CN108498878B - 一种具有“三明治”夹心结构的生物医用水凝胶涂层及其制备方法 - Google Patents
一种具有“三明治”夹心结构的生物医用水凝胶涂层及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种具有“三明治”夹心结构的生物医用水凝胶涂层及其制备方法。制备方法为:先对需要改性的基材进行清洗、干燥处理;然后将处理后的基材置于缓冲溶液中,再向溶液中加入多巴胺,在10~30℃条件下,反应0.5~4h;再将反应后的基材顺次放入聚阳电解质溶液、多酚化合物溶液和聚阴电解质溶液中进行反应,完成一个反应周期;最后重复反应周期10~200次,得最终产品。采用本发明中的方法,可以制备一种力学性能优良、药物释放速率缓慢的生物医用水凝胶涂层,能够有效解决薄膜稳定性差以及释放药物速率过快的技术问题。
Description
技术领域
本发明属于医用材料技术领域,具体涉及一种具有“三明治”夹心结构的生物医用水凝胶涂层及其制备方法,该涂层可用于心血管、骨科等医疗器械的表面改性。
背景技术
1966年,Iler等最早报道了通过交替吸附即“层层自组装”来获得超薄膜的方法。层层自组装技术主要基于氢键、主客体作用、配位键、静电作用和分子识别作用等非共价键作用,其具有样品制备简单、膜层数可控的特点。常用的层层组装组元包括聚电解质、纳米微粒、胶束囊泡、蛋白质等材料,其可以在任何形状和基底材料,包括生物医疗器械表面、半导体表面、药物微颗粒、多孔材料及图案化表面和三维复杂的机械表面实现自组装薄膜物理化学的精确控制和调节。经过半个世纪的发展,层层自组装原理和技术已经在生物材料表面改性、传感器、药物控释、能源等研究领域得到了广泛的应用。文献中报道的薄膜材料主要是基于非共价键组装,存在薄膜稳定性差,易受外界环境刺激而导致结构改变,从而破坏薄膜的功能和影响材料的使用寿命。在生物材料表面改性中,自组装薄膜往往需要具有一定的药物装载能力和长期的结构稳定性,但非共价键组装薄膜由于药物装载量有限,释放药物速率快,大大的限制了其应用。
发明内容
针对上述现有技术,本发明提供一种具有“三明治”夹心结构的生物医用水凝胶涂层及其制备方法,以解决薄膜稳定性差以及释放药物速率过快的技术问题。
为了达到上述目的,本发明所采用的技术方案是:提供一种具有“三明治”夹心结构的生物医用水凝胶涂层的制备方法,包括以下步骤:
1)、对需要改性的基材进行清洗、干燥处理;
2)、将经过步骤1)处理后的基材置于pH=8~9的缓冲溶液中,再向溶液中加入浓度为0.1~5mg/ml的多巴胺,在10~30℃条件下,反应0.5~4h;清洗、干燥后备用;
3)、将经过步骤2)处理后的基材先在4~50℃条件下,于浓度为0.01~2mM、pH=6.5~7.5的聚阳电解质溶液中反应1~30min,取出用去离子水清洗3~5次;然后在10~30℃条件下,于浓度为0.01~10mM、pH=5.5~8.0的多酚化合物溶液中反应5~20min,取出用去离子水清洗3~5次;最后在10~30℃条件下,于浓度为0.001~2mM、pH=5.5~8.0的聚阴电解质溶液中反应2~20min,取出用去离子水清洗3~5次,完成一个反应周期;
4)、重复反应周期10~200次,得最终产品。
在上述技术方案的基础上,本发明还可以做如下改进。
