CN113215101A - 一种构建具有异质功能纤维和血管通道的纤维束/组织结构的方法 - Google Patents

一种构建具有异质功能纤维和血管通道的纤维束/组织结构的方法 Download PDF

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CN113215101A
CN113215101A CN202110598763.0A CN202110598763A CN113215101A CN 113215101 A CN113215101 A CN 113215101A CN 202110598763 A CN202110598763 A CN 202110598763A CN 113215101 A CN113215101 A CN 113215101A
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fiber bundle
cells
muscle
nerve
ink
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CN113215101B (zh
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熊卓
方永聪
张婷
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Tsinghua University
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Abstract

本发明公开了一种构建具有异质功能纤维和血管通道的纤维束/组织结构的方法。所述方法包括如下步骤：根据神经纤维束或肌肉纤维束的血管通道和多级结构设计预定义图案，并依此设置套筒；在套筒内载入分别载有相应细胞(神经来源细胞、肌肉来源细胞、基质细胞、血管生成细胞、神经外膜材料和肌外膜材料)，经挤出得到含异质功能纤维和血管通道的神经纤维束或肌肉纤维束。本发明制备方法可以一步成形高度异质的纤维束结构，同时能够在微观尺度上重构复杂纤维束的不同功能单元，很好地克服了微挤出式细胞3D打印技术的打印精度低等技术瓶颈。本发明方法适合于构建具有不同功能纤维和血管通道的复杂纤维束结构，可用于病损组织器官修复、药物开发与筛选和病理研究模型等。

Description

一种构建具有异质功能纤维和血管通道的纤维束/组织结构 的方法
技术领域
本发明涉及一种构建具有异质功能纤维和血管通道的纤维束/组织结构的方法，属于组织工程和生物制造技术领域。
背景技术
生物3D打印技术通过将含细胞的生物墨水按照预定义的打印路径，通过层层堆积形成3D结构，在复杂组织和器官的构建方面具有巨大的优势。其中，微挤出式生物3D打印技术由于材料适用范围广，生物墨水粘度范围可以在0.03～5×104Pa·s区间，具有成形制造复杂组织结构的潜力，成为目前主流的打印工艺。这种工艺将粘性生物墨水通过微型喷嘴时，在机械力或气压的驱动下受到挤压从而形成纤维。
人体各种组织与器官具有高度异质性，由多种细胞按照复杂的方式排布组成。其中，神经组织和肌肉组织作为典型的束状结构，由多种不同的功能纤维单元组装而成，同时含有丰富的血管和基质组织。因此，功能化神经和肌肉组织的体外构建面临着特殊的难度与挑战：
1)打印精度低，难以构建精度在百微米以下的结构特征(如微血管和神经)：微挤出式3D打印工艺中使用的喷嘴直径越小，生物墨水挤出经过喷嘴时承受的剪切力越大，对细胞造成的损伤也越大，限制了该工艺的打印精度(300～500μm范围)，而功能纤维单元的尺寸通常在几十到数百微米，从而限制了体外微纤维的可控组装。
