CN112972771A - 基于双（乙烯砜基）甲烷聚合的生物活性表面涂层制备方法 - Google Patents
基于双（乙烯砜基）甲烷聚合的生物活性表面涂层制备方法 Download PDFInfo
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Abstract
本发明公开一种基于双(乙烯砜基)甲烷聚合的生物活性表面涂层制备方法。所述的方法是在催化条件下使用双(乙烯砜基)甲烷在经前处理的基底材料表面反应聚合，聚合反应后经湿热灭菌实现对材料的生物活性修饰。该方法基于双(乙烯砜基)甲烷的自聚合，成膜厚度随反应时间延长而增加，可控性强；可对多种基底材料表面进行修饰，适用范围广；采用终端湿热灭菌法灭菌，操作简单，工艺环境要求低，对制备的涂层影响小；修饰后表面乙烯砜基涂层有利于细胞粘附，生物相容性好；无需无水无氧操作，反应条件温和，重现性好；是一种潜力巨大的生物活性表面涂层制备方法。
Description
技术领域
本发明属于生物材料表面修饰领域，具体涉及一种制备多种材料生物活性表面涂层的新方法，尤其涉及一种基于双(乙烯砜基)甲烷聚合修饰材料的表面涂层制备方法。
技术背景
生物材料是与细胞、组织、器官直接接触，作用于生物系统，能够诊断治疗生命系统疾病、替换修复损伤部位或诱导损伤部位组织再生的一类天然或人工、半人工合成的功能性材料。生物材料融合了材料学、生物学、化学、医学等多门学科，同时涵盖各种工程技术及制造技术。按生物材料功能性可分为传递或承受的负载功能，如骨、牙、关节；承担血液流动功能，如血管，心脏瓣膜；声、光、电传导功能，如晶状体、耳蜗。当生物材料与生命系统相接触时，材料表面最先与所处的生理环境发生相互作用。明确材料表界面的结构和性质对材料的后续应用具有重要意义。
生物功能表界面构筑方法主要有物理吸附和化学偶联两种。物理吸附是利用范德华力、静电作用、疏水作用等将功能性活性化合物分子固定在材料表面。物理固定方法操作简便，但存在吸附作用弱易脱离、重复性差和对材料性能影响很大的缺点。化学偶联是利用化学键将功能性活性化合物分子固定在材料表面，通过对表面化学结构的修饰构筑有生物功能的表界面。与物理吸附相比，化学偶联具有三点优势：第一，共价键比范德华力、静电作用力等物理吸附强度高得多，化学偶联的生物功能表界面稳定性高，使用寿命明显延长。第二，共价键结合点位固定，方便控制被固定生物分子的密度，有饱和性。第三，共价键结合方向固定，被固定的生物分子有良好的取向性。因此，化学偶联是最主要的生物功能表界面构筑方法。
然而化学偶联在构建过程中也存在很多问题：难以规律地控制反应速率，反应重现性差；不同材料表面性质差异较大，部分材料活化难度大，化学偶联剂难以做到材料的普适性；由于后续偶联分子种类不同，需要换用不同端基的偶联剂进行连接，难以做到通用的可反应性。研究发现双(乙烯砜基)甲烷在催化剂存在下能够在多种功能化材料表面聚合生成聚合物膜，反应条件温和，且未反应的烯基能进一步与巯基、氨基和羟基反应，是一种很有潜力的生物分子偶联剂。
发明内容
本发明旨在提供一种基于双(乙烯砜基)甲烷聚合的生物活性表面涂层制备方法，是在催化条件下使用双(乙烯砜基)甲烷在经前处理的材料表面反应聚合，聚合反应后经湿热灭菌实现对材料的生物活性修饰。所述方法包括如下步骤：将双(乙烯砜基)甲烷溶解于非质子极性溶剂，在催化剂存在条件下将经前处理的基底材料浸没在反应液中，调节pH 8-9，25-100℃反应1-48小时，再经湿热灭菌实现生物活性表面涂层的制备。
