CN116970304A - 一种MnO2-蛋白纤维复合颗粒凝胶墨水及其制备与应用 - Google Patents
一种MnO2-蛋白纤维复合颗粒凝胶墨水及其制备与应用 Download PDFInfo
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Abstract
本发明属于凝胶墨水的技术领域，公开了一种MnO2‑蛋白纤维复合颗粒凝胶墨水及其制备与应用。方法：1)采用GelMA，MEO2MA和UPyMA在KPS的作用下反应制备GMU颗粒凝胶；2)制备二氧化锰修饰的淀粉样蛋白纤维溶液；3)GMU颗粒凝胶和二氧化锰修饰的淀粉样蛋白纤维溶液在PBS溶液中混匀，获得MnO2‑蛋白纤维复合颗粒凝胶墨水。本发明的墨水在保持良好细胞相容性和维持间充质干细胞干性的同时具有良好的促细胞成骨分化的作用。本发明的墨水成型后具有较好的力学性能，保证了空间结构上所需的大孔结构，同时赋予该多孔颗粒凝胶体系良好的干细胞三维培养性能。本发明的墨水用于制备骨修复材料或干细胞的三维培养。
Description
技术领域
本发明属于水凝胶墨水的技术领域，具体涉及一种MnO2-蛋白纤维复合颗粒凝胶墨水及其制备方法与应用。
背景技术
用于细胞递送的可注射水凝胶基质的合成，可以使用物理或化学交联方法来桥接聚合物链。化学交联凝胶通常是使用交联剂和引发剂进行自由基聚合而形成的，这可能会使细胞暴露于细胞毒性化学物质、自由基或光照射下，一旦网络永久交联，通常难以获得良好的注射性。另外，带有非共价相互作用的官能团的改性天然聚合物通常具有优良的细胞相容性。用这些聚合物研发可注射水凝胶时，不需要其他化学反应，可避免引入损害细胞的小分子或自由基。
相关研究表明ROS在MSC(间充质干细胞)存活、增殖和终末分化中起着至关重要的作用。氧化环境对干细胞成骨或脂肪形成具有不同的调节作用。大多数移植的MSC经历氧化应激，并且宿主组织或MSC本身产生的过量ROS是造成细胞周期停滞和细胞死亡的主要原因。因此可通过调节ROS平衡来促进骨髓间充质干细胞向成骨分化[Martin JR，Patil P，YuF，Gupta MK，Duvall CL.Enhanced stem cell retention and antioxidativeprotection with injectable，ROS-degradable PEG hydrogels[J].Biomaterials.2020，263：120377]。
如何获得一种力学性能好、细胞存活率高、细胞干性维持时间长并具有促成骨分化性能的水凝胶是人们需要解决的问题之一。
发明内容
为解决用于细胞递送凝胶材料力学性能不足，细胞存活率较低，细胞干性维持不足等问题，同时兼顾促成骨分化等生物学性能，本发明提供了一种MnO2-蛋白纤维复合颗粒凝胶墨水及其制备方法。本发明的凝胶墨水为3D打印凝胶墨水。
本发明的另一目的在于提供上述凝胶墨水的应用。所述凝胶墨水用于制备具有调节活性氧微环境并协同间充质干细胞促成骨的凝胶制品。或者所述凝胶墨水用于制备骨修复材料或干细胞的三维培养支架材料。
本发明的目的通过下述方案实现。
一种MnO2-蛋白纤维复合颗粒凝胶墨水的制备方法，包括以下步骤：
