CN113599570A - 一种dna纳米复合水凝胶粘合剂及其制备与应用 - Google Patents
一种dna纳米复合水凝胶粘合剂及其制备与应用 Download PDFInfo
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Abstract
本发明属于水凝胶粘合剂的技术领域,公开了一种DNA纳米复合水凝胶粘合剂及其制备与应用。方法:1)将纳米粘土溶液、脱氧核糖核酸DNA和甲基丙烯酸酐改性明胶在磷酸缓冲溶液中混匀,获得预聚液;2)将预聚液与光引发剂混匀,获得混合液;3)在搅拌的条件下,将混合液于80~100℃解螺旋反应5~10min,然后紫外光照,静置,浸泡,获得粘合剂。本发明的水凝胶粘合剂是利用组分间的多重动态物理/化学交联形成的,具有良好力学性能、生物相容性、止血性能以及强的粘附性。本发明的水凝胶粘合剂用于制备止血促组织愈合的水凝胶敷料、伤口密封材料和/或促进软组织修复与再生的材料。
Description
技术领域
本发明涉及高分子材料技术领域,具体涉及一种DNA纳米复合水凝胶粘合剂及其制备与应用。
背景技术
水凝胶粘合剂是一种用于生物组织粘合、缺损组织出血封闭和修复的生物医用材料,在外科手术中用于替代缝合线和止血夹等传统手段,可以快速密封伤口,减轻痛苦,维持伤口良好的湿润环境并避免术后二次损伤及减少疤痕。
目前,各类粘合剂已用于对软组织创伤进行密封止血和修复。然而,大多数水凝胶粘合剂分子设计复杂,缺乏良好的动态力学特性,且在潮湿和动态的环境中,由于血液、组织液等的阻碍,很难实现强粘合和动态力学的协同,甚至缺乏良好的止血性能,这些都限制了此类粘合剂的应用范围。为解决这个问题,有必要开发一种兼具良好动态力学性能和强组织粘附性的水凝胶粘合剂,以满足应用需求。
本发明基于生物相容性材料DNA、甲基丙烯酸酐改性明胶(GelMA)和硅酸盐纳米粘土(Lap)构建水凝胶粘合剂。其中,DNA特异性的碱基互补序列赋予水凝胶良好的动态力学特性,Lap提供良好的凝血性能,GelMA上独特的RGD序列和基质金属蛋白酶水解位点赋予水凝胶良好的细胞相容性和可降解性。通过DNA的氢键作用,DNA、GelMA和纳米粘土三者间的静电作用,以及光交联后GelMA形成的化学交联,构成DNA纳米复合水凝胶粘合剂多重动态物理/化学交联网络,赋予水凝胶良好的生物相容性、优越的力学性能、强组织粘附性和优异的凝血止血性能。
本发明首次以DNA、GelMA和Lap三种聚合物为原料,合成了一种多重动态物理/化学交联的水凝胶粘合剂材料,该水凝胶粘合剂兼具良好动态力学性能和强组织粘附性。
发明内容
为了克服现有技术缺点和不足,本发明的目的在于提供一种DNA纳米复合水凝胶粘合剂及其制备方法。本发明以DNA、GelMA和Lap为基本材料,通过组分间的氢键、静电作用和光交联的多重物理/化学交联形成的一种兼具良好动态力学性能和强组织粘附的水凝胶粘合剂。
本发明的另一目的在于提供上述粘合剂的应用。本发明的粘合剂用于制备伤口水凝胶敷料,特别是止血促愈合敷料,有利于伤口的凝血止血、伤口密封并促进受损组织的修复。
为实现以上目的,本发明采用以下技术方案:
一种DNA纳米复合水凝胶粘合剂的制备方法,包括如下步骤:
1)将纳米粘土溶液、DNA和甲基丙烯酸酐改性明胶在磷酸缓冲溶液中混匀,获得预聚液;
2)将预聚液与光引发剂混匀,获得混合液;