2)异质细胞结构的可控组装困难：神经和肌肉纤维束包含高度异质的功能纤维，比如神经组织含有运动神经纤维、感觉神经纤维和血管，肌肉组织包含肌肉纤维、血管通道和神经纤维组成。目前通用方法是采用多喷头打印策略，使用含不同细胞的生物墨水交替进行打印，然后这种方法需要高度复杂的控制系统，同时打印耗时长。
综上，常规的生物3D打印技术在复杂神经和肌肉组织构建方面仍具有巨大的挑战，尚需成形工艺创新突破来实现。
发明内容
本发明的目的是提供一种具有异质功能纤维和血管通道的纤维束的方法，通过在预先定义的喷头套筒内加载不同生物墨水，同步挤出获得含血管结构和多种不同微纤维的纤维束，同时可进一步在空气、液体或悬浮介质中打印成形更加复杂的仿生异质神经或肌肉组织，可用于病损组织器官修复、药物开发与筛选和病理研究模型等，具有重要的医学转化和临床应用前景。
本发明所提供的构建具有异质功能纤维和血管通道的神经纤维束或肌肉纤维束或肌肉组织结构的方法，包括如下步骤：
S1、根据神经纤维束或肌肉纤维束的血管通道和多级结构设计预定义图案，并依此设置套筒；
S2、在所述套筒内载入分别载有相应细胞的生物墨水，经挤出得到含异质功能纤维和血管通道的神经纤维束或肌肉纤维束；
所述生物墨水为下述1)、3)、4)、5)或2)-4)、6)：
1)载神经来源细胞的生物墨水；
2)载肌肉来源细胞的生物墨水；
3)载基质细胞的生物墨水；
4)载血管生成细胞的牺牲生物墨水；
5)载神经外膜材料的生物墨水；
6)载肌外膜材料的生物墨水。
上述的方法中，所述神经纤维束由运动和感觉神经纤维细胞、血管、基质细胞和神经外膜形成；
所述肌肉纤维束由骨骼肌细胞、神经纤维细胞、血管、基质细胞和和肌外膜形成；
所述神经纤维束或所述肌肉纤维束的直径可为500μm～2000μm，具体可为1000μm～1200μm或1500μm～1750μm；
所述神经纤维束或所述肌肉纤维束中单根纤维束的直径可为50μm～250μm，具体可为100μm～120μm、120μm～150μm或200μm～250μm；
所述神经纤维束或所述肌肉纤维束中血管通道的直径可为50μm～500μm，具体可为200μm～250μm或300μm～350μm；
所述神经纤维束或所述肌肉纤维束中神经外膜或肌外膜的厚度可为10μm～200μm，所述神经外膜的厚度优选为100μm～150μm，所述肌外膜的厚度优选为50μm～100μm。
上述的方法中，所述生物墨水为含细胞的天然高分子水凝胶和/或合成高分子水凝胶；
所述天然高分子水凝胶可为透明质酸、纤维蛋白原、海藻酸钠、明胶、胶原、壳聚糖、丝素蛋白、硫酸软骨素、白蛋白以及它们的甲基丙烯酰化产物(如甲基丙烯酰化明胶(GelMA)、甲基丙烯酰化海藻酸钠(AlgMA)等)中的至少一种；
所述合成高分子水凝胶为聚乙二醇(PEG)、聚丙烯醇(PVA)、聚乙二醇二丙烯酸酯(PEGDA)、聚环氧乙烷(PEO)、聚丙烯酰胺(PAM)、聚丙烯酸(PAA)、聚磷腈(PAMPS)、聚N-异丙基丙烯酰胺类水凝胶(PNIPAAm)以及它们的甲基丙烯酰化产物(如凹臂聚乙二醇丙烯酸酯(4-arm-PEG-AC)、甲基丙烯酰化聚乙烯醇(PVAMA)等)中的至少一种。
上述的方法中，所述神经来源细胞由神经细胞和施旺细胞组成，可以为原代细胞来源、胚胎干细胞或诱导多能干细胞定向分化来源中的至少一种；
所述肌肉来源细胞为骨骼肌细胞，可以为原代细胞来源、胚胎干细胞或诱导多能干细胞定向分化来源中的至少一种；
所述基质细胞为神经或肌肉组织中结缔组织细胞，包括周细胞、成纤维细胞和巨噬细胞中的至少一种；
所述血管生成细胞为内皮细胞以及平滑肌细胞、周细胞和成纤维细胞中的至少一种；
所述神经外膜材料或所述肌外膜材料为细胞外基质材料，包括胶原、弹性蛋白、纤连蛋白、层粘连蛋白、蛋白多糖、透明质酸和纤维蛋白原中的至少一种。