进一步,步骤3)中基材先在20℃条件下,于浓度为1mM、pH=7.4的聚阳电解质溶液中反应10min,取出用去离子水清洗3~5次;然后在10℃条件下,于浓度为0.2mM、pH=7.0的多酚化合物溶液中反应10min,取出用去离子水清洗3~5次;最后在10℃条件下,于浓度为0.2mM、pH=7.0的聚阴电解质溶液中反应10min,取出用去离子水清洗3~5次,完成一个反应周期。
进一步,多酚化合物为表儿茶素、表没食子儿茶素、表没食子儿茶素没食子酸酯、表儿茶素没食子酸酯、没食子酸、茶黄素或单宁酸。
进一步,聚阳电解质为多氨基化合物。
进一步,聚阳电解质溶液的溶质为聚-L-赖氨酸氢溴酸盐、聚烯丙基胺盐酸盐、聚-L-精氨酸盐酸盐、聚乙烯亚胺、壳聚糖或聚己基紫腈。
进一步,聚阴电解质为聚丙烯酸、聚苯乙烯磺酸钠盐、海藻酸钠、胶原蛋白、抗淋巴细胞免疫球蛋白、透明质酸、葡聚糖、硫酸软骨素、硫酸皮肤素、硫酸角质素、肝素和硫酸乙酰肝素、聚谷氨酸或脱氧核糖核酸。
进一步,基材为金属基生物材料、陶瓷基生物材料或高分子基生物材料。
进一步,金属基生物材料为不锈钢、钴基合金、钛及其合金、金、锌合金或纯铁;所述陶瓷基生物材料为TiO2薄膜、各向同性热解碳、羟基磷灰石、金刚石或类金刚石;所述高分子基生物材料为涤纶、聚四氟乙烯、聚氨酯、聚甲醛、硅橡胶、聚乳酸、乙交酯-丙交酯共聚物、聚三亚甲基碳酸酯或聚己内酯。
采用本发明中的方法,可以制备一种力学性能优良、药物释放速率缓慢的生物医用水凝胶涂层。
本发明的有益效果是:
1.本发明方法,通过多酚类化合物作为聚阳电解质和聚阴电解质的夹心层,并通过层层自组装原理和技术制备原位自愈合水凝胶涂层。相比于传统的静电作用制备的涂层材料,该水凝胶涂层是基于聚电解质间的静电作用、氢键、以及多酚类化合物上的苯环结构与聚电解质上的糖环形成π-π配位作用和局部少量的共价键协同作用,提高了水凝胶涂层的结构稳定性和水凝胶涂层自愈合性能,水凝胶涂层致密的结构也为其后期药物的装载提供了可能。多酚类化合物具有良好的界面结合力,可以提高水凝胶涂层与基底的结合力。从功能方面考虑,多酚具有清除体内氧自由基的功能,因此具有良好的抗氧化性,起到延缓机体衰老的作用。从生物方面考虑,多酚化合物具有良好的抗炎、止痛作用,可以调节细胞的功能。因此,该涂层可广泛地应用于几乎所有的生物材料表面。
2.传统的水凝胶涂层,大多数以静电作用组装到材料表面,存在结构不稳定和载药能力差的缺点。经过官能化修饰共价反应的材料则存在制备过程复杂,副产物清楚不干净的问题。本发明利用天然大分子多酚作为夹心层,试验方法简单、无毒、高效、容易推广。
3.采用本发明中的方法所制备的夹心水凝胶涂层厚度可调,所得涂层均匀,制备样品所需原料投入很少,原料掺入量易于调控,该水凝胶涂层可以在多种材料表面进行修饰,主要用于心血管、骨科等医疗器械的表面改性。与传统的载药水凝胶涂层技术相比,操作简单,成本较低。
4.本发明材料中涉及的多酚类组分,均具有优异的抗氧化性,抗炎、调节细胞的功能。
附图说明
图1为内皮细胞在传统水凝胶涂层CHI@ALg水凝胶涂层(不添加多酚)上培养1天后的光学照片;照片中没有看到细胞的粘附,说明了该涂层很不适合内皮细胞的粘附与生长;
图2为内皮细胞在以硅片为基材制备出的CHI@EGCG@ALg水凝胶涂层上培养1天后的荧光照片;培养一天后,材料表面长满了内皮细胞,并且细胞的形态非常好,说明多酚的加入很有利于内皮细胞在涂层表面的粘附生长;
图3为传统的CHI@ALg与改性的CHI@EGCG@ALg水凝胶涂层的紫外吸收光谱,从图中我们可以看出,多酚的加入涂层出现了峰转移,说明EGCG成功组装到了涂层中。
具体实施方式
下面结合实施例对本发明的具体实施方式做详细的说明。
