微流控血脑屏障器官芯片系统的构建及评估应用

doi:10.6023/A25110381

综述

微流控血脑屏障器官芯片系统的构建及评估应用

王玉珍^a, 常亚冉^a,b,*, 郭广生^a, 汪夏燕^a,*

^a北京工业大学化学与生命科学学院化学系材料循环低碳再生全国重点实验室环境安全与生物效应卓越中心北京 100124;
^b北京大学材料科学与工程学院北京 100871

投稿日期:2025-11-24
通讯作者: *E-mail: yaranchang@pku.edu.cn; xiayanwang@bjut.edu.cn
作者简介:王玉珍, 就读于北京工业大学化学与生命科学学院, 2023级化学专业硕士. 主要研究方向为血脑屏障芯片构建及应用. 常亚冉, 博士, 北京大学材料科学与工程学院博士后, 2024年毕业于北京工业大学, 获得工学博士学位, 主要研究方向为微流控芯片的构建与应用. 郭广生, 博士, 北京工业大学化学与生命科学学院教授, 国务院特殊津贴获得者、北京市首批战略科技人才. 研究方向包括微流控芯片系统的构建与应用、微纳尺度分离分析和新型微纳分析仪器研制等. 汪夏燕, 博士, 北京工业大学化学与生命科学学院教授, 国家杰出青年科学基金获得者、国家“万人计划”科技创新领军人才、国务院特殊津贴获得者、北京市优秀教师. 研究方向包括微流控芯片系统的构建与应用、微纳尺度分离分析、单细胞分析和新型微纳分析仪器研制等.
基金资助:
国家自然科学基金((Nos. 22327805, 22476223)和北京市卓越青年科学家项目(BJJWZYJH01201910005017)资助.

Construction and Evaluation of Microfluidic Blood-Brain Barrier Organ-on-Chips System

Wang Yuzhen^a, Chang Yaran^a,b,*, Guo Guangsheng^a, Wang Xiayan^a,*

^aCenter of Excellence for Environmental Safety and Biological Effects, State Key Laboratory of Materials Low-Carbon Recycling, Department of Chemistry, College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China;
^bSchool of Materials Science and Technology, Peking University, Beijing 100871, China

Received:2025-11-24
Supported by:
National Natural Science Foundation of China (Nos. 22327805, 22476223) and the Beijing Outstanding Young Scientist Program (BJJWZYJH01201910005017).

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摘要/Abstract

血脑屏障是维持中枢神经系统稳态的关键生理结构, 其高度选择性在保护脑组织免受外源性物质侵害的同时, 也严重限制了治疗药物的脑内递送. 目前, 对血脑屏障生理功能的认识仍较为有限, 主要归因于缺乏能够准确模拟其复杂结构与功能的体外模型. 近年来, 微流控技术凭借其在微尺度流体操控、多细胞共培养及仿生微环境构建等方面的优势, 已成为开发高仿生血脑屏障模型的重要平台. 本文系统综述了基于微流控血脑屏障器官芯片系统在芯片设计、流体驱动及细胞来源等方面的研究进展, 总结了常用的屏障完整性评估方法, 包括跨内皮细胞电阻测量、通透性检测及特异性蛋白表达分析, 并讨论了该技术当前面临的挑战与未来发展方向.

关键词: 微流控技术, 器官芯片, 血脑屏障, 血脑屏障器官芯片, 体外模型

The blood-brain barrier (BBB) serves as a crucial physiological structure that maintains homeostasis within the central nervous system. While its highly selective permeability protects the brain from exogenous substances, it also hinders the delivery of therapeutic agents. The current understanding of the physiological functions of the BBB remains relatively limited, primarily due to the absence of reliable in vitro models capable of accurately replicating its complex architecture and functionality. In recent years, microfluidic technology has emerged as a pivotal platform for developing highly biomimetic BBB models, capitalizing on its distinctive advantages in microscale fluid manipulation, establishment of multicellular co-culture systems, and reconstruction of physiologically relevant microenvironments. This review systematically summarizes recent advances in microfluidic BBB-on-a-chip systems, with particular focus on three key aspects: chip design configurations, fluid driving mechanisms, and cellular source selection. In terms of chip architecture, the discussion encompasses various structural designs, including sandwich-structured design, parallel channel design, three-dimensional tubular design, and angiogenic design. Regarding fluid propulsion methods, the analysis covers both pump-driven systems and gravity-driven approaches. The examination of cellular sources includes immortalized cell lines, primary cell isolates, and stem cell-derived endothelial populations. Furthermore, the review comprehensively outlines established methodologies for evaluating barrier integrity and function. These assessment techniques include measuring transendothelial electrical resistance, performing permeability assays with molecular tracers, and analyzing the expression of tight junction proteins and specialized transporters. The review concludes by addressing the current challenges confronting microfluidic BBB technology and proposing strategic directions for future development. These perspectives include enhancing model biomimicry through the incorporation of additional neurovascular unit components, promoting technical standardization to ensure experimental reproducibility and comparability, developing personalized diagnostic and therapeutic models through integration of patient-specific cells, and exploring innovative applications through synergistic combination with artificial intelligence technologies. This comprehensive analysis aims to provide valuable guidance for researchers working at the intersection of biomedical engineering, neuroscience, and pharmaceutical development.