上述的方法中，所述生物墨水中细胞的密度可为106/mL～108/mL，具体可为0.1～2×106/mL；
所述生物墨水中凝胶材料的质量-体积浓度为10～100mg/mL。
上述的方法中，步骤S2中，采用高压气体同步驱动或采用多个注射泵分别驱动所述生物墨水的挤出；
所述高压气体的气动压力可为1～100kPa，优选30～40kPa；
所述注射泵的挤出速率可为0.01～10mL/h，优选0.1～0.5mL/h。
在得到含血管结构和多种不同微纤维的纤维束的基础上，还可进一步构建形更加复杂的仿生异质神经或肌肉组织：
A)将所述神经纤维束或所述肌肉纤维束进行3D打印，构建仿生的神经组织结构或肌肉组织结构；
B)所述3D打印结束后，经整体交联，同时溶出牺牲墨水，即得到具有异质功能纤维和血管通道的神经组织结构或肌肉组织结构。
步骤A)中，可在空气中、交联液中或悬浮介质中进行所述3D打印；
所述交联液可为氯化钙溶液或凝血酶溶液，与生物墨水能够快速交联的溶液；
所述悬浮介质为具有自愈合特性的水凝胶材料，具体为超分子自愈合水凝胶和/或微凝胶结构；
在所述悬浮介质中进行所述3D打印时，经所述整体交联后，还包括溶出所述悬浮介质的步骤；
所述悬浮介质的去除方法包括温度变化、摇晃、水洗、酶溶解等方式中至少一种。
步骤B)中，所述整体交联方法包括光照交联、离子交联、温度交联、酶交联和共价交联方式中至少一种；
所述牺牲墨水的牺牲方式可为温度变化、pH变化和离子作用中至少一种。
本发明方法构建的具有异质功能纤维和血管通道的神经纤维束/神经组织结构或肌肉纤维束/肌肉组织结构也属于本发明的保护范围。
本发明提供的制备方法，可以一步成形高度异质的纤维束结构，省去了常规3D打印工艺中多种纤维逐层组装步骤，更加简单快速；同时能够在微观尺度上重构复杂纤维束的不同功能单元，比如运动神经纤维和感觉神经纤维，肌肉纤维和血管通道，很好地克服了微挤出式细胞3D打印技术的打印精度低等技术瓶颈。本发明提供的方法适合于构建具有不同功能纤维和血管通道的复杂纤维束结构，可用于病损组织器官修复、药物开发与筛选和病理研究模型等。
附图说明
图1为多通道注射泵驱动喷头内多种生物墨水挤出的示意图；
其中，1为载基质细胞的生物墨水，2为载神经细胞或肌肉细胞的生物墨水，3为载血管生成细胞的生物墨水，4为载神经外膜或肌外膜来源材料的生物墨水，5为基质组织，6为神经或肌肉纤维束，7为血管通道，8为神经外膜或肌外膜。
图2为高压气体驱动喷头内多种生物墨水挤出的示意图；
其中，9为高压气体，10为缓冲溶液。
具体实施方式
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1、仿生神经纤维束的体外构建
1、制备不同生物墨水
i)制备载神经细胞和施旺细胞的生物墨水。
神经细胞和施旺细胞从原代大鼠大脑中提取，墨水材料为质量体积浓度为60mg/mL的海藻酸钠溶液、质量体积浓度为100mg/mL的透明质酸溶液与体积分数为40％的Matrigel溶液按1:2:1的比例均匀混合，细胞密度为2×107/mL。
ii)制备载内皮细胞的牺牲生物墨水。
内皮细胞为人脐静脉内皮细胞(Human Umbilical Vein Endothelial Cells，HUVEC)，墨水材料为质量体积浓度为5.0％的明胶溶液，细胞密度为5×106/mL。
iii)制备载基质细胞的生物墨水。
基质细胞由成纤维细胞和周细胞按2:1比例混合组成，墨水材料为质量体积浓度为40mg/mL的海藻酸钠溶液、质量体积浓度为50mg/mL的纤维蛋白原溶液与质量体积浓度为12mg/mL的胶原溶液按3:3:2的比例均匀混合(凝胶材料的质量-体积浓度为36.75mg/mL)，细胞密度为2×106/mL。
iv)制备载神经外膜材料的生物墨水。