本发明的方法在实施过程中,所采用的多酚化合物为表儿茶素(L-Epicatechin,EC)、表没食子儿茶素((-)-epigallocatechin,EGC)、表没食子儿茶素没食子酸酯(Epigallocatechin gallate,EGCG)、表儿茶素没食子酸酯((-)-Epicatechin gallate,ECG)、没食子酸(Gallic acid)、茶黄素(Theaflavins)、单宁酸(Tannic acid)等中的一种。
所采用的聚阳电解质为多氨基化合物,如:聚-L-赖氨酸氢溴酸盐(Poly-L-lysinehydrobromide,PLL)、聚烯丙基胺盐酸盐(Poly(allylamine hydrochloride)PAH)、聚-L-精氨酸盐酸盐(Poly-L-arginine hydrochloride)、聚乙烯亚胺(Poly(ethyleneimine),PEI)、壳聚糖(Chitosan)、聚己基紫腈(polyhexylviologen PXV)等中的一种;所采用的聚阴电解质为:聚丙烯酸(Poly(acrylic acid),PAA)、聚苯乙烯磺酸钠盐(Poly(styrenesulfonic acid sodium salt),PSS)、海藻酸钠(Alginic acid sodium salt)、胶原蛋白(Collagenase)、抗淋巴细胞免疫球蛋白(Antilymphocyte globulin,ALg)、透明质酸(Hyaluronidase,HA)、葡聚糖(Dextran)、硫酸软骨素(Chondroitin sulfate)、硫酸皮肤素(Derma sulfate)、硫酸角质素(Keratin sulfate)、肝素、硫酸乙酰肝素(Heparinsulfate)、聚谷氨酸(Polyglutamic acid,PGA)、脱氧核糖核酸(Deoxyribonucleic acid,DNA)等中的一种。
本发明中的基材,即基底材料可为金属基生物材料、陶瓷基生物材料或高分子基生物材料。其中,金属基生物材料可以为生物医用金属材料,如:不锈钢、钴基合金、钛及其合金、镁及其合金、纯铁等;陶瓷基生物材料可以为医用无机材料与薄膜-TiO2、各向同性热解碳LTIC、羟基磷灰石、金刚石及类金刚石等;高分子基生物材料可以为涤纶PET、聚四氟乙烯PTFE、聚氨酯PU、聚甲醛POM、硅橡胶、聚乳酸PLA和乙交酯-丙交酯共聚物PLGA,聚三亚甲基碳酸酯PTMC、聚己内酯PCL等。
由于采用上述材料,最终所取得的效果基本相同,因此,没有对每一种材料单独给出实施例。本发明的具体实施例拣选其中具有代表性的几种材料,对具有“三明治”夹心结构的生物医用水凝胶涂层的制备方法进行详细说明。
实施例一
一种具有“三明治”夹心结构的生物医用水凝胶涂层的制备方法,由如下步骤获得:
A、将需要改性的硅片进行清洗、干燥;
B、将A步骤所得样品放置于pH=8.5的PBS缓冲液中,然后向溶液中加入浓度为3mg/ml的多巴胺,在10℃条件下,反应2h,去离子水清洗3~5次后经N2干燥并立即放入真空干燥箱中保存备用;
C、先将B步骤所得样品放入浓度为1mM、pH=7.4的壳聚糖(CHI)溶液中,在20℃条件下,反应10min,取出用去离子水清洗3次;然后将样品放入浓度为0.2mM、pH=7.0的表没食子儿茶素没食子酸酯(EGCG)溶液中,在10℃条件下,反应10min,取出用去离子水清洗3次;再将样品放入浓度为0.2mM、pH=7.0的抗淋巴细胞免疫球蛋白(ALg)溶液中,在10℃条件下,反应10min,取出用去离子水清洗3次,完成一个反应周期;
