CN105504190A - 一种光交联仿生水凝胶及其制备和应用 - Google Patents
一种光交联仿生水凝胶及其制备和应用 Download PDFInfo
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Abstract
本发明公开了一种光交联仿生水凝胶及其制备和应用。所述光交联仿生水凝胶的单体为:甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐。所述制备方法包括磷酸二胆碱化壳聚糖盐酸盐的合成、甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐的合成、以及加入光引发剂制备甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐水凝胶三个步骤。本发明所述的光交联仿生水凝胶成型条件快速、温和,具有的局域分枝双正电荷结构的磷酸二胆碱基团可兼顾改善亲水性、细胞毒性、抗菌性和抑制蛋白吸附,得到的仿生水凝胶在生理环境条件下具有显著的广谱抗菌效果,对正常细胞无毒,且可抑制蛋白吸附,在医疗、健康护理等生物医用领域有重要的应用价值。
Description
技术领域
本发明属于高分子凝胶技术领域,具体涉及一种光交联仿生水凝胶及其制备和应用。
背景技术
水凝胶是一种通过共价键、氢键或范德华力等作用相互交联构成的具有三维网状结构的聚合物材料。由于其物理性状与活体组织类似,往往具有优良的生物相容性,因而在组织工程、药物输送系统、植入及介入医疗器械等生物医用领域表现出广阔的应用前景。
制备凝胶常用的交联方法有物理交联、化学交联、高能射线辐照交联和光交联等。物理交联凝胶的力学性能及稳定性不理想;化学交联的化学引发剂增加了其细胞毒性且交联过程不易控制;高能射线辐照交联对原位凝胶的形成受限等原因。光交联的反应条件温和,副产物少,反应过程容易控制,反应效率高,尤其适用于生物医用领域。
壳聚糖是自然界唯一的碱性氨基多糖,它无毒无害,具有生物可降解性、良好的生物相容性、易于加工等许多优点,以其为基材构建的水凝胶等材料已广泛应用于生物医用领域[HuiYunZhou,LingJuanJiang,PeiPeiCao,JunBoLi,XiGuangChen.Glycerophosphate-basedchitosanthermosensitivehydrogelandtheirbiomedicalapplications.CarbohydratePolymers,2015,117,524-536;HangLi,AndrewM.Koenig,PatriciaSloan,NicD.Leipzig.Invivoassessmentofguidedneuralstemcelldifferentiationingrowthfactorimmobilizedchitosan-basedhydrogelscaffolds.Biomaterials35(2014)9049-9057]。但仍然存在生理条件下抗菌性不佳、易导致非特异性蛋白吸附等不足,限制了其临床应用。
当前,细菌等微生物黏附及随后形成的生物膜是导致植入物感染和医疗器械故障失效的主要原因之一,严重威胁着人类的身体健康和生命安全。此外,源于非特异性蛋白吸附导致的不良生物反应也是影响植入及介入等医疗器械治疗效果的重要因素。为此,人们一直致力开发兼有抗菌和抑制蛋白吸附的生物医用材料。
发明内容
为解决现有技术的缺点和不足之处,本发明的首要目的在于提供一种光交联仿生水凝胶。该光交联仿生水凝胶兼有抗菌性和抗蛋白吸附。
本发明的另一目的在于提供上述光交联仿生水凝胶的制备方法。
本发明的另一目的在于提供上述光交联仿生水凝胶的应用。
本发明目的通过以下技术方案实现:
一种光交联仿生水凝胶,所述光交联仿生水凝胶的单体为:甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐(PDCCs-GMA),其分子结构如式I所示:
其中,x/n=0~0.2,即壳聚糖的脱乙酰度为80%~100%;y/n=0.25~0.75,即磷酸二胆碱基团的取代度优选为25%~75%;z/n=0.1~0.4,即甲基丙烯酸缩水甘油酯(GMA)取代度优选为10%~40%;n为结构式中重复单元数。