1)采用溶剂将甲基丙烯酸改性明胶(GelMA)配成溶液；将甲基丙烯酸改性明胶溶液与MEO2MA(二(乙二醇)甲基醚甲基丙烯酸酯)和KPS过硫酸钾混匀，加入2-(3-(6-甲基-4-氧代-1，4-二氢嘧啶-2)脲基)甲基丙烯酸乙酯(UPyMA)搅拌均匀，除氧，加入N，N，N′，N′-四甲基乙二胺，室温静置8～12h，透析，冻干，获得GMU颗粒凝胶；所述溶剂为水和乙醇的混合物，水与乙醇的体积比为(2～4)∶1；
所述UPyMA的结构为所述MEO2MA的结构为n为2；
所述UPyMA在使用前采用pH＝13-14碱性水溶液溶解；所述透析的温度为25℃-37℃；所述双键改性明胶(GelMA)∶MEO2MA的质量体积比为0.2g∶0.2mL，GelMA∶UPyMA质量比为0.1∶0.01；透析时间5-7d；GelMA∶KPS质量比为0.1∶(0.001～0.01)；
2)在搅拌的条件下，向淀粉样蛋白纤维AF的溶液中滴加KMnO4溶液，滴加完后反应3～5h，获得二氧化锰修饰的淀粉样蛋白纤维(MnO2-AF)溶液；所述淀粉样蛋白纤维AF的溶液的浓度为0.1-1wt％，所述KMnO4溶液的浓度1～20mg/mL；所述滴加的速度为8～12μL/秒；淀粉样蛋白纤维AF与高锰酸钾的质量比为1∶(10～50)；所述搅拌速度300-500rpm；
3)GMU颗粒凝胶和二氧化锰修饰的淀粉样蛋白纤维(MnO2-AF)溶液在PBS溶液中混匀，获得MnO2-蛋白纤维复合颗粒凝胶墨水。
所述GMU颗粒凝胶在墨水中的浓度为5-50mg/mL。
GMU颗粒凝胶和二氧化锰修饰的淀粉样蛋白纤维的质量比为5∶(0.1～1)。
淀粉样蛋白纤维AF的溶液通过以下方法得到：
将鸡蛋清溶菌酶溶于pH＝2的酸溶液中，在85～95℃中孵育8～12h，即可得到AF溶液。所述鸡蛋清溶菌酶与pH＝2的酸溶液的质量体积比为0.5g∶(4～5)mL。
所述MnO2-蛋白纤维复合颗粒凝胶墨水通过上述方法制备得到。
所述MnO2-蛋白纤维复合颗粒凝胶墨水于制备具有调节活性氧微环境并协同间充质干细胞促成骨的凝胶制品。或者所述凝胶墨水用于制备骨修复材料或干细胞的三维培养支架材料。
所述本发明以GMU颗粒凝胶作为有机相，以MnO2-蛋白纤维作为调节活性氧微环境的纤维基质，并且释放的锰粒子可进一步作为骨诱导活性组分，构建一种可调节活性氧微环境并协同间充质干细胞促成骨的颗粒凝胶墨水。
所述MnO2-蛋白纤维复合颗粒凝胶墨水为3D打印凝胶墨水，可3D打印支架材料。
本发明的墨水为可响应细胞活性氧微环境的纳米纤维复合颗粒凝胶墨水，维持细胞干性并对细胞具有一定的保护功能，避免了目前干细胞递送治疗中涉及的细胞免疫源性、低存活率等问题；同时，二氧化锰消耗活性氧后释放的锰粒子，可有效提升材料的成骨活性，预期可更好地满足骨缺损临床治疗需求。
本发明基于物理交联的方法，在GMU颗粒凝胶内部网络物理嵌合功能性纳米纤维材料。该GMU颗粒凝胶中的GelMA组分具有RGD序列，可促进细胞黏附；其中PMEO2MA链段脱水并组装成簇，从而提供疏水微环境，进一步促进UPy二聚化以连接聚合物链，从而形成协同氢键和疏水交联网络。并将该颗粒凝胶进一步与MnO2修饰的淀粉样蛋白原纤维复合。其中MnO2纳米粒子可通过与ROS反应来调节活性氧微环境，从而有效提高MSC的生存能力，并且释放的Mn2+可进一步促进干细胞的成骨分化。纤维也可作为黏附细胞的基质，并能进一步提升凝胶墨水体系的力学强度和机械性能。