墨水材料为质量体积浓度为40mg/mL的海藻酸钠溶液、质量体积浓度为20mg/mL的胶原溶液、质量体积浓度为4mg/mL的纤连蛋白溶液与4mg/mL的层粘连蛋白溶液按3:3:2:2的比例均匀混合(凝胶材料的质量-体积浓度为19.6mg/mL)。
2、根据神经组织的免疫组化结果，分析神经纤维束的组成成分和形态特征，设计具有相应图案的套筒(如图2所示)，并嵌入到10mL注射器喷头内，并在套筒的不同区域内分别载入相应的生物墨水，并通过高压氮气同步驱动多种生物墨水在钙离子液中的打印，气动压力为35kPa，如图2所示。打印速度为2mm/s，打印温度为21℃。打印完成后放入培养箱中孵育30分钟，溶出明胶牺牲墨水，从而得到具有仿生形态的神经纤维束结构。
其中，整个神经纤维束的直径为1500μm～1750μm，单根神经纤维的直径为200μm～250μm，血管通道的直径为300μm～350μm，神经外膜的厚度为100μm～150μm。
实施例2、神经驱动的血管化肌肉组织的体外构建
1、制备不同生物墨水
采用人诱导多能干细胞体外培养、并诱导分化获得多能干细胞来源的神经细胞、肌细胞和血管内皮细胞，采用自主合成可光交联的甲基丙烯酸酯明胶(GelMA)作为主要的凝胶材料，分别制备载不同细胞的生物墨水。
i)制备载肌细胞的生物墨水，墨水材料为质量体积浓度为100mg/mL的GelMA溶液、质量体积浓度为15mg/mL的纤维蛋白原溶液与体积分数为20％的Matrigel溶液按3:1:1的比例均匀混合，细胞密度为2×107/mL。
ii)制备载神经细胞的生物墨水，墨水材料为质量体积浓度为60mg/mL的GelMA溶液、质量体积浓度为100mg/mL的透明质酸溶液与体积分数为30％的Matrigel溶液按3:2:1的比例均匀混合，细胞密度为1×107/mL。
iii)制备载内皮细胞的牺牲生物墨水，墨水材料为质量分数为7.5％的明胶溶液，细胞密度为4×106/mL。
iv)制备载基质细胞的生物墨水，基质细胞由成纤维细胞和骨髓间充质干细胞按1:1比例混合组成，墨水材料为质量体积浓度为40mg/mL的GelMA溶液、质量体积浓度为50mg/mL的丝素蛋白溶液与质量体积浓度为12mg/mL的胶原溶液按3:1:2的比例均匀混合(凝胶材料的质量-体积浓度为32.3mg/mL)，细胞密度为1×106/mL。
2、根据肌肉组织的免疫组化结果，分析肌肉纤维束、神经纤维束和血管的组成比例和形态特征，设计含有嵌入式套筒的喷头(如图1所示)，同时具有多个通道出口。将不同生物墨水加载到相应注射器中、并固定到注射泵上，并分别与喷头的不同出口相连，如图1所示。通过注射泵分别驱动相应生物墨水的挤出，获得含异质功能纤维和血管通道的纤维束，其中，载肌细胞的生物墨水的挤出速率为0.3mL/h，载神经细胞的生物墨水的挤出速率为0.3mL/h，载内皮细胞的牺牲生物墨水的挤出速率为0.2mL/h，载基质细胞的生物墨水的挤出速率为0.1mL/h。
3、通过复合凝聚反应制备出明胶颗粒作为悬浮介质，颗粒尺寸为10μm～20μm。在温敏性明胶悬浮介质中打印，打印速度为1mm/s，打印温度为21℃。打印完成后用光照射交联的方式进行整体交联，然后放入培养箱中孵育30分钟，溶出明胶悬浮介质和牺牲墨水，从而得到复合神经纤维和血管的功能化肌肉组织。
其中，整个肌肉纤维束的直径为1000μm～1200μm，单根神经纤维的直径为120μm～150μm，单根肌纤维的直径为100μm～120μm，血管通道的直径为200μm～250μm，肌外膜的厚度为50μm～100μm。培养两周后，对神经纤维进行电场刺激，刺激频率为1Hz，强度为5V/cm，可以观察到整个肌肉组织的同步收缩。

Claims (10)

1.一种构建具有异质功能纤维和血管通道的神经纤维束或肌肉纤维束的方法，包括如下步骤：
