CN115154674A - 一种基于类骨器官的3d生物打印类骨组织工程支架 - Google Patents
一种基于类骨器官的3d生物打印类骨组织工程支架 Download PDFInfo
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Abstract
本发明属于骨缺损支架技术领域，公开了一种基于类骨器官的3D生物打印类骨组织工程支架，包括壳体，壳体内填充有骨类器官微球，壳体外侧设有人工仿生骨膜，人工仿生骨膜包括左旋聚乳酸、透明质酸HA、血管内皮生长因子、I型胶原、聚已内酯PCL、胶原蛋白和纳米羟基磷灰石，壳体两端连接有固定块，壳体的内侧开设有末端，末端连接有骨类器官填充腔，骨类器官填充腔的空腔直径为500～1000微米，骨类器官填充腔中填充体外培养的骨类器官微球，上下两个骨类器官填充腔之间连接有微通道，仿生支架通过多喷头3D打印机一体化打印成型；本发明解决了当前骨组织工程支架修复大段骨缺损效果不佳的难题，适用于构建基于骨类器官的骨缺损修复支架。
Description
技术领域
本发明属于骨缺损支架技术领域，具体涉及一种基于类骨器官的3D生物打印类骨组织工程支架。
背景技术
骨缺损是骨科常见病。骨缺损长度在一定范围内时骨组织可自行修复重建，但是当超过该范围后无法自行愈合，即为临界骨缺损。目前临床上将临界骨缺损的长度定为长骨直径的1.5倍，约为1.5～3.0cm。全世界每年因严重的创伤、骨折合并感染、骨折后治疗不当、骨肿瘤或先天性疾病导致的骨缺损患者，需骨移植治疗的超过200万例，其中因移植物血管化及功能化性能不佳引起手术失败率25％，并发症发生率30％～60％。骨缺损伤员救治困难、花费高，给个人、家庭和社会带来沉重的负担。
临界尺寸骨缺损修复是骨科医师面临的棘手临床难题。目前临界尺寸骨缺损治疗的金标准是自体骨移植。然而，供区骨组织数量有限，术后供区骨缺损、疼痛、感染等多种并发症严重限制了自体骨移植的推广应用。特别是在临界尺寸骨缺损的修复中，移植物血管化不足易导致死骨形成、肢体功能难以恢复。因此，研发具有良好血管化及功能化的骨替代材料是国内外研究的热点。
近年来，应用类器官技术构建成骨支架修复大段骨缺损成为热点。对于成骨支架的构建而言，快速、精确和功能化十分重要。但目前类器官构建还存在诸多问题：例如类器官形态及组成的可控性差；同批次类器官个体之间，以及不同批次类器官样本之间均存在显著差异；建模周期长(培养周期需要4-6周)，而且建模过程缺乏自动化操控，耗时费力。因此，应用3D生物打印技术，有望实现类器官的批量自动化稳定构建，进而制备更为有效的成骨支架，解决大段骨缺损修复难题。
发明内容
本发明提供了一种基于类骨器官的3D生物打印类骨组织工程支架，解决了当前骨组织工程支架修复大段骨缺损效果不佳的难题。
为解决上述技术问题，本发明技术方案如下：
一种基于类骨器官的3D生物打印类骨组织工程支架，包括壳体，所述壳体内填充骨类器官微球，所述壳体外侧设有人工仿生骨膜，所述壳体的上下端均开有末端，所述壳体内设有若干条微通道，所述微通道的上下两端均内连通有骨类器官充腔，所述骨类器官充腔的自由端与末端相连通，所述仿生支架通过多喷头3D打印机一体化打印成型。
本发明技术方案的原理如下：
壳体具有散在贯通孔径，可以方便内部骨类器官的氧气、营养物质与代谢物质交换，末端具有宏观孔径结构，方便自体血管及新鲜骨组织长入，微通道用于氧气、营养物质与代谢物质交换，骨类器官充腔的作用是容纳骨类器官微球。采用本设计方案，当大段骨缺损的患者需要进行修复时，先采集患者数据，用3D打印技术制备出本发明类骨器官仿生支架，然后将类骨器官仿生支架安装在患者的骨缺损处，仿生支架内部的骨类器官充腔可通过末端、微通道骨类器官充腔和末端与患者骨组织进行能量、物质及信号传递，从而促进骨组织的再生，进行骨修复。
