CN113559328A - 一种生物墨水及其制备方法 - Google Patents
一种生物墨水及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种生物墨水及其制备方法,所述墨水包括A组分和B组分,所述A组分为活性凝胶微球和活体细胞的共混溶液,所述活性凝胶微球包括两亲性多乙烯基大分子单体和巯基化天然高分子;所述B组分为大分子交联剂,所述大分子交联剂为巯基功能化大分子交联剂。本发明的生物墨水中活性水凝胶微球表面含有大量的双键官能团,大分子交联剂分子骨架上含有大量巯基功能团,将A和B两组分混合时,大分子交联剂的巯基可以和微球表面的双键在生理条件发生迈克尔加成反应,得到包埋有活体细胞的颗粒凝胶材料。本发明制备的生物墨水的成分无毒,且对细胞损伤小,交联固化不引入额外的引发剂等毒性组分,不需要紫外、高温等刺激性固化方式,并且最终打印支架的孔隙可调,适宜于活体细胞的增长、分化和迁移。
Description
技术领域
本发明涉及化学、材料学及生物医药技术领域,尤其涉及一种生物墨水及其制备方法。
背景技术
三维生物打印(Three-Dimensional Bioprinting)是建立在增材制造技术上的一种新兴技术,是将生物医学与三维打印技术相结合来解决临床医学和生命健康等领域的问题。生物三维打印技术通过将活细胞、细胞外基质和其他生物材料相结合,“自下而上”式构建人工器管模型或生物相容性支架等。
生物墨水(Bioinks)的开发一直是生物三维打印技术中的核心问题。生物墨水的开发要兼顾可打印性、生物相容性、机械性能等方面。目前较为常见的生物墨水体系包括明胶、透明质酸、胶原蛋白和海藻酸盐等天然材料和聚乙烯醇、聚乙二醇等合成材料。这些墨水体系具有剪切稀化特征、良好的形状保证度以及优异的生物相容性,满足了大多数活性材料的打印需求。专利CN110790954A公开了一种光固化生物墨水制备方法,将巯基化水溶性高分子溶解在水性溶液中形成巯基化水溶性高分子溶液,将接枝双键的水溶性高分子溶解在水性溶液中形成接枝双键的水溶性高分子溶液,将两种溶液混合搅拌均匀后,加添加剂以及光引发剂,得到溶的液转移至3D打印机中进行打印,在紫外光源照射下使溶液固化,该技术方案光添加了引发剂进行固化,同时需要额外的光照射,原料成分复杂以及制备步骤繁琐。
但总的来说,现有生物墨水存在以下问题:(1)一般需要额外的光照或变温实现材料的交联固化,因而工艺较为复杂;(2)打印支架材料孔隙过小或不可调,一定程度妨碍了细胞的增殖、分化和迁移;(3)涉及一些有毒的组分,如交联剂剂等;(4)长时间打印过程细胞容易沉降,导致打印墨水组分变化。
发明内容
发明目的:本发明的目的是提供一种无毒、稳定、打印支架孔隙可调的生物墨水;本发明的另一目的是提供一种生物墨水的制备方法。
技术方案:本发明的生物墨水,包括A组分和B组分,所述A组分为活性凝胶微球和活体细胞的共混溶液,所述活性凝胶微球包括两亲性多乙烯基大分子单体和巯基化天然高分子;所述B组分为大分子交联剂,所述大分子交联剂为巯基功能化大分子交联剂。
进一步地,巯基化天然高分子和/或巯基功能化大分子为巯基化透明质酸、巯基化海藻酸钠、巯基化明胶、巯基化胶原等中的一种或几种混合物。
进一步地,A组分中两亲性多乙烯基大分子单体分为线性聚乙二醇、多臂聚乙二醇、树枝状聚乙二醇或超支化聚乙二醇中的一种或几种混合物。
进一步地,线性聚乙二醇为琥珀酰亚胺碳酸酯-聚乙二醇、二马来酰亚胺聚乙二醇、二丙烯酸酯聚乙二醇、二甲基丙烯酸酯聚乙二醇;所述的多臂聚乙二醇为二臂聚乙二醇、三臂聚乙二醇、四臂聚乙二醇、六臂聚乙二醇、八臂聚乙二醇马来酰亚胺;树枝状聚乙二醇为(mPEG)4-(PEG)2-MAL;超支化聚乙二醇为超支化聚乙二醇二丙烯酸酯。