S1、根据神经纤维束或肌肉纤维束的血管通道和多级结构设计预定义图案，并依此设置套筒；
S2、在所述套筒内载入分别载有相应细胞的生物墨水，经挤出得到含异质功能纤维和血管通道的神经纤维束或肌肉纤维束；
所述生物墨水为下述1)、3)、4)、5)或2)-4)、6)：
1)载神经来源细胞的生物墨水；
2)载肌肉来源细胞的生物墨水；
3)载基质细胞的生物墨水；
4)载血管生成细胞的牺牲生物墨水；
5)载神经外膜材料的生物墨水；
6)载肌外膜材料的生物墨水。
2.根据权利要求1所述的方法，其特征在于：所述神经纤维束由运动和感觉神经纤维细胞、血管、基质细胞和神经外膜形成；
所述肌肉纤维束由骨骼肌细胞、神经纤维细胞、血管、基质细胞和和肌外膜形成；
所述神经纤维束或所述肌肉纤维束的直径为500μm～2000μm；
所述神经纤维束或所述肌肉纤维束中单根纤维束的直径为50μm～250μm；
所述神经纤维束或所述肌肉纤维束中血管通道的直径为50μm～500μm；
所述神经纤维束或所述肌肉纤维束中神经外膜或肌外膜的厚度为10μm～200μm。
3.根据权利要求1或2所述的方法，其特征在于：所述生物墨水为含细胞的天然高分子水凝胶和/或合成高分子水凝胶。
4.根据权利要求3所述的方法，其特征在于：所述天然高分子水凝胶为透明质酸、纤维蛋白原、海藻酸钠、明胶、胶原、壳聚糖、丝素蛋白、硫酸软骨素、白蛋白以及它们的甲基丙烯酰化产物中的至少一种；
所述合成高分子水凝胶为聚乙二醇、聚丙烯醇、聚乙二醇二丙烯酸酯、聚环氧乙烷、聚丙烯酰胺、聚丙烯酸、聚磷腈、聚N-异丙基丙烯酰胺类水凝胶以及它们的甲基丙烯酰化产物中的至少一种。
5.根据权利要求1-4中任一项所述的方法，其特征在于：所述神经来源细胞由神经细胞和施旺细胞组成；
所述肌肉来源细胞为骨骼肌细胞；
所述基质细胞为神经或肌肉组织中结缔组织细胞；
所述血管生成细胞为内皮细胞以及平滑肌细胞、周细胞和成纤维细胞中的至少一种；
所述神经外膜材料或所述肌外膜材料为细胞外基质材料。
6.根据权利要求1-5中任一项所述的方法，其特征在于：所述生物墨水中细胞的密度为106/mL～108/mL；
所述生物墨水中凝胶材料的质量-体积浓度为10～100mg/mL。
7.根据权利要求1-6中任一项所述的方法，其特征在于：步骤S2中，采用高压气体同步驱动或采用多个注射泵分别驱动所述生物墨水的挤出；
所述高压气体的气动压力为1～100kPa；
所述注射泵的挤出速率为0.01～10mL/h。
8.根据权利要求1-7中任一项所述的方法，其特征在于：所述方法还包括下述步骤A)-B)：
A)将所述神经纤维束或所述肌肉纤维束进行3D打印，构建仿生的神经组织结构或肌肉组织结构；
B)所述3D打印结束后，经整体交联，同时溶出牺牲墨水，即得到具有异质功能纤维和血管通道的神经组织结构或肌肉组织结构。
9.根据权利要求8所述的方法，其特征在于：步骤A)中，在空气中、交联液中或悬浮介质中进行所述3D打印；
所述交联液为氯化钙溶液或凝血酶溶液；
所述悬浮介质为具有自愈合特性的水凝胶材料，具体为超分子自愈合水凝胶和/或微凝胶结构；
在所述悬浮介质中进行所述3D打印时，经所述整体交联后，还包括溶出所述悬浮介质的步骤；
所述悬浮介质的去除方法包括温度变化、摇晃、水洗、酶溶解等方式中至少一种；
步骤B)中，所述整体交联方法包括光照交联、离子交联、温度交联、酶交联和共价交联方式中至少一种；
所述牺牲墨水的牺牲方式为温度变化、pH变化和离子作用中至少一种。
10.权利要求1-9中任一项所述方法构建的具有异质功能纤维和血管通道的纤维束/神经组织结构或肌肉纤维束/肌肉组织结构。
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