Liu Nian, Zhu Yuanbo, Yu Kang, Gu Zeming, Lv Shang, Chen Yuewei, He Chaofan, Fu Jianzhong, He Yong
State Key Laboratory of Fluid Power and Mechatronic Systems, School of Mechanical Engineering, Zhejiang University, Hangzhou, 310027, China.
Key Laboratory of 3D Printing Process and Equipment of Zhejiang Province, College of Mechanical Engineering, Zhejiang University, Hangzhou, 310027, China.
Adv Healthc Mater. 2023 Feb;12(4):e2201984. doi: 10.1002/adhm.202201984. Epub 2022 Nov 30.
The functional blood-brain barrier (BBB) model can provide a reliable tool for better understanding BBB transport mechanisms and in vitro preclinical experimentation. However, recapitulating microenvironmental complexities and physiological functions in an accessible approach remains a major challenge. Here, a new BBB model with a high-cell spatial density and tightly connected biomimetic minitissue is presented. The minitissue, pivotal functional structure of the BBB model, is fabricated by a novel and easy-to-use liquid substrate culture (LSC) method, which allows cells to self-assemble and self-heal into macrosized, tightly connected membranous minitissue. The minitissue with uniform thickness can be easily harvested in their entirety with extracellular matrix. Attributed to the tightly connected minitissue formed by LSC, the fabricated BBB biomimetic model has 1 to 2 orders of magnitude higher transendothelial electric resistance than the commonly reported BBB model. It also better prevents the transmission of large molecular substances, recapitulating the functional features of BBB. Furthermore, the BBB biomimetic model provides feedback regarding BBB-destructive drugs, exhibits selective transmission, and shows efflux pump activity. Overall, this model can serve as an accessible tool for life science or clinical medical researchers to enhance the understanding of human BBB and expedite the development of new brain-permeable drugs.
功能性血脑屏障（BBB）模型可为更好地理解血脑屏障转运机制和体外临床前实验提供可靠工具。然而，以一种可及的方式重现微环境复杂性和生理功能仍然是一项重大挑战。在此，我们提出了一种具有高细胞空间密度和紧密连接的仿生微组织的新型血脑屏障模型。该微组织是血脑屏障模型的关键功能结构，通过一种新颖且易于使用的液体底物培养（LSC）方法构建而成，该方法允许细胞自组装并自我修复成宏观尺寸、紧密连接的膜状微组织。具有均匀厚度的微组织可轻松与细胞外基质一起完整收获。由于LSC形成的紧密连接微组织，所构建的血脑屏障仿生模型的跨内皮电阻比通常报道的血脑屏障模型高1至2个数量级。它还能更好地阻止大分子物质的传输，重现血脑屏障的功能特征。此外，血脑屏障仿生模型可提供有关破坏血脑屏障药物的反馈，表现出选择性传输，并具有外排泵活性。总体而言，该模型可作为生命科学或临床医学研究人员增强对人类血脑屏障理解并加速新型脑渗透性药物开发的可及工具。