3)在搅拌的条件下,将混合液于80~100℃解螺旋反应5~10min,然后紫外光照,静置,浸泡,获得粘合剂。
步骤1)中所述纳米粘土溶液是由纳米粘土与水配置而成;所述纳米粘土为硅酸镁锂纳米粘土(德国毕克BYK的硅酸镁锂纳米粘土,XLG-XR),又称锂藻土;
纳米粘土溶液(Lap溶液)浓度为0.2~5wt%,优选为0.2~3wt%。
所述DNA为鲱鱼或鲑鱼睾丸的脱氧核糖核酸钠盐(DNA),其熔融温度为87.5℃,平均分子量为1.3×106g/mol,相当于2000个碱基对。
所述预聚液中DNA的浓度为2~6wt%,GelMA的浓度为1~5wt%,纳米粘土Lap的浓度0.1~3wt%;
所述DNA和GelMA质量比为1∶1~2∶1。
所述GelMA的接枝率为65~90%。
步骤1)中所述混匀是指在搅拌的条件下进行混匀,混匀的温度为40~60℃,搅拌的时间为8~12h,搅拌的速度为50~100rpm。
步骤2)中所述光引发剂为2-羟基-4′-(2-羟乙氧基)-2-甲基苯丙酮(I2959)、酰基亚膦酸锂(LAP)或曙红-Y/乙胺;所述光引发剂的用量为预聚液质量的0.2~1%;
步骤2)中所述混匀的条件:温度为40~60℃,时间为30~60min,所述混匀在搅拌的条件下进行,搅拌的速度为50~100rpm。
步骤3)中所述搅拌的速度为100~200rpm。
步骤3)中所述解螺旋反应的温度优选为85~95℃。
所述紫外光照的条件:照射时间为0.5~3min;紫外灯波长300~365nm,紫外光光强为10~300mw/cm2;所述静置的时间为1~3h;所述浸泡的时间为12~24h,浸泡的温度为20~25℃。所述浸泡是指采用PBS浸泡。
本发明的粘合剂是以脱氧核糖核酸(DNA)、甲基丙烯酸改性明胶(GelMA)和硅酸盐纳米粘土(Lap)为基体,在光引发剂和紫外光作用下基于氢键、静电作用和化学键等多重物理/化学交联形成。
与现有技术相比,本发明具有如下优点:
(1)本发明未使用任何化学交联剂和有机溶剂,有利于提高材料的安全性,具有良好的生物相容性;
(2)本发明的DNA纳米复合水凝胶粘合剂具有良好的力学性能,优异的粘附性能和凝血性能;
(3)本发明制备的DNA纳米复合水凝胶粘合剂在外力破坏后能进行自愈恢复,以便对动态的组织进行修复,拓宽其应用范围;
(4)本发明制备的DNA纳米复合水凝胶粘合剂的结构、机械性能和凝血性能可以通过改变组分配比和Lap含量进行调控,以满足各种应用的需要;
(5)本发明制备的DNA纳米复合水凝胶粘合剂的形状可以通过调节模具的形式来实现,便于适应不同应用的需要;
(6)本发明制备的DNA纳米复合水凝胶粘合剂可通过注射形式应用于不规则损伤组织;
(7)本发明制备的DNA纳米复合水凝胶粘合剂可对潮湿组织进行粘附并对泄漏组织部位进行密封;
(8)本发明制备的DNA纳米复合水凝胶粘合剂制备工艺简单易行,无需特殊的设备,便于批量生产,有较大应用推广价值。
附图说明
图1是实施例3制备的DNA/GelMA/Lap1水凝胶粘合剂的成型图;
图2是实施例1~4制备的DNA纳米复合水凝胶粘合剂的应力-应变曲线;DNA/GelMA/Lap0~DNA/GelMA/Lap2.0对应实施例1~4;
图3是实施例3制备的DNA/GelMA/Lap1水凝胶粘合剂的自愈合性能测试图;
图4是实施例3制备的DNA/GelMA/Lapl水凝胶粘合剂对1.5g新鲜猪心组织的粘附性能测试图;