与现有技术相比，本发明具有如下优点：
(1)本发明基于物理交联，通过颗粒凝胶间的氢键和疏水相互作用，以及颗粒凝胶与MnO2-蛋白纤维的相互作用，不仅提升了GMU颗粒凝胶的力学性能，保证了空间结构上所需的大孔结构，同时赋予该多孔颗粒凝胶体系良好的干细胞三维培养性能，为凝胶材料在干细胞递送领域的研究应用提供了新的可能。
(2)本发明通过控制反应条件(GMU颗粒凝胶浓度和MnO2-AF浓度等)，使所制备的可调节活性氧微环境的MnO2-蛋白纤维复合颗粒凝胶墨水在保持良好细胞相容性和维持间充质干细胞干性的同时具有良好的促细胞成骨分化的作用。
附图说明
图1为实施例1中GMU颗粒凝胶体经异硫氰酸荧光素(FITC)染色后的荧光照片；
图2为实施例1中GMU颗粒凝胶的SEM图；
图3为实施例2中MnO2-AF的TEM图；
图4为实施例2中MnO2-AF/GMU颗粒凝胶的SEM图；
图5为MnO2-AF/GMU颗粒凝胶体系的时间-模量扫描曲线；
图6为实施例3中MnO2-AF/GMU颗粒凝胶墨水的3D打印支架图；
图7为实施例4中MnO2-AF/GMU颗粒凝胶墨水作为平台进行嵌入3D打印图；
图8为Mn2+的释放曲线图；
图9为GMU/MnO2-AF颗粒凝胶体外清除活性氧的测试结果；
图10为PBS(control)、GMU颗粒凝胶、GMU/MnO2-AF颗粒凝胶分别和hBMSCs细胞共同注射后培养6h和3d后的细胞活力测试结果；
图11为实施例1和实施例2中GMU和MnO2-AF/GMU颗粒凝胶与hBMSCs细胞共培养7、14天后的细胞干性基因Oct4的表达水平图；
图12为实施例2中MnO2-AF/GMU颗粒凝胶与hBMSCs细胞在H2O2模拟的活性氧微环境中共培养7、14天后的细胞成骨基因OCN的表达水平图。
具体实施方式
为了更好的理解本发明，下面结合实施例对本发明作进一步说明，但是本发明要求保护的范围并不局限于实施例所示的范围。
以下实施例采用SEM扫描以分析颗粒凝胶墨水的孔隙结构，采用Anton Paar MCR302流变仪测试颗粒凝胶墨水的流变性能。
实施例1
步骤一：改性明胶(GelMA)合成
(1)将6g明胶加入60mL PBS溶液中，40℃下搅拌至溶解；
(2)按照投料比(明胶∶甲基丙烯酸酐＝1g∶2mL)加入12mL甲基丙烯酸酐，50℃下反应5h；
(3)将反应液转移到截留分子量为8000的透析袋中，40℃透析7d；
(4)对预冻好的透析液进行冷冻干燥，即可得到所需的GelMA。
步骤二：GMU颗粒凝胶的制备
(1)将0.2g GelMA在40℃搅拌溶解，溶剂为2.4mL去离子水和1mL乙醇；
(2)将(1)中溶液降温到25℃然后加入200μL MEO2MA和0.01g KPS，搅拌均匀；
(3)加入400μL UPyMA(0.05g/mL，碱性条件溶解，pH＝13-14)搅拌均匀；
(4)随后通氮气10min，去除溶液中的氧气；
(5)加入25μL N，N，N′，N′-四甲基乙二胺，放置室温过夜成胶；
(6)将制备的凝胶在去离子水中透析7天；
(7)将透析好的凝胶通过高速搅拌器进行破碎，再使用冻干机冷冻干燥获得GMU颗粒凝胶粉末。
图1为GMU颗粒凝胶体经异硫氰酸荧光素(FITC)染色后通过共聚焦拍摄的的荧光照片。