上述生物墨水的制备方法,包括以下步骤:
(1)将两亲性多乙烯基单体、巯基化天然高分子、大分子交联剂分别溶于分散液中,振荡至完全溶解,分别得到分散相P1、分散相P2和分散相P3;
(2)将分散相P1、分散相P2混合后加入油相中,通过乳液分散法形成乳液并静置10~120min固化,洗涤除去油相得到活性凝胶微球;所述油相配制方法为将1-5%的表面活性剂溶于甲基硅油、氟化油、动物油、植物油、矿物油或硬脂酸中,形成油相;
(3)细胞离心后去除上清液并分散在步骤(2)的活性凝胶微球间,然后在细胞和活性凝胶微球间添加分散相P3使微球相互交联,得到生物墨水。
进一步地,步骤(1)中,分散液为纯水、PBS缓冲液、HEPES缓冲液或细胞培养基等中的一种或几种。
进一步地,步骤(1)中,巯基化天然高分子为巯基化透明质酸、巯基化海藻酸钠、巯基化明胶、巯基化胶原中的一种或几种混合物,其中巯基取代度在20%~40%,分子量在10kDa~200kDa;大分子交联剂优选为巯基化天然高分子,其中巯基取代度在20%~40%,分子量在10kDa~200kDa,分散相P3中巯基化天然高分子浓度为0.1~20wt%。
进一步地,步骤(2)中,乳液分散法为微流控乳化法或悬浮聚合法。步骤(2)中的活性凝胶微球由两亲性多乙烯基大分子单体和巯基化天然高分子通过迈克尔加成反应,由分散于油相中的水相微液滴作为模板制备而成的,得到的活性凝胶微球占分散相P1和分散相P2总体积的30-85%,水相微液滴尺寸为10~1000μm;
进一步地,步骤(3)中,细胞为任意一种脊椎动物的细胞或几种组合,细胞的具体类型取决于所构建的器官类型,可为骨髓间充质干细胞、脂肪间充质干细胞、皮肤细胞、上皮细胞、血管细胞、软骨细胞、心肌细胞、人脐静脉内皮细胞、成纤维细胞、胚胎干细胞/诱导多能干细胞。
本发明的生物墨水中活性水凝胶微球是使用分散于油相的水滴为模板制备而成的,两亲性的多乙烯基单体会在水-油界面发生组装行为,从而得到表面富集有大量的双键官能团活性凝胶微球;同时,大分子交联剂分子骨架上含有大量巯基功能团,因此,将A和B两组分混合时,大分子交联剂的巯基可以和微球表面的双键在生理条件发生迈克尔加成反应,实现微球间的交联,获得包埋有活体细胞的颗粒凝胶材料。
本发明的生物墨水体由微米级的活性凝胶微球作为生物墨水体系的基本构筑单元,其中,活性凝胶微球间通过生物相容性极好的巯基功能化大分子交联剂相交联。微球与微球间形成了大孔间隙,并且间隙大小可以通过改变活性凝胶微球的尺寸进行调控,因而有利于为各类细胞的增长、分化和迁移提供适宜的空间。由此,基于该墨水体系的打印支架在生理条件即可实现微球的原位交联,不引入额外的引发剂、交联蛋白质,不需要紫外、高温等刺激性固化方式,解决了传统块状凝胶墨水生物相容性低、孔隙不可调等缺点。
有益效果:与现有技术相比,本发明具有如下显著优点:
(1)生物墨水的成分无毒,且对细胞损伤小,交联固化不引入额外的引发剂等毒性组分,不需要紫外、高温等刺激性固化方式;
(2)生物墨水中的凝胶微球的大小可调,且可相应调节打印支架材料的孔隙,便于负载细胞的增殖、分化和迁移和各类人造器官的体外构建;
(3)生物墨水具备良好的可打印性和机械性能,且其中的凝胶微球为微米级,活性水凝胶微球和细胞的共混合防止长时间打印过程中细胞沉降,提高了打印的稳定性。
附图说明
图1为本发明的制备流程示意图;
图2为本发明的水、油相界面两亲性多乙烯基单体集聚机理示意图;
图3为本发明墨水打印得到的大孔颗粒凝胶支架SEM图;
图4为实施例1的生物墨水的应变-模量曲线;
图5为实施例1的生物墨水剪切稀化的剪切率-粘度曲线;