进一步地，所述壳体的两端均设有固定块。
通过上述设置，通过固定块进行髓内插入，增强仿生支架与骨缺损处的连接稳定性。
进一步地，所述人工仿生骨膜的制作原料为左旋聚乳酸、透明质酸HA、血管内皮生长因子、I型胶原、聚已内酯PCL、胶原蛋白和纳米羟基磷灰石。
通过上述设置，骨膜具有适宜的孔隙结构，利于骨细胞生长和骨组织修复，工艺简单，易于转化。
进一步地，所述骨类器官充腔中填充体外培养的骨类器官微球，所述骨类器官充腔的空腔直径为500～1000微米，所述微通道内填充有内皮细胞。
通过上述设置，类骨器官可在体外自发地组装成能够修复骨缺损的大段骨组织，其再生骨的形态特征与天然胫骨相似，骨组织通过骨类器官充腔的细胞在支架上迁移、增殖，其充腔有利于氧气、营养和促生长因子(例如激素等)的运输传递，从而促进骨组织生长，利于血管化及骨修复。
进一步地，所述骨类器官充腔的获取方式为：先将人骨膜源干性细胞在体外培养成为干细胞球，然后将干细胞球打印至支架上，继续进行培养生长得到微细胞组织，接着将支架上的微细胞组织进行皮下植入，评估培养得到的微细胞组织在体内成熟成骨能力，最后选择具有在体内成熟成骨能力的微细胞组织合成骨类器官充腔。
通过上述设置，得到骨类器官充腔的微细胞组织在体内能够成熟成骨，有益于骨细胞的生长和骨组织修复等。
进一步地，评估培养微细胞组织的成熟成骨能力的方法为：利用免疫缺陷小鼠实验，在免疫缺陷小鼠中植入琼脂糖微孔平台，确保微细胞组织保持在微孔内，异位植入四周后，利用纳米计算机断层扫描，扫描显示形成了不同的矿化球体，这些微细胞组织在体内形成骨微器官，证实这些植入物在体内表现为单个半自主骨形成模块，充当愈伤组织类器官，具备体内成熟成骨的能力。
通过上述设置，利用小鼠实验，实验的经济性好，可靠性高。
本发明的有益效果：
(1)本发明一种基于类骨器官的3D生物打印类骨组织工程支架，设有壳体、骨膜和骨类器官充腔，壳体、骨膜和骨类器官充腔分别用不同的方法3D打印而成，可与患者的骨缺损部位充分接触，稳定性更好、适配效果更佳；本发明设有微通道、末端和充腔，可使移植物血管化，可使内皮祖细胞在支架上迁移、增殖，从而稳定地传输氧气、营养和促生长因子，促进骨组织生长。
(2)本发明一种基于类骨器官的3D生物打印类骨组织工程支架，通过3D逐层打印的方式克服了传统支架制造方法在结构复杂性和空间异质性上的限制；3D生物打印克服了支架制造－细胞接种方法的弊端，将细胞在打印过程中直接封装在支架内，即同时将生物材料和细胞沉积到设计的位置，可高通量制造，并对细胞进行精准控制。
附图说明
图1为本发明一种基于类骨器官的3D生物打印类骨组织工程支架的结构示意图；
图2为本发明一种基于类骨器官的3D生物打印类骨组织工程支架的正剖图；
图3为图2中A-A处的剖视图；
附图中标记如下所示：
壳体1、人工仿生骨膜2、末端3、微通道4、骨类器官充腔5、固定块6。
具体实施方式
下面结合附图和具体实施方式对本发明作进一步详细的说明：
如图1至图3所示，一种基于类骨器官的3D生物打印类骨组织工程支架，包括壳体1，壳体1内填充骨类器官微球，壳体1外侧设有人工仿生骨膜2，壳体1上下两端的外侧均连接有固定块6，壳体1上下端的内侧均开设有多个末端3，多个末端3远离壳体1端面的一侧均连接有骨类器官充腔5，骨类器官充腔5内设有多个直径为500～1000微米的空腔，上下两端的骨类器官充腔5之间均连接有微通道4，仿生支架通过多喷头3D打印机一体化打印成型。