一种光交联仿生水凝胶的制备方法,所述光交联仿生水凝胶为甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐水凝胶,所述制备方法包括如下步骤:
(1)将6-O-三苯基甲醚化壳聚糖(Cs-Tr)溶于反应介质;加入双取代胆碱膦酸酯,其中6-O-三苯基甲醚化壳聚糖(Cs-Tr)中的氨基与双取代胆碱膦酸酯的摩尔比为1:(2~10),0~40℃搅拌反应4~24h;旋干溶剂,加入甲酸,室温搅拌0.5~6h;旋干甲酸,用生理盐水和去离子水透析,冷冻干燥,得到磷酸二胆碱化壳聚糖盐酸盐;
(2)配制磷酸二胆碱化壳聚糖盐酸盐水溶液,将甲基丙烯酸缩水甘油酯加入到磷酸二胆碱化壳聚糖盐酸盐水溶液中,惰性气体氛围保护下50℃~80℃反应4h~12h后,透析,冷冻干燥,得到甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐(PDCCs-GMA);
(3)配制甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐的水溶液,加入光引发剂;然后在紫外光下照射,即得到透明、均匀、具有良好力学性能的甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐(PDCCs-GMA)水凝胶。
步骤(1)中所述的6-O-三苯基甲醚化壳聚糖(Cs-Tr),按照文献“S.J.Nishmura,O.Kohgo,K.Kurita,Macromolecules24(1991)4745-4748.”中的制备方法由壳聚糖改性得到:①邻苯二甲酸酐(NPTH)和壳聚糖(其中NPTH和壳聚糖-NH2摩尔比为3:1)在无水N,N-二甲基甲酰胺中氮气保护下130℃反应8h,过滤除去不溶物后倒入高速搅拌的冰水中,然后过滤,并且用乙醇,乙醚洗涤后烘干得邻苯二甲酰化壳聚糖(NPTH-Cs);②邻苯二甲酰化壳聚糖(NPTH-Cs)和三苯基氯甲烷(Tr)(摩尔比1:10)在无水吡啶中氮气保护下90℃反应24h,过滤除去不溶物后倾入高速搅拌的乙醇中,然后过滤,并且用乙醇,乙醚洗涤后烘干得NPTH-Cs-Tr;③NPTH-Cs-Tr按照1g/20mL的量加入到50%水合肼中,氮气保护下反应16h,然后过滤后,用乙醇,乙醚洗涤后烘干,即得Cs-Tr。
步骤(1)中所述的反应介质优选为N,N-二甲基乙酰胺,或是三乙胺和四氯化碳的混合溶液,或是N,N-二甲基乙酰胺、三乙胺和四氯化碳的混合溶液;其中每100mLN,N-二甲基乙酰胺中含有1~10g的6-O-三苯基甲醚化壳聚糖,优选为含有1~2g;其中三乙胺、四氯化碳与6-O-三苯基甲醚化壳聚糖的氨基摩尔比例优选为6:4:1。
步骤(1)中所述的6-O-三苯基甲醚化壳聚糖(Cs-Tr)中的氨基与双取代胆碱膦酸酯的摩尔比优选为1:(4~8)。
步骤(1)中所述的搅拌反应的条件优选为0~40℃搅拌反应10~12h。
步骤(1)中所述的室温搅拌的时间优选为2~6h。
步骤(1)中所述的双取代胆碱膦酸酯由氯化胆碱和亚磷酸二苯酯按摩尔比2:1在二甲亚砜/吡啶混合溶剂中反应2小时制得。
步骤(1)中所述的甲酸与Cs-Tr中-NH2摩尔比优选为5~50。
步骤(2)中所述的磷酸二胆碱化壳聚糖盐酸盐(PDCCs)中氨基与甲基丙烯酸缩水甘油酯(GMA)的摩尔比优选为0.5~2。
步骤(2)中所述的反应时间优选为4h~12h;反应温度优选为50℃~80℃。
步骤(2)中所述的磷酸二胆碱化壳聚糖盐酸盐水溶液的浓度优选为0.1~10mg/mL;更优选为1~10mg/mL。
步骤(2)所述的惰性气体优选为氮气。
步骤(3)中所述的甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐的水溶液的浓度优选为40~200mg/mL。
步骤(3)中所述的光引发剂优选为烷基苯酮类光引发剂;更优选为2-羟基-4-(2-羟乙氧基)-2-甲基苯丙酮(I2959)。
步骤(3)中所述的光引发剂加入量优选为0.1%~1%(w/v)。
步骤(3)中所述的紫外光优选为近紫外光(n=365nm)。
步骤(3)中所述紫外光强度优选为10~100mW/cm2。
步骤(3)中所述的紫外光照射时间优选为5~30min。