对于上文所述的技术方案中，优选的情况下，所述的非质子极性溶剂选自乙腈、丙酮、N,N-二甲基甲酰胺、二甲基亚砜、四氢呋喃、二噁烷、二氯甲烷和氯仿。
对于上文所述的技术方案中，优选的情况下，所述的催化剂为乙醇钠、三乙胺、六亚甲基四胺、N,N-二甲氨基吡啶，更为优选的情况下，催化剂为N,N-二甲氨基吡啶。
对于上文所述的技术方案中，优选的情况下，所述催化剂的摩尔浓度为双(乙烯砜基)甲烷摩尔浓度的1～10％。
对于上文所述的技术方案中，所述的基底材料选自无机硅、金属、金属氧化物、玻璃、有机玻璃和聚合物。优选的情况下，所述的金属选自钛、钢，金属氧化物选自氧化铝，聚合物选自聚丙烯、聚苯乙烯、聚四氟乙烯、聚醚醚酮。
对于上文所述的技术方案中，优选的情况下，所述的材料前处理为600-1500#砂纸均匀打磨材料表面后，乙醇冲洗、干燥，更为优选的情况下，所述的砂纸为1200目。
对于上文所述的技术方案中，优选的情况下，所述的反应温度为25-40℃。
对于上文所述的技术方案中，优选的情况下，所述的反应时间为6-12小时。
对于上文所述的技术方案中，优选的情况下，所述的湿热灭菌条件为100-130℃水蒸气处理15-60分钟，更为优选的情况下，所述的湿热灭菌时间为20-30分钟。
此外，本发明还保护利用上文所述的基于双(乙烯砜基)甲烷聚合的生物活性表面涂层制备方法所制备的生物活性表面涂层材料。
有益效果：
本发明所述的基于双(乙烯砜基)甲烷聚合的生物活性表面涂层制备方法，相对于传统方法有以下优势：
(1)可控性强，该方法基于双(乙烯砜基)甲烷的自聚合，成膜厚度随反应时间延长而增加；
(2)广谱性好，可对多种基底材料表面进行修饰，底物适用范围广，优于多巴胺沉积法；
(3)工艺环境要求低，不需全程无菌操作，采用终端湿热灭菌，操作简单且涂层不被破坏。
(4)生物相容性好，修饰后生物活性表面涂层有利于细胞粘附；
(5)反应条件温和，无需无水无氧；采用常规溶液即可进行反应，操作简单易行；重现性好。
综上，本方法是一种潜力巨大的生物活性表面涂层制备新方法。
附图说明
本发明附图:4幅，其中：
图1：双(乙烯砜基)甲烷涂层修饰前后多种材料表面的静态水接触角。
图2：氧化铝表面双(乙烯砜基)甲烷涂层厚度随反应时间的变化。
图3：双(乙烯砜基)甲烷涂层修饰前后聚醚醚酮表面红外谱图。
图4：双(乙烯砜基)甲烷涂层修饰前后钛表面细胞增殖实验。
具体实施方式
本发明公开一种基于双(乙烯砜基)甲烷聚合的表面涂层制备方法，并将该方法应用于多种材料表面。所述的多种材料选自无机硅、金属、金属氧化物、玻璃、有机玻璃和聚合物。金属材料优选钛、钢，金属氧化物优选氧化铝，聚合物优选聚丙烯、聚苯乙烯、聚四氟乙烯、聚醚醚酮。所述的多种材料经过前处理，处理方法为使用600-1500#砂纸均匀打磨材料表面，乙醇冲洗、干燥。所述的催化剂为吡啶、三乙胺、1,5-二氮杂双环[4.3.0]壬-5-烯、六亚甲基四胺和N-甲基吗啉。
以下具体实施例的是对本发明的内容作进一步说明，不应理解为对本发明任何形式的限定。
实施例1：三乙胺催化双(乙烯砜基)甲烷聚合制备多种材料生物活性表面涂层