其中，人工仿生骨膜2的制作原料为左旋聚乳酸、透明质酸HA、血管内皮生长因子、I型胶原、聚已内酯PCL、胶原蛋白和纳米羟基磷灰石；骨类器官充腔5中填充体外培养的骨类器官微球；骨类器官充腔5的获取方式为：先将人骨膜源干性细胞在体外培养成为干细胞球，然后将干细胞球打印至支架上，继续进行培养生长得到微细胞组织，接着将支架上的微细胞组织进行皮下植入，评估培养得到的微细胞组织在体内成熟成骨能力，最后选择具有在体内成熟成骨能力的微细胞组织合成骨类器官充腔5。其中，评估培养微细胞组织的成熟成骨能力的方法为：利用免疫缺陷小鼠实验，在免疫缺陷小鼠中植入琼脂糖微孔平台，确保微细胞组织保持在微孔内，异位植入四周后，利用纳米计算机断层扫描，扫描显示形成了不同的矿化球体，这些微细胞组织在体内形成骨微器官，证实这些植入物在体内表现为单个半自主骨形成模块，充当愈伤组织类器官，具备体内成熟成骨的能力。
具体实施过程如下：
当大段骨缺损的患者需要进行骨修复时，先采集患者数据，然后准备仿生支架各组件所需的各类组织细胞，之后用3D打印技术制备出适合患者的类骨器官仿生支架，先在体外利用末端3的宏观孔径结构，长入血管及新鲜骨组织，直至各种新鲜骨组织长入另一侧骨类器官充腔5处后，接着安装仿生支架，将仿生支架两端的固定块6插入患者缺损部位两侧的骨髓处，然后在仿生支架表面铺设钢板，作进一步固定后，再次通过末端3长入新鲜骨组织，直至另一测末端3，最后利用具备体内成熟成骨能力的微细胞组织完成骨细胞的生长和骨组织修复。
以上所述的仅是本发明的实施例，方案中公知的具体结构及特性等常识在此未作过多描述。应当指出，对于本领域的技术人员来说，在不脱离本发明结构的前提下，还可以作出若干变形和改进，这些也应该视为本发明的保护范围，这些都不会影响本发明实施的效果和专利的实用性。本申请要求的保护范围应当以其权利要求的内容为准，说明书中的具体实施方式等记载可以用于解释权利要求的内容。
Claims (6)
1.一种基于类骨器官的3D生物打印类骨组织工程支架，其特征在于：包括壳体，所述壳体内侧填充有骨类器官微球，所述壳体外侧设有人工仿生骨膜，所述壳体的上下端均开有末端，所述壳体内设有若干条微通道，所述微通道的上下两端的内侧均连通有骨类器官充腔，所述骨类器官充腔的自由端与末端相连通，所述仿生支架通过多喷头3D打印机一体化打印成型。
2.根据权利要求1所述的一种基于类骨器官的3D生物打印类骨组织工程支架，其特征在于：所述壳体的两端均设有固定块。
3.根据权利要求1所述的一种基于类骨器官的3D生物打印类骨组织工程支架，其特征在于：所述人工仿生骨膜的制作原料为左旋聚乳酸、透明质酸HA、血管内皮生长因子、I型胶原、聚已内酯PCL、胶原蛋白和纳米羟基磷灰石。
4.根据权利要求3所述的一种基于类骨器官的3D生物打印类骨组织工程支架，其特征在于：所述骨类器官充腔中填充体外培养的骨类器官微球，所述骨类器官充腔的空腔直径为500～1000微米，所述微通道内填充有内皮细胞。
5.根据权利要求4所述的一种基于类骨器官的3D生物打印类骨组织工程支架，其特征在于：所述骨类器官充腔的获取方式为：先将人骨膜源干性细胞在体外培养成为干细胞球，然后将干细胞球打印至支架上，继续进行培养生长得到微细胞组织，接着将支架上的微细胞组织进行皮下植入，评估培养得到的微细胞组织在体内成熟成骨能力，最后选择具有在体内成熟成骨能力的微细胞组织合成骨类器官充腔。
6.根据权利要求5所述的一种基于类骨器官的3D生物打印类骨组织工程支架，其特征在于：评估培养微细胞组织的成熟成骨能力的方法为：利用免疫缺陷小鼠实验，在免疫缺陷小鼠中植入琼脂糖微孔平台，确保微细胞组织保持在微孔内，异位植入四周后，利用纳米计算机断层扫描，扫描显示形成了不同的矿化球体，这些微细胞组织在体内形成骨微器官，证实这些植入物在体内表现为单个半自主骨形成模块，充当愈伤组织类器官，具备体内成熟成骨的能力。
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