本发明所述的光交联仿生水凝胶可以应用在生物医学领域,尤其是应用于植入及介入医疗器械、组织工程材料、医用敷料中。
与现有技术相比,本发明具有以下优点及有益效果:
本发明所述的光交联仿生水凝胶成型条件快速、温和,具有的局域分枝双正电荷结构的磷酸二胆碱基团(PDC)可兼顾改善亲水性、细胞毒性、抗菌性和抑制蛋白吸附,得到的仿生水凝胶在生理环境条件下具有显著的广谱抗菌效果,对正常细胞无毒,且可抑制蛋白吸附,在医疗、健康护理等生物医用领域有重要的应用价值。
附图说明
图1是实施例1制备的甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐(PDCCs-GMA)的1HNMR谱图。
图2是实施例1制备的甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐(PDCCs-GMA)的31PNMR谱图。
图3是实施例1制备的甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐(PDCCs-GMA)水凝胶的蛋白吸附量图。
具体实施方式
下面结合实施例和附图对本发明作进一步详细的描述,但本发明的实施方式不限于此。
实施例1
一种甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐水凝胶制备方法,包括如下步骤:
步骤(1):磷酸二胆碱化壳聚糖盐酸盐(PDCCs)的合成
取200mg由壳聚糖(x/n=0)改性得到的6-O-三苯基甲醚化壳聚糖(Cs-Tr)溶于10mL无水N,N-二甲基乙酰胺,同时加入1.05mL的三乙胺和0.475mL的四氯化碳;缓慢加入10mL溶解0.475mL双取代胆碱膦酸酯的异丙醇,其中Cs-Tr中的氨基与双取代胆碱膦酸酯的摩尔比为1:5,室温搅拌反应12小时;旋干溶剂,加入甲酸,室温搅拌2小时;旋干甲酸,用生理盐水和去离子水透析,冷冻干燥,得到磷酸二胆碱化壳聚糖盐酸盐,其中磷酸二胆碱基团的取代度为42%。
步骤(2):甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐(PDCCs-GMA)的合成
取0.5g步骤(1)制得的磷酸二胆碱化壳聚糖盐酸盐溶于100mL去离子水中,加入0.275mL的甲基丙烯酸缩水甘油酯,氮气氛围保护下65℃反应6h后去离子水透析,冷冻干燥,得到甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐(PDCCs-GMA)单体,其中甲基丙烯酸缩水甘油酯取代度为25%。
步骤(3):甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐(PDCCs-GMA)水凝胶的制备:
取步骤(2)制得的甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐(PDCCs-GMA)单体,并配制成7%(w/v)甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐的水溶液,按0.8%(w/v)的比例加入光引发剂I2959[2-羟基-4'-(2-羟乙氧基)-2-甲基苯丙酮],在光强度为10mW/cm2的近紫外光下照射15min,即得到透明、均匀、具有良好力学性能的甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐(PDCCs-GMA)水凝胶。
实施例2
一种甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐水凝胶制备方法,包括如下步骤:
步骤(1):磷酸二胆碱化壳聚糖盐酸盐(PDCCs)的合成
取200mg由壳聚糖(x/n=0)改性得到的6-O-三苯基甲醚化壳聚糖(Cs-Tr)溶于10mL无水N,N-二甲基乙酰胺,同时加入1.05mL的三乙胺和0.475mL的四氯化碳;缓慢加入10mL溶解0.285mL双取代胆碱膦酸酯的异丙醇,其中Cs-Tr中的氨基与双取代胆碱膦酸酯的摩尔比为1:3,室温搅拌反应12小时;旋干溶剂,加入甲酸,室温搅拌4小时;旋干甲酸,用生理盐水和去离子水透析,冷冻干燥,得到磷酸二胆碱化壳聚糖盐酸盐,其中磷酸二胆碱基团的取代度为25%。