图6为实施例1的生物墨水细胞毒性实验数据;
图7为实施例1的生物墨水挤出和生物支架实物图;
图8为实施例7的体外构建皮肤器官及培养示意图。
具体实施方式
下面结合附图对本发明的技术方案作进一步说明。
实施例1
如图1所示,三维生物打印时,生物墨水中的A、B组分混合,通过打印头挤出即可得到由交联颗粒凝胶构成的3-D打印物。生物墨水的制备方法包括:(1)前驱液制备:将100mg超支化聚乙二醇二丙烯酸酯(HB-PEGDA)溶于pH=7.4的1mL 1×PBS中,配置成浓度为10%(w/v)分散相P1;将30mg巯基化透明质酸(SH-HA)溶于pH=7.4的2mL 1×PBS中,配置成浓度为1.5%(w/v)分散相P2;将7.5mg巯基化透明质酸(SH-HA)溶于pH=7.4的500μL 1×PBS中,配置成浓度为1.5wt%大分子交联剂,记为P3分散相,其中P3分散相即为组分B;
(2)活性凝胶微球:将表面活性剂FE-surf溶于氟化油中配制成2%(w/w),记为P4油相;取10mL P4油相于25mL烧瓶中,烧瓶中内含直径1.5cm磁力搅拌子,将P1、P2按照体积比1:2混合均匀成3mL前驱液加入到烧瓶中,通过磁力搅拌器以400rpm转速搅拌10~60s形成乳液并静置1~3h以达到完全固化,经过洗涤,得到2.5~3mL活性凝胶微球,并用培养基多次置换;
(3)活性凝胶微球交联:将细胞浓度为5×106的已培养好的骨髓间充质干细胞分散在步骤(2)的活性凝胶微球间,轻微振荡以分散均匀,用无菌滤布吸去培养基,记为组分A;将步骤(1)中的组分B(P3分散)加入组分A中,使微球间交联形成生物墨水;其中,步骤(1)中,可采用纯水HEPES缓冲液或细胞培养基等中的一种或几种代替PBS缓冲液配置各分散相,P3分散相中可采用巯基化海藻酸钠(SH-SA)、巯基化明胶(SH-Gel)、巯基化胶原(SH-Gelatin)中的一种或几种混合物替代透明质酸(SH-HA)配置组分B,P4油相中表面活性剂可溶于甲基硅油、动物油、植物油、矿物油或硬脂酸中,制备出的生物墨水。
力学表征和毒性表征分析:(1)为表征墨水的可打印性,对墨水做了相关的流变学表征,其中测试温度为25℃,转子尺寸为8mm,转子离样品的距离为1mm;在控制频率1Hz,在0.1-1000%应变条件对比了5%,10%两个浓度HB-PEGDA与1.5%(w/v)SH-HA形成的活性凝胶微球交联后的应变-模量数据图,如图4所示,两者浓度下交联的微球的储能模量在1000-1500Pa,这对于细胞生长提供了良好的支撑性;如图5所示,墨水具有剪切变稀特性,具备良好的可打印性。如图7所示,本实施例制备的生物墨水可挤出,同时能构建生物支架;
(2)采用CKK-8法对交联的活性微球进行了毒性实验,如图6所示,墨水具有良好的生物相容性。
实施例2
本实施例制备过程与实施例1相同,与实施例1不同的是,步骤(1),分散相P1中用线性聚乙二醇替换超支化聚乙二醇二丙烯酸酯(HB-PEGDA),线性聚乙二醇为二甲基丙烯酸酯聚乙二醇(MA-PEG-MA);组分B用巯基化海藻酸钠(SH-SA)替换巯基化透明质酸(SH-HA)。其中,P1分散性中可采用其他线性聚乙二醇,琥珀酰亚胺碳酸酯-聚乙二醇(SC-PEG-SC),二马来酰亚胺聚乙二醇(MAL-PEG-MAL)、二丙烯酸酯聚乙二醇(DA-PEG-DA)制备生物墨水。
力学表征和毒性表征分析:测试步骤同实施例1,结果发现,本实施例制备的生物墨水在可打印性、生物相容性的表现都与实施例1相似。
实施例3