配制100mmol/L双(乙烯砜基)甲烷(BVS，Tci)以及10mmol/L的三乙胺(TEA，Aladdin)的丙酮溶液作为反应液，使用氢氧化钠调节反应液pH至8.5。分别取2cm×2cm的无机硅片、钢片、钛片、玻璃片、氧化铝片、聚丙烯片、聚苯乙烯片、聚四氟乙烯片、聚醚醚酮片经800#SiC砂纸均匀打磨后，乙醇冲洗、干燥。所得基底材料样品浸没到配好的反应液中，25℃静置反应。分别在反应6h和24h后取出样品，大量丙酮冲洗后干燥，经121℃水蒸气湿热灭菌20分钟。用2μL超纯水测量其静态水接触角，每个样品至少测量三次取平均值，结果如附图1所示。双(乙烯砜基)甲烷对多种材料表面修饰后，表面接触角均达到50°左右(聚苯乙烯样品在24小时内部分溶解在丙酮中)。该结果表明基于双(乙烯砜基)甲烷聚合制备的表面涂层制备方法可适用于多种底物，具有广谱性。
实施例2：1,5-二氮杂双环[4.3.0]壬-5-烯催化双(乙烯砜基)甲烷聚合制备氧化铝生物活性表面涂层
配制100mmol/L双(乙烯砜基)甲烷(BVS，Tci)以及1mmol/L的1,5-二氮杂双环[4.3.0]壬-5-烯(DBN，Aladdin)的二氯甲烷溶液作为反应液，使用氢氧化钠调节反应液pH至8.5。2cm×2cm的氧化铝片经1200#SiC砂纸均匀打磨后，乙醇冲洗、干燥。所得氧化铝片浸没到配好的反应液中，37℃静置反应。在设定时刻(反应开始之后到反应48小时结束之前的反应过程中每隔1h)取出氧化铝片，大量二氯甲烷冲洗后干燥，经121℃水蒸气湿热灭菌30分钟。用椭偏仪测量氧化铝片上双(乙烯砜基)甲烷的厚度变化情况。每个样品至少测量三次取平均值，结果如附图2所示。涂层厚度增长随双(乙烯砜基)甲烷处理时间的增加而分两个不同的阶段：在最初的2小时内增长缓慢，随后迅速增长直到12小时后，涂层厚度超出椭圆偏振光检测极限。该结果表明基于双(乙烯砜基)甲烷聚合制备的表面涂层厚度随反应时间延长而增加，具有可控性。
实施例3：六亚甲基四胺催化双(乙烯砜基)甲烷聚合制备聚醚醚酮生物活性表面涂层
配制100mmol/L双(乙烯砜基)甲烷(BVS，Tci)以及8mmol/L的六亚甲基四胺(HMTA，北京伊诺凯科技有限公司)的四氢呋喃溶液作为反应液，使用氢氧化钠调节反应液pH至8.5。2cm×2cm的聚醚醚酮片经1500#砂纸均匀打磨后，乙醇冲洗、干燥。所得聚醚醚酮片浸没到配好的反应液中，40℃静置反应24小时。取出聚醚醚酮片，大量四氢呋喃冲洗后干燥，经121℃水蒸气湿热灭菌25分钟，记作灭菌-PEEK。未加入催化剂的含100mmol/L BVS的四氢呋喃溶液作为对照组，记作BVS-PEEK。使用红外光谱进行表征：反应24小时后取出聚醚醚酮片后干燥，测量其表面红外光谱图。经湿热灭菌后重复测量其红外光谱，每个样品至少测量三次取平均值，结果如附图3所示。测量时以清洁的聚醚醚酮原片为背景，反应结束后，在六亚甲基四胺催化条件下，红外光谱中的峰1(～1324cm-1)和峰2(～1129cm-1)被归属为S＝O不对称和对称拉伸振动峰，且湿热灭菌处理对表面涂层的稳定性不产生影响。以上结果表明成功制备了双(乙烯砜基)甲烷聚合修饰的材料表面涂层。
实施例4：N-甲基吗啉催化双(乙烯砜基)甲烷聚合制备钛生物活性表面涂层