D、重复C步骤100次可制备水凝胶自组装膜。
实施例二
一种具有“三明治”夹心结构的生物医用水凝胶涂层的制备方法,由如下步骤获得:
A、将不锈钢基底材料进行清洗、干燥;
B、将A步骤所得样品放置于pH=8.5的Tris-HCl缓冲液中,然后向溶液中加入浓度为1.2mg/ml多巴胺,在20℃条件下,反应2h,去离子水清洗3~5次后经N2干燥并立即放入真空干燥箱中保存备用;
C、先将B步骤所得样品放入浓度为0.01mM、pH=6的壳聚糖(CHI)溶液中,在10℃条件下,反应30min,取出用去离子水清洗3次;然后将所得样品放入浓度为0.01mM、pH=5.5的没食子酸溶液中,在30℃条件下,反应5min,取出用去离子水清洗3次;再将所得样品放入浓度为0.01mM、pH=5.5的胶原蛋白中,在30℃条件下,反应2min,取出用去离子水清洗3次;完成一个反应周期;
D、重复C步骤50次可制备水凝胶自组装膜。
实施例三
一种具有“三明治”夹心结构的生物医用水凝胶涂层的制备方法,由如下步骤获得:
A、将钛片材料进行清洗、干燥;
B、将A步骤所得样品放置于pH=8的三乙醇胺缓冲液中,然后向溶液中加入浓度为2.0mg/ml多巴胺,在10℃条件下,反应4h,去离子水清洗3~5次后经N2干燥并立即放入真空干燥箱中保存备用;
C、先将B步骤所得样品放入浓度为2mM、pH=7.4的赖氨酸溶液中,在50℃条件下,反应4min,取出用去离子水清洗3次;然后将样品放入浓度为1mM、pH=6.8的表没食子儿茶素没食子酸酯(EGCG)溶液中,在10℃条件下,反应20min,取出用去离子水清洗3次;再将样品放入1mM、pH=6.8的聚苯乙烯磺酸钠(PSS)中,在10℃条件下,反应20min,取出用去离子水清洗3次,完成一个反应周期;
D、重复C步骤200次可制备水凝胶自组装膜。
实施例四
一种具有“三明治”夹心结构的生物医用水凝胶涂层的制备方法,由如下步骤获得:
A、将聚四氟乙烯PTFE材料进行清洗、干燥;
B、将A步骤所得样品放置于pH=9的缓冲溶液中,然后向溶液中加入浓度为1mg/ml多巴胺,在30℃条件下,反应0.5h,去离子水清洗3~5次后经N2干燥并立即放入真空干燥箱中保存备用;
C、先将B步骤所得样品放入浓度为2mM、pH=7.4的聚乙烯亚胺(PEI)溶液中,在30℃条件下,反应20min,取出用去离子水清洗3次;然后将样品放入浓度为10mM、pH=6.9的表儿茶素没食子酸酯(ECG)溶液中,在20℃条件下,反应20min,取出用去离子水清洗3次;再将样品放入浓度为0.9mM、pH=6.9的海藻酸钠溶液中,在20℃条件下,反应10min,取出用去离子水清洗3次,完成一个反应周期;
D、重复C步骤20次可制备水凝胶自组装膜。
实施例五
一种具有“三明治”夹心结构的生物医用水凝胶涂层的制备方法,由如下步骤获得:
A、将需要改性的纯铁材料进行抛光、清洗、干燥;
B、将A步骤所得样品放置于pH=8.5的缓冲溶液中,然后向溶液中加入浓度为4mg/ml多巴胺,在10℃条件下,反应2h,去离子水清洗3~5次后经N2干燥并立即放入真空干燥箱中保存备用;
C、先将B步骤所得样品放入浓度为2M、pH=7.4的聚赖氨酸(PLL)溶液中,在20℃条件下,反应10min,取出用去离子水清洗3次;然后将样品放入浓度为10mM、pH=6.9的表儿茶素(EC)溶液中,在10℃条件下,反应10min,取出用去离子水清洗3次;再将样品放入浓度为0.9mM、pH=6.9的海藻酸钠溶液中,在10℃条件下,反应10min,取出用去离子水清洗3次,完成一个反应周期;