图5是不同Lap含量的DNA纳米复合水凝胶粘合剂搭接剪切测试的粘附力-位移曲线;DNA/GelMA/Lap0~DNA/GelMA/Lap2.0对应实施例1~4;
图6是空白孔板和不同Lap含量的DNA纳米复合水凝胶粘合剂的凝血时间图;0对应实施例1,0.5对应实施例2,1对应实施例3,2对应实施例4。
具体实施方式
下面结合具体实施例来对本发明作进一步具体描述,但本发明的实施方式不限于此。
以下实施例所采用的原料来源说明:脱氧核糖核酸钠盐(来源于鲱鱼睾丸)、明胶、二甲基丙烯酸酐均采购自Sigma-Aldrich公司,硅酸镁锂纳米粘土,购自德国毕克BYK,型号XLG-XR。
GelMA通过以下方法制备:在40~60℃下用磷酸缓冲溶液将明胶溶解,加入甲基丙烯酸酸酐,控制pH为7.4~11.0;反应1~5h,终止反应,纯化产物,冷冻干燥,得到产物GelMA;甲基丙烯酸酸酐与明胶的体积质量比为2∶1~10∶1(mL/g)。
实施例1
一种DNA纳米复合水凝胶粘合剂的制备方法,包括如下步骤:
(1)GelMA的制备:
①称取6g明胶于100ml容器中,加入60ml磷酸缓冲溶液,密封容器,300rpm匀速搅拌,在50℃水浴下溶解30min至明胶完全溶解为淡黄色澄清液体;
②在步骤①所得溶液中加入12ml甲基丙烯酸酸酐(MA),控制体系pH为7.4~11.0,MA的滴加速率控制为4-6s一滴;
③反应5h,将混合液与磷酸缓冲溶液以1∶10的体积混合终止反应,过夜静置混合液后除去沉淀物;再用去离子水透析反应液7d,每天换水2次,透析袋截留分子量为14000,随后取出透析袋中液体冻干,最终得到泡沫状固体产物GelMA,-20℃下密封保存备用。
(2)DNA纳米复合水凝胶粘合剂的制备:
①称取40mgDNA和步骤(1)中20mgGelMA,溶于PBS中配成1ml溶液(相当于1g的溶液),40℃,50rpm下搅拌8-12h;
②在步骤①所得混合溶液中加入2mg引发剂I2959,避光搅拌30min;
③将步骤②所得混合溶液加热到90℃,100rpm下反应5-10min;
④将步骤③所得混合溶液冷却到25-37℃,UV交联2min,静置2h,然后浸泡于PBS中12h,即可得到DNA/GelMA/Lap0水凝胶粘合剂。
实施例2
一种DNA纳米复合水凝胶粘合剂的制备方法,包括如下步骤:
(1)GelMA的制备:
①称取6g明胶于100ml容器中,加入60ml磷酸缓冲溶液,密封容器,300rpm匀速搅拌,在50℃水浴下溶解30min至明胶完全溶解为淡黄色澄清液体;
②在步骤①所得溶液中加入12ml甲基丙烯酸酸酐(MA),控制体系pH为7.4~11.0,MA的滴加速率控制为4-6s一滴;
③反应5h,将混合液与磷酸缓冲溶液以1∶10的体积混合终止反应,过夜静置混合液后除去沉淀物;再用去离子水透析反应液7d,每天换水2次,透析袋截留分子量为14000,随后取出透析袋中液体冻干,最终得到泡沫状固体产物GelMA,-20℃下密封保存备用。
(2)DNA纳米复合水凝胶粘合剂的制备:
①称取100mg纳米粘土(Lap)粉末溶于超纯水中,剧烈搅拌12h,配制5ml浓度为2wt%的Lap溶液;
②称取40mgDNA和步骤(1)制得的20mgGelMA,取250μl步骤①中2%Lap溶液,溶于PBS中配成1ml溶液,40℃,50rpm下搅拌8-12h;