步骤三：GMU颗粒凝胶墨水的制备
(1)取0.5g GMU颗粒凝胶粉末溶于10mL PBS中，搅拌均匀，即可获得GMU微凝胶墨水。
图2为GMU颗粒凝胶体系经冷冻干燥后的SEM图，其具有一定的孔隙结构。
实施例2
步骤一：MnO2-AF的制备
(1)将0.5g鸡蛋清溶菌酶加入4.5mLpH＝2的稀盐酸溶液中，搅拌至溶解；
(2)将上述溶液在90℃中孵育10h，即可得到所需的AF溶液(浓度为10wt％)；
(2)取2mL 10wt％的AF溶液，并加入17.5mL去离子水调节其浓度为1wt％；
(4)搅拌状态下逐滴加入500μL浓度为20mg/mL KMnO4溶液，每秒滴加10μL；
(5)滴加结束后，再避光反应4h，得到MnO2-AF溶液。
图3为MnO2-AF的透射电子显微镜(TEM)图。
步骤二：MnO2-AF/GMU颗粒凝胶墨水的制备
(1)取0.5g GMU颗粒凝胶粉末(实施例1制备的凝胶粉末)和10mL MnO2-AF溶液(浓度为1wt％)，搅拌混合均匀，即可获得MnO2-AF/GMU颗粒凝胶墨水。图4为MnO2-AF/GMU颗粒凝胶体系经冷冻干燥后的SEM照片，其也具有一定的孔隙结构。
图5为MnO2-AF/GMU颗粒凝胶体系的时间-模量扫描曲线，随着MnO2-AF含量的增加(MnO2-AF溶液的占比为0，0.2wt％，0.5wt％，1.0wt％)，其储能模量有所提升。
实施例3
(1)取0.5g GMU颗粒凝胶粉末(实施例1制备的)，10mL MnO2-AF溶液(实施例2中，浓度为1wt％)和50uL亚甲基蓝溶液(1mg/mL)，搅拌混合均匀，即可获得MnO2-AF/GMU颗粒凝胶墨水；
(2)将已物理交联的上述颗粒凝胶墨水通过挤出式3D打印机进行打印性能研究。打印温度为25℃。图6为该颗粒凝胶墨水打印的支架。
实施例4
(1)取0.5g GMU颗粒凝胶粉末，10mL MnO2-AF溶液(实施例2中，浓度为1wt％)和5mL PBS溶液，搅拌混合均匀，即可获得MnO2-AF/GMU颗粒凝胶墨水；
(2)将已物理交联的上述颗粒凝胶墨水通过注入圆形模具中以制备颗粒凝胶平台；
(3)将罗丹明溶液作为墨水，通过挤出式3D打印机进行颗粒凝胶平台嵌入打印性能研究。图7为该颗粒凝胶墨水作为平台进行嵌入3D打印的图片。
本发明制备MnO2纳米粒子修饰的纤维-微凝胶墨水，通过调节活性氧微环境并与间充质干细胞协同作用来促进骨修复。其中MnO2纳米粒子可通过与ROS反应来调节活性氧微环境，从而有效提升MSC的生存能力。图8为Mn2+的释放曲线图，对比直接复合MnO2，当MnO2复合到AF上时，其从颗粒凝胶体系中的释放速率相对更缓慢，具有缓释的作用。图9为GMU/MnO2-AF颗粒凝胶体外清除活性氧的测试结果，随着MnO2-AF含量(MnO2-AF溶液的体占比分别为0、0.2wt％，0.5wt％和1wt％)的增加，其消耗活性氧的效率具有显著提升。图10为PBS(control)、GMU颗粒凝胶、GMU/MnO2-AF颗粒凝胶(实施例2中)分别和hBMSCs细胞共同注射后培养6h和3d后的细胞活力测试结果，表明该GMU颗粒凝胶在注射过程中对细胞具有保护作用。图11为GMU微凝胶、GMU/MnO2-AF颗粒凝胶(实施例2)和hBMSCs细胞共培养7、14天后，细胞干性基因Oct4的表达水平结果。图12为GMU/MnO2-AF颗粒凝胶(实施例2)和hBMSCs细胞在H2O2模拟的活性氧微环境中共培养7、14天后，成骨基因OCN的表达水平结果。以上研究结果表明GMU/MnO2-AF颗粒凝胶可作为hBMSCs的三维培养体系，可有效维持干细胞活性和干性；并且MnO2-AF可有效调节活性氧微环境，释放的Mn2+可促进成骨基因OCN表达水平的上调，从而表现出协同干细胞促成骨效应。
