37℃条件下静置反应6小时；最后用PBS漂洗样品，保存待用；C. Co-immobilization of laminin/heparin First, mix the laminin solution with a concentration of 30 μg/ml and the sodium heparin solution with a concentration of 3 mg/ml in equal volumes, and incubate at 37°C for 1 hour; configure the molar ratio 2:1:1 EDC/NHS/MES (0.05mol) buffer solution, added to the laminin/heparin mixture at a volume ratio of 1:10, and allowed to stand at room temperature for 1 minute; then in step B The titanium sheet coated with PLL was soaked in the above-mentioned laminin/heparin sodium mixture, and left to react at 37°C for 6 hours; finally, the sample was rinsed with PBS and stored for later use;
D、SDF-1α的装载将C步骤获得的样品浸入50ng/ml的SDF-1α溶液中，在4℃条件下静置反应8小时，PBS漂洗后即得。D. Loading of SDF-1α Immerse the sample obtained in step C into 50ng/ml SDF-1α solution, let it stand for reaction at 4°C for 8 hours, and rinse with PBS.
实施例三Embodiment three
一种在钛表面构建Ln/Hep/SDF-1α生物微环境的方法，其步骤为：A method for constructing Ln/Hep/SDF-1α biological microenvironment on titanium surface, the steps are:
A、碱热活化纯钛经表面抛光和清洗处理后，浸入浓度为3mol/L的NaOH溶液中，在80℃条件下反应12小时，单蒸水超声清洗后，浸入双蒸水中，80℃条件下反应12小时，单蒸水超声清洗后，37℃烘干；A. Alkaline heat activated pure titanium is polished and cleaned on the surface, immersed in NaOH solution with a concentration of 3mol/L, and reacted at 80°C for 12 hours. React for 12 hours, after ultrasonic cleaning with single distilled water, dry at 37°C;
B、表面氨基化将A步骤中碱热活化的样品浸泡于2.5mg/ml的多聚赖氨酸(PLL，MW150～300KDa)溶液中，在4℃条件下静置反应12小时，然后用磷酸盐缓冲液(PBS)清洗样品，保存待用；B. Surface amination Soak the sample activated by alkali heat in step A in 2.5mg/ml polylysine (PLL, MW150～300KDa) solution, let it stand at 4°C for 12 hours, and then wash it with phosphoric acid Wash the sample with salt buffer solution (PBS) and save it for later use;
C、层粘连蛋白/肝素的共固定首先将浓度为200mg/ml的层粘连蛋白溶液与浓度为5mg/ml的肝素钠溶液等体积共混，37℃条件下静置孵育2小时；配置摩尔比为2:1:1的EDC/NHS/MES(0.05mol)缓冲液，以1:10的体积比加入至层粘连蛋白/肝素的混合液中，室温下静置3分钟；然后将B步骤中涂覆有PLL的钛片浸泡于上述层粘连蛋白/肝素钠混合液中，37℃条件下静置反应4小时；最后用PBS漂洗样品，保存待用；C. Co-immobilization of laminin/heparin First, the laminin solution with a concentration of 200mg/ml and the heparin sodium solution with a concentration of 5mg/ml are mixed in equal volumes, and incubated at 37°C for 2 hours; configure the molar ratio 2:1:1 EDC/NHS/MES (0.05mol) buffer solution, added to the laminin/heparin mixture at a volume ratio of 1:10, and allowed to stand at room temperature for 3 minutes; then in step B The titanium sheet coated with PLL was soaked in the above-mentioned laminin/heparin sodium mixture, and left to react at 37°C for 4 hours; finally, the sample was rinsed with PBS and stored for later use;
SDF-1α的装载将C步骤获得的样品浸入200ng/ml的SDF-1α溶液中，在4℃条件下静置反应12小时，PBS漂洗后即得。Loading of SDF-1α Immerse the sample obtained in step C into 200ng/ml SDF-1α solution, let it stand for reaction at 4°C for 12 hours, and rinse with PBS.
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