③在步骤②所得混合溶液中加入2mg引发剂I2959,避光搅拌30min;
④将步骤③所得混合溶液加热到90℃,100rpm下反应5-10min;
⑤将步骤④所得混合溶液冷却到25-37℃,UV交联2min,静置2h,然后浸泡于PBS中12h,即可得到DNA/GelMA/Lap0.5水凝胶粘合剂。
实施例3
一种DNA纳米复合水凝胶粘合剂的制备方法,包括如下步骤:
(1)GelMA的制备:
①称取6g明胶于100ml反应容器中,加入60ml磷酸缓冲溶液,密封容器,300rpm匀速搅拌,在50℃水浴下溶解30min至烧瓶中明胶完全溶解为淡黄色澄清液体;
②在步骤①所得溶液中加入12ml甲基丙烯酸酸酐(MA),控制体系pH为7.4~11.0,MA的滴加速率控制为4-6s一滴;
③反应5h,将混合液与磷酸缓冲溶液以1∶10的体积混合终止反应,过夜静置混合液后除去沉淀物;再用去离子水透析反应液7d,每天换水2次,透析袋截留分子量为14000,随后取出透析袋中液体冻干,最终得到泡沫状固体产物GelMA,-20℃下密封保存备用。
(2)DNA纳米复合水凝胶粘合剂的制备:
①称取100mg纳米粘土(Lap)粉末溶于超纯水中,剧烈搅拌12h,配制5ml浓度为2%的Lap溶液;
②称取40mgDNA和步骤(1)制得的20mgGelMA,取500μl步骤①中2%Lap溶液,溶于去离子水中配成1ml溶液(相当于1g溶液),40℃,50rpm下搅拌8-12h;
③将步骤②所得混合溶液中加入2mg引发剂I2959,避光搅拌30min;
④将步骤③所得混合溶液加热到90℃,100rpm下反应5-10min;
⑤将步骤④所得混合溶液冷却到25-37℃,UV交联2min,静置2h,然后浸泡于PBS中12h,即可得到DNA/GelMA/Lap1水凝胶粘合剂。
实施例4
一种DNA纳米复合水凝胶粘合剂的制备方法,包括如下步骤:
(1)GelMA的制备:
①称取6g明胶于100ml反应器容器中,加入60ml磷酸缓冲溶液,密封容器,300rpm匀速搅拌,在50℃水浴下溶解30min至烧瓶中明胶完全溶解为淡黄色澄清液体;
②在步骤①所得溶液中加入12ml甲基丙烯酸酸酐(MA),控制体系pH为7.4~11.0,MA的滴加速率控制为4-6s一滴;
③反应5h,将混合液与磷酸缓冲溶液以1∶10的体积混合终止反应,过夜静置混合液后除去沉淀物;再用去离子水透析反应液7d,每天换水2次,透析袋截留分子量为14000,随后取出透析袋中液体冻干,最终得到泡沫状固体产物GelMA,-20℃下密封保存备用。
(2)DNA纳米复合水凝胶粘合剂的制备:
①称取100mg、150mg纳米粘土(Lap)粉末分别溶于超纯水中,剧烈搅拌12h,配制5ml浓度为2%和3%的Lap溶液;
②称取40mgDNA和步骤(1)制得的20mgGelMA,取步骤①中250μl 2%Lap溶液和500μl 3%Lap溶液,溶于去离子水中配成1ml溶液,40℃,50rpm下搅拌8-12h;
③在步骤②所得混合溶液中加入2mg引发剂I2959,避光搅拌30min;
④将步骤③所得混合溶液加热到90℃,100rpm下反应5-10min;
⑤将步骤④所得混合溶液冷却到25-37℃,UV交联2min,静置2h,然后浸泡于PBS中12h,即可得到DNA/GelMA/Lap2水凝胶粘合剂。
性能测试:
图1为实施例3制备的DNA/GelMA/Lap1水凝胶粘合剂的成型图。DNA/GelMA/Lap1水凝胶粘合剂成型性好,外观为不透明白色凝胶。
图2为实施例1~4制备的DNA纳米复合水凝胶粘合剂的应力-应变曲线。对实施例制备的不同Lap含量的DNA纳米复合水凝胶粘合剂进行压缩应力-应变测量。测试条件为:规格为直径8.43mm、高4.00mm的圆柱形DNA纳米复合水凝胶样品在静态压缩模式下通过使用动态机械分析仪(DMA Q800,美国)以0.5N/min-1的线性斜坡力进行压缩至样品发生屈服,每组测试重复5次;从应力-应变曲线看出,在相同应变下,随着Lap含量提高,DNA纳米复合水凝胶的具有更大的应力,同时模量、韧性也提高,说明加入Lap后,水凝胶的抗压强度显著提高,能提供更多的能量耗散,机械性能更强。
图3为实施例3制备的DNA/GelMA/Lap1水凝胶粘合剂的自愈合性能测试图。测试条件为:将DNA/GelMA/Lap1水凝胶切开分成4段,用罗丹明和亚甲基蓝染料分别染色,将4段水凝胶在37℃下接触1h,结果发现水凝胶能很好的自愈合并承受自身重量。
图4为实施例3制备的DNA/GelMA/Lap1水凝胶粘合剂对1.5g新鲜猪心组织的粘附性能测试图。水凝胶具有良好的湿组织粘附性;
图5为实施例1~4制备的DNA纳米复合水凝胶粘合剂搭接剪切测试的粘附力-位移曲线。水凝胶粘合剂搭接剪切测试,测试条件:搭接剪切测试根据针对组织粘合剂修改的ASTM F2255-05标准进行[Annabi N,Rana D,Sani E S,et al.Engineering a sprayableand elastic hydrogel adhesive with antimicrobial properties for wound healing[J].Biomaterials,2017,139:229-243.]。先将20wt%明胶溶液在45℃下涂敷在载玻片上,室温静置干燥形成2.5cm×1.5cm的明胶层,再将200μL水凝胶预聚液注射到明胶层上,并用毛细管固定高度,形成2.5cm×1.0cm×0.3em的水凝胶层,随后立即覆上另一片载玻片,固定两片载玻片的相对位置,并用高强度紫外灯(50mW/cm2)照射1~3min光引发聚合,使载玻片粘合在一起。使用质构仪固定载玻片的一端,另一端以1mm/min的应变速率拉伸,在分离点记录最大拉伸应力。结果可见,随着Lap含量提高,水凝胶粘合剂的最大拉伸应力提高,说明Lap的添加有利于提高水凝胶的粘附性,在Lap含量为1%时最高,但Lap含量达2%时,可能由于体系黏度过高,内部分散不均而导致内聚力较差,从而使粘附性下降。
图6为空白孔板和不同Lap含量的DNA纳米复合水凝胶粘合剂(对应实施例1~4)的凝血时间图。水凝胶粘合剂凝血测试:称一定量水凝胶(200mg)于48孔板,水凝胶用PBS漂洗3次;将兔全血、水凝胶、CaCl2溶液、磷酸缓冲溶液(PBS)置于37℃下孵育30min;预热后每孔加10μl CaCl2溶液和190μl兔全血,轻轻浇在水凝胶上,使样品表面完全覆盖;在37℃孵育,每隔15s取出孔板,缓慢沿壁加1ml PBS,洗3次,去除未凝血液,观察凝血时间,并与空白孔板对比。从凝血时间结果可看出,含有Lapl和Lap2组水凝胶分别在1.5±0.25min、0.25±0.25min内均开始凝血,明显快于不含Lap组水凝胶和空白孔板,说明该多孔凝胶有效促进了血液凝结,Lap能够增强凝血效果,实现快速凝血,且Lap含量越高凝血效果越好。