本实施例制备过程与实施例1相同,与实施例1不同的是,步骤(1),分散相P1中用多臂聚乙二醇替换超支化聚乙二醇二丙烯酸酯(HB-PEGDA),多臂聚乙二醇为四臂聚乙二醇(4Arm(PEG-Allyl)4);组分B用巯基化明胶(SH-Gel)替换巯基化透明质酸(SH-HA)。其中,P1分散性中可采用其他多臂聚乙二醇,二臂聚乙二醇、三臂聚乙二醇、六臂聚乙二醇、八臂聚乙二醇马来酰亚胺制备生物墨水。
力学表征和毒性表征分析:测试步骤同实施例1,结果发现,本实施例制备的生物墨水在可打印性、生物相容性的表现都与实施例1相似。
实施例4
本实施例制备过程与实施例1相同,与实施例1不同的是,步骤(1),分散相P1中用树形聚乙二醇换超支化聚乙二醇二丙烯酸酯(HB-PEGDA),树形聚乙二醇为(mPEG)4-(PEG)2-MAL;组分B用巯基化海藻酸钠(SH-SA)替换巯基化透明质酸(SH-HA)。
力学表征和毒性表征分析:测试步骤同实施例1,结果发现,本实施例制备的生物墨水在可打印性、生物相容性的表现都与实施例1相似。
实施例5
本实施例制备过程与实施例1相同,与实施例1不同的是,步骤(1),分散相P1中用质量比例1:1的超支化聚乙二醇二丙烯酸酯(HB-PEGDA)与树形聚乙二醇(mPEG)4-(PEG)2-MAL混合物替换超支化聚乙二醇二丙烯酸酯(HB-PEGDA);组分B用质量比例(1:1)的巯基化海藻酸钠(SH-SA)与巯基化胶原(SH-Gelatin)混合。
力学表征和毒性表征分析:测试步骤同实施例1,结果发现,本实施例制备的生物墨水在可打印性、生物相容性的表现都与实施例1相似。
实施例6
(1)前驱液制备:将100mg树形聚乙二醇为(mPEG)4-(PEG)2-MAL溶于pH=7.4的1mL1×PBS中,配置成浓度为10%(w/v)分散相P1;将30mg巯基化海藻酸钠(SH-SA)溶于pH=7.4的2mL 1×PBS中,配置成浓度为1.5%(w/v)分散相P2;将7.5mg巯基化透明质酸(SH-HA)溶于pH=7.4的500μL 1×PBS中,配置成浓度为1.5wt%大分子交联剂,记为P3分散相,其中P3分散相即为组分B;
(2)活性凝胶微球:将表面活性剂Span 80溶于二甲基硅油中配制成2%(w/w),记为P4油相;用注射器吸取P4油相、P1分散相、P2分散相通过PE管与微流控芯片连接,将注射器固定在注射泵以控制三种液体流速,P1分散相、P2分散相在芯片管道内混合被P4油相剪切形成油包水液滴,P4油相、P1分散相、P2分散相流速比设置为16:1:2,收集微球与试管中,经过洗涤,得到2.5~3mL活性凝胶微球,并用培养基多次置换;
(3)活性凝胶微球交联:将细胞浓度为5×106的已培养好的骨髓间充质干细胞分散在步骤(2)的活性凝胶微球间,轻微振荡以分散均匀,用无菌滤布吸去培养基,记为组分A;将步骤(1)中的组分B(P3分散相)加入组分A中,使微球间交联形成生物墨水。
力学表征和毒性表征分析:测试步骤同实施例1,结果发现,本实施例制备的生物墨水在可打印性、生物相容性的表现都与实施例1相似。
实施例7:体外构建人造皮肤器官
本发明制备的生物墨水用于构建人造皮肤器官,其中以每2天更换一次新鲜培养基,如图8所示,具体的步骤包括:
(1)基底层的构建
打印墨水配方:A组分为体积分数为70%的活性凝胶微球溶液,其组成为:10%(w/v)超支化聚乙二醇二丙烯酸酯(HB-PEGDA)与1.5%(w/v)巯基化胶原(SH-Gelatin)以体积比(1:2),在pH为7.4条件下通过悬浮聚合制备得到;平均尺寸为200μm;纯化后的微球分散于成纤维细胞培养基。B组分为4%(w/v)巯基化透明质酸(SH-HA)大分子交联剂,其分子量为400k Da。
基底层打印:采用挤出式生物打印机,设置打印速度为400mm/min,挤出为气压20psi;接着将A,B组分分别填装到的料筒,由21G针头挤出,构建基底层。
