Wang Ling, Bai Luge, Wang Sen, Zhou Jiajia, Liu Yingjie, Zhang Chenrui, Yao Siqi, He Jiankang, Liu Chaozong, Li Dichen
State Key Laboratory for Manufacturing System Engineering, School of Mechanical Engineering, Xi'an Jiaotong University, China.
National Medical Products Administration (NMPA) Key Laboratory for Research and Evaluation of Additive Manufacturing Medical Devices, Xi'an Jiaotong University, China.
Mater Today Bio. 2024 Aug 2;28:101176. doi: 10.1016/j.mtbio.2024.101176. eCollection 2024 Oct.
The lack of accurate and reliable brain models hinders the development of brain science and research on brain diseases. Owing to the complex structure of the brain tissue and its highly nonlinear characteristics, the construction of brain-like tissue models remains one of the most challenging research fields in the construction of living tissues. This study proposes a multi-scale design of a brain-like model with a biomimetic cortical structure, which includes the macroscopic structural features of six layers of different cellular components, as well as micrometer-scale continuous fiber structures running through all layers vertically. To achieve integrated biomanufacturing of such a complex multi-scale brain-like model, a multi-material composite printing/culturing integrated bioprinting platform was developed in-house by integrating cell-laden hydrogel ink direct writing printing and electrohydrodynamic fiber 3D printing technologies. Through integrated bioprinting, multi-scale models with different cellular components and fiber structural parameters were prepared to study the effects of macroscopic and microscopic structural features on the directionality of neural cells, as well as the interaction between glial cells and neurons within the tissue model in a three-dimensional manner. The results revealed that the manufactured biomimetic cortical model achieved morphological connections between the layers of neurons, reflecting the structure and cellular morphology of the natural cortex. Micrometer-scale (10 μm) cross-layer fibers effectively guided and controlled the extension length and direction of the neurites of surrounding neural cells but had no significant effect on the migration of neurons. In contrast, glial cells significantly promoted the migration of surrounding PC12 cells towards the glial layer but did not contribute to the extension of neurites. This study provides a basis for the design and manufacture of accurate brain-like models for the functionalization of neuronal tissues.
缺乏准确可靠的脑模型阻碍了脑科学的发展以及脑部疾病的研究。由于脑组织结构复杂且具有高度非线性特征，构建类脑组织模型仍然是活组织构建中最具挑战性的研究领域之一。本研究提出了一种具有仿生皮质结构的类脑模型的多尺度设计，该模型包括六层不同细胞成分的宏观结构特征，以及垂直贯穿所有层的微米级连续纤维结构。为了实现这种复杂多尺度类脑模型的一体化生物制造，通过整合载细胞水凝胶墨水直写打印和电流体动力学纤维3D打印技术，自主研发了一种多材料复合打印/培养一体化生物打印平台。通过一体化生物打印，制备了具有不同细胞成分和纤维结构参数的多尺度模型，以三维方式研究宏观和微观结构特征对神经细胞方向性的影响，以及组织模型内胶质细胞与神经元之间的相互作用。结果表明，制造的仿生皮质模型实现了神经元层之间的形态连接，反映了天然皮质的结构和细胞形态。微米级（10μm）的跨层纤维有效地引导和控制了周围神经细胞神经突的延伸长度和方向，但对神经元的迁移没有显著影响。相比之下，胶质细胞显著促进了周围PC12细胞向胶质层的迁移，但对神经突的延伸没有作用。本研究为设计和制造用于神经元组织功能化的精确类脑模型提供了依据。