本发明将DNA、GelMA和Lap联用,DNA、GelMA和Lap间的静电作用促进网络的稳定,构建可逆的物理交联网络,只有在这三种材料的共同作用下才能制备出性能优异的水凝胶粘合剂。本发明的水凝胶粘合剂具有良好动态力学性能、强组织粘附性、生物相容性和止血性能;并能通过注射成型。
Claims (10)
1.一种DNA纳米复合水凝胶粘合剂的制备方法,其特征在于:包括如下步骤:
1)将纳米粘土溶液、脱氧核糖核酸DNA和甲基丙烯酸酐改性明胶在磷酸缓冲溶液中混匀,获得预聚液;
2)将预聚液与光引发剂混匀,获得混合液;
3)在搅拌的条件下,将混合液于80~100℃解螺旋反应5~10min,然后紫外光照,静置,浸泡,获得粘合剂;
步骤1)中所述纳米粘土溶液是由纳米粘土与水配置而成;
所述DNA为鲱鱼或鲑鱼睾丸的脱氧核糖核酸钠盐;
所述预聚液中DNA的浓度为2~6wt%,甲基丙烯酸酐改性明胶的浓度为1~5wt%,纳米粘土的浓度0.1~3wt%。
2.根据权利要求1所述DNA纳米复合水凝胶粘合剂的制备方法,其特征在于:步骤1)中纳米粘土溶液的浓度为0.2~5wt%;所述纳米粘土为德国毕克BYK的硅酸镁锂纳米粘土,XLG-XR;
所述DNA,其熔融温度为87.5℃,平均分子量为1.3×106g/mol,相当于2000个碱基对;
所述甲基丙烯酸酐改性明胶的接枝率为65~90%。
3.根据权利要求1所述DNA纳米复合水凝胶粘合剂的制备方法,其特征在于:所述DNA和甲基丙烯酸酐改性明胶质量比为1∶1~2∶1。
4.根据权利要求1所述DNA纳米复合水凝胶粘合剂的制备方法,其特征在于:步骤3)中所述解螺旋反应的温度为85~95℃。
5.根据权利要求1所述DNA纳米复合水凝胶粘合剂的制备方法,其特征在于:所述紫外光照的条件:照射时间为0.5~3min;紫外灯波长300~365nm,紫外光光强为10~300mw/cm2。
6.根据权利要求1所述DNA纳米复合水凝胶粘合剂的制备方法,其特征在于:步骤3)中所述静置的时间为1~3h;所述浸泡的时间为12~24h,浸泡的温度为常温;所述浸泡是指采用PBS浸泡。
7.根据权利要求1所述DNA纳米复合水凝胶粘合剂的制备方法,其特征在于:步骤1)中所述混匀是指在搅拌的条件下进行混匀,混匀的温度为40~60℃,混匀的时间为8~12h,搅拌的速度为50~100rpm;
步骤2)中所述混匀的条件:温度为40~60℃,时间为30~60min,所述混匀在搅拌的条件下进行,搅拌的速度为50~100rpm;所述混匀在避光条件进行;
步骤3)中所述搅拌的速度为100~200rpm。
8.根据权利要求1所述DNA纳米复合水凝胶粘合剂的制备方法,其特征在于:步骤2)中所述光引发剂为2-羟基-4′-(2-羟乙氧基)-2-甲基苯丙酮、酰基亚膦酸锂或曙红-Y/乙胺;所述光引发剂的用量为预聚液质量的0.2~1%。
9.一种由权利要求1~8任一项所述制备方法得到的DNA纳米复合水凝胶粘合剂。
10.根据权利要求9所述DNA纳米复合水凝胶粘合剂的应用,其特征在于:所述DNA纳米复合水凝胶粘合剂用于制备止血促组织愈合的水凝胶敷料、伤口密封材料和/或促进软组织修复与再生的材料。
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