D、重复C步骤200次可制备水凝胶自组装膜。
实施例六
一种具有“三明治”夹心结构的生物医用水凝胶涂层的制备方法,由如下步骤获得:
A、将需要改性的涤纶(PET)进行清洗、干燥;
B、将A步骤所得样品放置于pH=8.5的缓冲溶液中,然后向溶液中加入浓度为0.5mg/ml多巴胺,在10℃条件下,反应2h,去离子水清洗3~5次后经N2干燥并立即放入真空干燥箱中保存备用;
C、先将B步骤所得样品放入浓度为2mM、pH=7.4的聚乙烯亚胺(PEI)溶液中,在30℃条件下,反应20min,取出用去离子水清洗3次;然后将样品放入浓度为10mM、pH=7.2的单宁酸(TA)溶液中,在10℃条件下,反应20min,取出用去离子水清洗3次;再将样品放入浓度为0.9mM、pH=6.8的聚苯乙烯磺酸钠溶液中,在10℃条件下,反应20min,取出用去离子水清洗3次,完成一个反应周期;
D、重复C步骤10次可制备水凝胶自组装膜。
实施例七
一种具有“三明治”夹心结构的生物医用水凝胶涂层的制备方法,由如下步骤获得:
A、将需要改性的镍钛合金进行清洗、干燥;
B、将A步骤所得样品放置于pH=8.5的缓冲溶液中,然后向溶液中加入浓度为1.2mg/ml多巴胺,在10℃条件下,反应2h,去离子水清洗3~5次后经N2干燥并立即放入真空干燥箱中保存备用;
C、先将B步骤所得样品放入浓度为0.1mM、pH=6.5的聚乙烯亚胺(PEI)溶液中,在20℃条件下,反应10min,取出用去离子水清洗3次;然后将样品放入浓度为2mM、pH=7.2的表儿茶素(EC)溶液中,在10℃条件下,反应10min,取出用去离子水清洗3次;再将样品放入浓度为2mM、pH=7.2的肝素溶液溶液中,在10℃条件下,反应20min,取出用去离子水清洗3次,完成一个反应周期;
D、重复C步骤80次可制备水凝胶自组装膜。
实施例八
一种具有“三明治”夹心结构的生物医用水凝胶涂层的制备方法,由如下步骤获得:
A、将需要改性的羟基磷灰石进行清洗、干燥;
B、将A步骤所得样品放置于pH=8.5的缓冲溶液中,然后向溶液中加入浓度为1.2mg/ml多巴胺,在10℃条件下,反应2h,去离子水清洗3~5次后经N2干燥并立即放入真空干燥箱中保存备用;
C、先将B步骤所得样品放入浓度为2mM、pH=6.5的壳聚糖溶液中,在10℃条件下,反应30min,取出用去离子水清洗3次;然后将样品放入浓度为2mM、pH=7.2的没食子酸溶液中,在10℃条件下,反应20min,取出用去离子水清洗3次;再将样品放入浓度为2mM、pH=7.2的肝素溶液中,在10℃条件下,反应10min,取出用去离子水清洗3次,完成一个反应周期;
D、重复C步骤100次可制备水凝胶自组装膜。
对比例
一种具有水凝胶涂层的制备方法,由如下步骤获得:
A、将不锈钢基底材料进行清洗、干燥;
B、将A步骤所得样品放置于pH=8.5的缓冲溶液中,然后向溶液中加入浓度为1.2mg/ml多巴胺,在20℃条件下,反应2h,去离子水清洗3~5次后经N2干燥并立即放入真空干燥箱中保存备用;
C、先将B步骤所得样品放入浓度为1mM、pH=7.4的壳聚糖(CHI)溶液中,在20℃条件下,反应10min,取出用去离子水清洗3次;再将样品放入浓度为0.2mM、pH=7.0的抗淋巴细胞免疫球蛋白(ALg)溶液中,在10℃条件下,反应10min,取出用去离子水清洗3次,完成一个反应周期;
D、重复C步骤100次可制备水凝胶自组装膜。