步骤(2):甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐(PDCCs-GMA)的合成
取0.5g步骤(1)制得的磷酸二胆碱化壳聚糖盐酸盐溶于100mL去离子水中,加入0.55mL的甲基丙烯酸缩水甘油酯,氮气氛围保护下65℃反应8h后去离子水透析,冷冻干燥,得到甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐(PDCCs-GMA)单体,其中甲基丙烯酸缩水甘油酯取代度为39%。
步骤(3):甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐(PDCCs-GMA)水凝胶的制备:
取步骤(2)制得的甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐(PDCCs-GMA)单体,并配制成20%(w/v)甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐的水溶液,按1%(w/v)的比例加入光引发剂I2959[2-羟基-4'-(2-羟乙氧基)-2-甲基苯丙酮],在光强度为100mW/cm2的近紫外光下照射15min,即得到透明、均匀、具有良好力学性能的甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐(PDCCs-GMA)水凝胶。
实施例3:甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐水凝胶的抑菌性能评价。
以大肠杆菌(Escherichiacoli)(市售)(革兰氏阴性菌)为细菌模型,测定实施例1制备的甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐水凝胶在37℃,pH=7条件下的抑菌性。将大肠杆菌菌液OD598=0.1(106~108CFU/mL)100μL滴加在甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐水凝胶表面上(1cm2),37℃湿度大于90%的恒温恒湿摇床内培养3h后,将其放入无菌水中超声10min,洗脱表面细菌。取50μL洗脱液均匀涂布于LB固体培养基中培养18h,观察细菌生长情况,结果表明甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐水凝胶抑菌率高于99%,满足抗菌材料对细菌的抑菌要求。
实施例4:甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐(PDCCs-GMA)水凝胶的细胞相容性评价
依据国家标准GB/T16886.5测试实施例1制备的甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐(PDCCs-GMA)水凝胶的体外细胞毒性。结果表明甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐(PDCCs-GMA)水凝胶对L929的细胞毒性为0级,具有良好的细胞相容性,满足医用材料对细胞相容性的要求。
实施例5:实施例1制备的甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐(PDCCs-GMA)水凝胶抗蛋白吸附评价
将直径16mm,厚度1mm的凝胶圆片浸入5mL1mg/mL的牛血清蛋白溶液中,在37℃的摇床中孵育3h。取0.5mL上清液加入到3mL的考马斯亮蓝的标准溶液中,摇振平衡5min后,以加入0.5mL去离子水于3mL标准考马斯亮蓝溶液为空白对照组,测595nm下的吸光度值。根据实验前测出的吸光度与牛血清蛋白浓度对应关系的标准曲线算出溶液中的蛋白剩余量,从而计算出凝胶的牛血清蛋白吸附量。同时以甲基丙烯酸缩水甘油酯-壳聚糖水凝胶(Cs-GMA)和聚乙二醇二丙烯酸酯(PEG700DA)水凝胶为对照组测试蛋白吸附量。结果如图3所示。结果表明:磷酸二胆碱化壳聚糖盐酸盐水凝胶的蛋白吸附量远远低于未经改性的壳聚糖材料,甚至比PEG700DA凝胶的蛋白吸附量还要低,所以磷酸二胆碱化壳聚糖盐酸盐水凝胶可显著抑制蛋白吸附。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (10)