配制100mmol/L双(乙烯砜基)甲烷(BVS，Tci)以及3mmol/L的N-甲基吗啉(天津市科密欧化学试剂)的二甲基亚砜溶液作为反应液，使用氢氧化钠调节反应液pH至8.5。2cm×2cm的钛片经1500#SiC砂纸均匀打磨后，乙醇冲洗、干燥。所得钛片浸没到配好的反应液中，30℃静置反应。在设定时刻取出钛片，大量二甲基亚砜冲洗后干燥，经121℃水蒸气湿热灭菌40分钟。取经传代培养的SD大鼠骨髓间充质细胞(原代细胞取自3周龄SD大鼠股骨髓腔)，以1.5×105cells/cm2的细胞密度接种至所得钛片表面，培养0-3天后进行CCK-8实验，利用酶标仪检测450nm的吸光度，测量结果如附图4所示。空白对照组为接种在α-MEM培养基(37℃)上的细胞增殖情况。未经修饰的纯钛片组的实验结果显示，细胞几乎未在纯钛表面增殖，且初始细胞数量小于空白对照组。双(乙烯砜基)甲烷修饰的钛片细胞增值情况明显，增殖趋势与空白对照组类似，说明双(乙烯砜基)甲烷聚合制备的生物活性表面涂层有良好的的生物相容性，不影响细胞正常生长。
对于任何熟悉本领域的技术人员而言，在不脱离本发明技术方案范围情况下，都可利用上述揭示的技术内容对本发明技术方案作出许多可能的变动和修饰，或修改为等同变化的等效实施例。因此，凡是未脱离本发明技术方案的内容，依据本发明的技术实质对以上实施例所做的任何简单修改、等同变化及修饰，均应仍属于本发明技术方案保护的范围内。
Claims (10)
1.一种基于双(乙烯砜基)甲烷聚合的生物活性表面涂层制备方法，其特征在于，所述方法包括如下步骤：将双(乙烯砜基)甲烷溶解于非质子极性溶剂，在催化剂存在条件下将经前处理的基底材料浸没在反应液中，调节pH 8-9，25-100℃反应1-48小时，再经湿热灭菌得到生物活性表面涂层。
2.根据权利要求1所述的一种基于双(乙烯砜基)甲烷合的生物活性表面涂层制备方法，其特征在于，所述的非质子极性溶剂选自乙腈、丙酮、氯仿、二噁烷、二氯甲烷、四氢呋喃、二甲基亚砜和N,N-二甲基甲酰胺。
3.根据权利要求1所述的一种基于双(乙烯砜基)甲烷聚合的生物活性表面涂层制备方法，其特征在于，所述的催化剂选自吡啶、三乙胺、1,5-二氮杂双环[4.3.0]壬-5-烯、六亚甲基四胺和N-甲基吗啉。
4.根据权利要求1所述的一种基于双(乙烯砜基)甲烷聚合的生物活性表面涂层制备方法，其特征在于，所述的催化剂的用量为双(乙烯砜基)甲烷摩尔浓度的1～10％。
5.根据权利要求1所述的一种基于双(乙烯砜基)甲烷聚合的生物活性表面涂层制备方法，其特征在于，所述的基底材料选自无机硅、金属、金属氧化物、玻璃、有机玻璃和聚合物。
6.根据权利要求5所述的一种基于双(乙烯砜基)甲烷合的生物活性表面涂层制备方法，其特征在于，所述的金属选自钛、钢，所述的金属氧化物选自氧化铝，所述的聚合物选自聚丙烯、聚苯乙烯、聚四氟乙烯、聚醚醚酮。
7.根据权利要求1所述的一种基于双(乙烯砜基)甲烷聚合的生物活性表面涂层制备方法，其特征在于，所述的材料前处理为600-1500#砂纸均匀打磨材料表面后，乙醇冲洗、干燥。
8.根据权利要求1所述的一种基于双(乙烯砜基)甲烷聚合的生物活性表面涂层制备方法，其特征在于，所述的反应温度为25-40℃；反应时间6-12小时。
9.根据权利要求1所述的一种基于双(乙烯砜基)甲烷聚合的生物活性表面涂层制备方法，其特征在于，所述的湿热灭菌为100-130℃水蒸气处理15-60分钟。
10.权利要求1-9中任意一项所述的方法制备的生物活性表面涂层。
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