结果分析
以实施例一和对比例为例,内皮细胞在传统水凝胶涂层CHI@ALg水凝胶涂层(不添加多酚)与改性后的CHI@EGCG@ALg水凝胶涂层上培养1天后的照片分别如图1和图2所示。照片中传统组没有看到细胞的粘附,说明了该涂层很不适合内皮细胞的粘附与生长;而改性组表面长满了内皮细胞,并且细胞的形态非常好,说明多酚的加入很有利于内皮细胞在涂层表面的粘附生长。图3为传统的CHI@ALg(1#)与改性的CHI@EGCG@ALg(2#)水凝胶涂层的紫外吸收光谱,从图中我们可以看出,多酚的加入涂层出现了峰转移,说明EGCG成功组装到了涂层中。
虽然结合附图对本发明的具体实施方式进行了详细地描述,但不应理解为对本专利的保护范围的限定。在权利要求书所描述的范围内,本领域技术人员不经创造性劳动即可作出的各种修改和变形仍属本专利的保护范围。
Claims (8)
1.一种具有“三明治”夹心结构的生物医用水凝胶涂层的制备方法,其特征在于,包括以下步骤:
1)、对需要改性的基材进行清洗、干燥处理;
2)、将经过步骤1)处理后的基材置于pH=8~9的缓冲溶液中,再向溶液中加入浓度为0.1~5mg/ml的多巴胺,在10~30℃条件下,反应0.5~4h;清洗、干燥后备用;
3)、将经过步骤2)处理后的基材先在20℃条件下,于浓度为1mM、pH=7.4的聚阳电解质溶液中反应10min,取出用去离子水清洗3~5次;然后在10℃条件下,于浓度为0.2mM、pH=7.0的多酚化合物溶液中反应10min,取出用去离子水清洗3~5次;最后在10℃条件下,于浓度为0.2mM、pH=7.0的聚阴电解质溶液中反应10min,取出用去离子水清洗3~5次,完成一个反应周期;
4)、重复反应周期10~200次,得最终产品。
2.根据权利要求1所述的具有“三明治”夹心结构的生物医用水凝胶涂层的制备方法,其特征在于:所述多酚化合物为表儿茶素、表没食子儿茶素、表没食子儿茶素没食子酸酯、表儿茶素没食子酸酯、没食子酸、茶黄素、邻苯二酚或单宁酸。
3.根据权利要求1所述的具有“三明治”夹心结构的生物医用水凝胶涂层的制备方法,其特征在于:所述聚阳电解质为多氨基化合物。
4.根据权利要求3所述的具有“三明治”夹心结构的生物医用水凝胶涂层的制备方法,其特征在于:所述聚阳电解质溶液的溶质为聚-L-赖氨酸氢溴酸盐、聚烯丙基胺盐酸盐、聚-L-精氨酸盐酸盐、聚乙烯亚胺或壳聚糖。
5.根据权利要求1所述的具有“三明治”夹心结构的生物医用水凝胶涂层的制备方法,其特征在于:所述聚阴电解质溶液的溶质为聚丙烯酸、聚苯乙烯磺酸钠盐、海藻酸钠、胶原蛋白、抗淋巴细胞免疫球蛋白、透明质酸、葡聚糖、硫酸软骨素、硫酸皮肤素、硫酸角质素、肝素和硫酸乙酰肝素、聚谷氨酸或脱氧核糖核酸。
6.根据权利要求1所述的具有“三明治”夹心结构的生物医用水凝胶涂层的制备方法,其特征在于:所述基材为金属基生物材料、陶瓷基生物材料或高分子基生物材料。
7.根据权利要求6所述的具有“三明治”夹心结构的生物医用水凝胶涂层的制备方法,其特征在于:所述金属基生物材料为不锈钢、钴基合金、钛及其合金、金、锌合金或纯铁;所述陶瓷基生物材料为TiO2薄膜、各向同性热解碳、羟基磷灰石、金刚石或类金刚石;所述高分子基生物材料为涤纶、聚四氟乙烯、聚氨酯、聚甲醛、硅橡胶、聚乳酸、乙交酯-丙交酯共聚物、聚三亚甲基碳酸酯或聚己内酯。
8.采用权利要求1~7任一项所述的制备方法所制备的水凝胶涂层。
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