1.一种光交联仿生水凝胶,其特征在于,所述光交联仿生水凝胶的单体为甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐,其分子结构如式I所示:
式I中,x/n=0~0.2,y/n=0.25~0.75,z/n=0.1~0.4,n为结构式中重复单元数。
2.一种光交联仿生水凝胶的制备方法,其特征在于,包括如下步骤:
(1)将6-O-三苯基甲醚化壳聚糖溶于反应介质,加入双取代胆碱膦酸酯,其中6-O-三苯基甲醚化壳聚糖中的氨基与双取代胆碱膦酸酯的摩尔比为1:(2~10),0~40℃搅拌反应4~24h;旋干溶剂,加入甲酸与6-O-三苯基甲醚化壳聚糖中的氨基摩尔比为(5~50):1,其中室温搅拌0.5~6h;旋干甲酸,用生理盐水和去离子水透析,冷冻干燥,得到磷酸二胆碱化壳聚糖盐酸盐;
(2)配制磷酸二胆碱化壳聚糖盐酸盐水溶液,将甲基丙烯酸缩水甘油酯加入到磷酸二胆碱化壳聚糖盐酸盐水溶液中,惰性气体保护下反应,透析,冷冻干燥,得到甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐;
(3)配制甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐的水溶液,加入光引发剂;然后在紫外光下照射,得到所述光交联仿生水凝胶。
3.根据权利要求2所述的光交联仿生水凝胶的制备方法,其特征在于,
步骤(1)中所述的6-O-三苯基甲醚化壳聚糖由壳聚糖改性得到;
步骤(1)中所述的双取代胆碱膦酸酯由氯化胆碱和亚磷酸二苯酯按摩尔比2:1在二甲亚砜/吡啶混合溶剂中反应2小时制得;
步骤(1)中所述的甲酸与Cs-Tr中-NH2摩尔比为5~50。
4.根据权利要求2所述的光交联仿生水凝胶的制备方法,其特征在于,步骤(1)中所述的反应介质为N,N-二甲基乙酰胺,或是三乙胺和四氯化碳的混合溶液;其中每100mLN,N-二甲基乙酰胺中含有1~10g的6-O-三苯基甲醚化壳聚糖,三乙胺、四氯化碳与6-O-三苯基甲醚化壳聚糖的氨基摩尔比例为6:4:1。
5.根据权利要求2所述的光交联仿生水凝胶的制备方法,其特征在于,步骤(1)中所述的6-O-三苯基甲醚化壳聚糖中的氨基与双取代胆碱膦酸酯的摩尔比为1:(3~8)。
6.根据权利要求2所述的光交联仿生水凝胶的制备方法,其特征在于,步骤(2)中所述的磷酸二胆碱化壳聚糖盐酸盐中氨基与甲基丙烯酸缩水甘油酯的摩尔比为0.5~2。
7.根据权利要求2所述的光交联仿生水凝胶的制备方法,其特征在于,
步骤(1)中所述的搅拌反应的时间为10~12h;
步骤(1)中所述的室温搅拌的时间为2~6h;
步骤(2)中所述的反应时间为4h~12h,反应温度为50℃~80℃。
8.根据权利要求2所述的光交联仿生水凝胶的制备方法,其特征在于,
步骤(2)中所述的磷酸二胆碱化壳聚糖盐酸盐水溶液的浓度为0.1~10mg/mL;
步骤(3)中所述的甲基丙烯酸缩水甘油酯-磷酸二胆碱化壳聚糖盐酸盐的水溶液的浓度为40~200mg/mL。
9.根据权利要求2所述的光交联仿生水凝胶的制备方法,其特征在于,
步骤(3)中所述的光引发剂为烷基苯酮类光引发剂;光引发剂加入量为0.1%~1%(w/v);
步骤(3)中所述的紫外光为n=365nm的近紫外光;
步骤(3)中所述紫外光强度为10~100mW/cm2;
步骤(3)中所述的紫外光照射时间为5~30min。
10.权利要求1所述的光交联仿生水凝胶在生物医学领域中的应用。
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CN112625268A (zh) * | 2020-12-22 | 2021-04-09 | 暨南大学 | 一种细胞膜仿生聚酰胺-胺树枝状大分子水凝胶及其制备方法与应用 |
CN112625268B (zh) * | 2020-12-22 | 2022-09-27 | 暨南大学 | 一种细胞膜仿生聚酰胺-胺树枝状大分子水凝胶及其制备方法与应用 |
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