Claims (8)
1.一种MnO2-蛋白纤维复合颗粒凝胶墨水的制备方法，其特征在于：包括以下步骤：
1)采用溶剂将GelMA配成甲基丙烯酸改性明胶溶液；将甲基丙烯酸改性明胶溶液，MEO2MA和过硫酸钾混匀，加入UPyMA搅拌均匀，除氧，加入N，N，N′，N′-四甲基乙二胺，室温静置8～12h，透析，破碎，冻干，获得GMU颗粒凝胶；所述溶剂为水和乙醇的混合物，水与乙醇的体积比为(2～4)∶1；
所述UPyMA的结构为
所述MEO2MA的结构为n为2；
2)在搅拌的条件下，向淀粉样蛋白纤维的溶液中滴加KMnO4溶液，滴加完后反应3～5h，获得二氧化锰修饰的淀粉样蛋白纤维溶液；淀粉样蛋白纤维与KMnO4的质量比为1∶(10～50)；
3)GMU颗粒凝胶和二氧化锰修饰的淀粉样蛋白纤维溶液在PBS溶液中混匀，获得MnO2-蛋白纤维复合颗粒凝胶墨水。
2.根据权利要求1所述MnO2-蛋白纤维复合颗粒凝胶墨水的制备方法，其特征在于：步骤1)中所述UPyMA在使用前采用pH＝13-14碱性水溶液溶解；所述透析的温度为25℃-37℃；
所述GelMA∶MEO2MA的质量体积比为0.2g∶0.2mL，GelMA∶UPyMA质量比为0.1∶0.01；透析时间5-7d；GelMA：过硫酸钾质量比为0.1∶(0.001～0.01)；
步骤2)中所述淀粉样蛋白纤维的溶液在体系中的终浓度为0.1～1wt％，所述KMnO4溶液的浓度1～20mg/mL；所述滴加的速度为8～12μL/秒；所述搅拌速度300-500rpm。
3.根据权利要求1所述MnO2-蛋白纤维复合颗粒凝胶墨水的制备方法，其特征在于：
所述GMU颗粒凝胶在墨水中的浓度为5-50mg/mL；
GMU颗粒凝胶和二氧化锰修饰的淀粉样蛋白纤维的质量比为5∶(0.1～1)。
4.根据权利要求1所述MnO2-蛋白纤维复合颗粒凝胶墨水的制备方法，其特征在于：所述淀粉样蛋白纤维的溶液通过以下方法得到：
将鸡蛋清溶菌酶溶于pH＝2的酸溶液中，在85～95℃中孵育8～12h，得到AF溶液。
5.根据权利要求4所述MnO2-蛋白纤维复合颗粒凝胶墨水的制备方法，其特征在于：所述鸡蛋清溶菌酶与pH＝2的酸溶液的质量体积比为0.5g∶(4～5)mL。
6.一种由权利要求1～5任一项所述制备方法得到的MnO2-蛋白纤维复合颗粒凝胶墨水。
7.根据权利要求6所述MnO2-蛋白纤维复合颗粒凝胶墨水的应用，其特征在于：所述MnO2-蛋白纤维复合颗粒凝胶墨水用于制备具有调节活性氧微环境并协同间充质干细胞促成骨的凝胶制品。
8.根据权利要求6所述MnO2-蛋白纤维复合颗粒凝胶墨水的应用，其特征在于：所述凝胶墨水用于制备骨修复材料或干细胞的三维培养支架材料。
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