(2)真皮层的构建
打印墨水配方:A组分为体积分数为70%的活性凝胶微球与人源成纤维细胞(HDFs,浓度5×106个/mL)组成的混合组分。其中活性微球制备组分及制备方法同步骤一;分散液为成纤维细胞培养基。B组分为1.5%(w/v)巯基化胶原(SH-Gelatin)大分子交联剂。
真皮层打印:同基底层的构建的打印工艺。打印完成后将其转移至培养基中培养48-72h后实施步骤3。
(3)表皮层的构建
打印墨水配方:人源角质形成细胞分散液(HEKs,细胞浓度5.5×106个/mL)的,分散液为角质细胞培养基。
表皮层打印:采用喷墨打印方式,直接将角质均匀的覆盖于真皮层上,种植密度约为3.5×104/cm2。
如图2所示,两亲性多乙烯基单体会自发的集聚与水油液滴水/油界面处,在水油界面发生组装行为。
本发明的用于人造器官的生物墨水体系,生理条件即可实现微球的原位交联,不引入额外的引发剂、交联蛋白质,不需要紫外、高温等刺激性固化方式,不仅降低了制备成本,更重要的是大大降低了对细胞的损伤。此外,打印支架材料的孔隙可以通过调节凝胶微球的大小进行调节,便于负载细胞的增殖、分化和迁移和各类人造器官的体外构建。
Claims (9)
1.一种生物墨水,其特征在于,包括A组分和B组分,所述A组分为活性凝胶微球和活体细胞的共混溶液,所述活性凝胶微球包括两亲性多乙烯基大分子单体和巯基化天然高分子;所述B组分为大分子交联剂,所述大分子交联剂为巯基功能化大分子交联剂。
2.根据权利要求1所述的生物墨水,其特征在于,所述巯基化天然高分子和/或巯基功能化大分子为巯基化透明质酸、巯基化海藻酸钠、巯基化明胶、巯基化胶原等中的一种或几种混合物。
3.根据权利要求1所述的生物墨水,其特征在于,所述A组分中两亲性多乙烯基大分子单体分为线性聚乙二醇、多臂聚乙二醇、树枝状聚乙二醇或超支化聚乙二醇中的一种或几种混合物。
4.根据权利要求3所述的生物墨水,其特征在于,所述线性聚乙二醇为琥珀酰亚胺碳酸酯-聚乙二醇、二马来酰亚胺聚乙二醇、二丙烯酸酯聚乙二醇或二甲基丙烯酸酯聚乙二醇;所述多臂聚乙二醇为二臂聚乙二醇、三臂聚乙二醇、四臂聚乙二醇、六臂聚乙二醇或八臂聚乙二醇马来酰亚胺;所述树枝状聚乙二醇为(mPEG) 4-(PEG)2-MAL;所述超支化聚乙二醇为超支化聚乙二醇二丙烯酸酯。
5.一种生物墨水的制备方法,其特征在于,包括以下步骤:
(1)将两亲性多乙烯基单体、巯基化天然高分子、大分子交联剂分别溶于分散液中,振荡至完全溶解,分别得到分散相P1、分散相P2和分散相P3;
(2)将分散相P1、分散相P2混合后加入油相中,通过乳液分散法形成乳液并静置一段时间,洗涤除去油相得到活性凝胶微球;
(3)细胞离心后去除上清液并分散在步骤(2)的活性凝胶微球间,然后在细胞和活性凝胶微球间添加分散相P3使微球相互交联,得到生物墨水。
6.根据权利要求5所述的生物墨水的制备方法,其特征在于,步骤(1)中,分散液为纯水、PBS缓冲液、HEPES缓冲液或细胞培养基中的一种或几种。
7.根据权利要求5所述的生物墨水的制备方法,其特征在于,步骤(2)中,乳液分散法为微流控乳化法或悬浮聚合法。
8.根据权利要求5所述的生物墨水的制备方法,其特征在于,步骤(3)中,细胞为任意一种脊椎动物的细胞或几种组合。
9.根据权利要求5所述的生物墨水的制备方法,其特征在于,步骤(3)中,细胞为骨髓间充质干细胞、脂肪间充质干细胞、皮肤细胞、上皮细胞、血管细胞、软骨细胞、心肌细胞、人脐静脉内皮细胞、成纤维细胞、胚胎干细胞或诱导多能干细胞。
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