Key words: microfluidics, organ-on-a-chip, blood-brain barrier, BBB organ-on-chips, in vitro models

引用此文

王玉珍, 常亚冉, 郭广生, 汪夏燕. 微流控血脑屏障器官芯片系统的构建及评估应用[J]. 化学学报, doi: 10.6023/A25110381.

Wang Yuzhen, Chang Yaran, Guo Guangsheng, Wang Xiayan. Construction and Evaluation of Microfluidic Blood-Brain Barrier Organ-on-Chips System[J]. Acta Chimica Sinica, doi: 10.6023/A25110381.

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参考文献

[1] Chen T.; Dai Y.; Hu C.; Lin Z.; Wang S.; Yang J.; Zeng L.; Li S.; Li W.Fluids Barriers CNS 2024, 21, 60.
[2] Lacoste B.; Prat A.; Freitas-Andrade, M.; Gu, C.Cold Spring Harbor Perspect. Biol. 2025, 7, a020412.
[3] Vetter J.; Palagi I.; Waisman A.; Blaeser A.Acta Biomater. 2025, 197, 1.
[4] Peng B.; Hao S.; Tong Z.; Bai H.; Pan S.; Lim K. L.; Li L.; Voelcker N. H.; Huang W.Lab Chip 2022, 22, 3579.
[5] Shi S. M.; Suh R. J.; Shon D. J.; Garcia F. J.; Buff J. K.; Atkins M.; Li L.; Lu N.; Sun B.; Luo J.; To N.-S.; Cheung T. H.; McNerney, M. W.; Heiman, M.; Bertozzi, C. R.; Wyss-Coray, T.Nature 2025, 639, 985.
[6] Ding S.; Khan A. I.; Cai X.; Song Y.; Lyu Z.; Du D.; Dutta P.; Lin Y.Mater. Today 2020, 37, 112.
[7] Wu D.; Chen Q.; Chen X.; Han F.; Chen Z.; Wang Y.Signal Transduct. Target. Ther. 2023, 8, 217.
[8] Nehra G.; Bauer B.; Hartz A. M.S.Pharmacol. Ther. 2022, 234, 108119.
[9] Huang X.; Wei P.; Fang C.; Yu M.; Yang S.; Qiu L.; Wang Y.; Xu A.; Hoo R. L.C.; Chang, J.J. Neuroinflamm. 2024, 21, 265.
[10] Pfau S. J.; Langen U. H.; Fisher T. M.; Prakash I.; Nagpurwala F.; Lozoya R. A.; Lee W.-C.A.; Wu, Z.; Gu, C.Nat. Neurosci. 2024, 27, 1892.
[11] da Silva, G. G.; Sacomani, D. P.; de Carvalho, B. G.; Porcionatto, M. A.; Gobbi, A.; Lima, R. S.; de la Torre, L. G.ACS Biomater. Sci. Eng. 2025, 11, 3789.
[12] Deli M. A.; Porkoláb G.; Kincses A.; Mészáros M.; Szecskó A.; Kocsis A. E.; Vigh J. P.; Valkai S.; Veszelka S.; Walter F. R.; Dér A. Lab Chip 2024, 24, 1030.
[13] Choi J. W.; Kim K.; Mukhambetiyar K.; Lee N. K.; Sabate Del Rio, J.; Joo, J.; Park, C. G.; Kwon, T.; Park, T. E. ACS Nano 2024, 18, 14388.
[14] Zhang X.; Chen S.; Fang, J. Prog. Biochem. Biophys.2026, 53, 223 (in Chinese).
(张雪桐, 陈铄, 方瑾, 生物化学与生物物理进展, 2026, 53, 223.)
[15] Zou R.; Shi Z.; Li C.; Xu F.; Zheng X.; Du X.; Huang X.; Qiu B.; Ding W. Bio-Des. Manuf.2025, 8, 639.
[16] Thorsen T.; Maerkl S. J.; Quake S. R. Science2002, 298, 580.
[17] Li S.; Liu Y.; Yang D.Acta Chim. Sinica 2025, 83, 428 (in Chinese).
(李帅, 刘亚婷, 仰大勇, 化学学报, 2025, 83, 428.)
[18] Chu X.; Zhang L.; M, Q.; Yin, Y.; Xi, G.; Wang, Y.; Zhou, L.; Liu, J.; Li, Q.; Tao, S.Chem. Ind. Eng. Prog. 2026, DOI: 10.16085/j.issn.1000-6613.2025-1100 (in Chinese).
(初向南, 张兰岐, 马起, 殷玉龙, 习国才, 王有福, 周李宸, 刘建行, 李晴, 陶胜洋, 化工进展, 2026, DOI: 10.16085/j.issn.1000-6613.2025-1100.)
[19] Ying-Jin, S.; Yuste, I.; González-Burgos, E.; Serrano, D. R.Bioprinting 2025, 46, e00394.
[20] Yuan H.; Song G.; Qi, X; Zhang Y.; Chen L.; Xiang N.; Wang, Q. Chin. J. Biotechnol.2025, 41, 4004 (in Chinese).
(袁会领, 宋国田, 齐显尼, 张媛媛, 陈李, 项楠, 王钦宏, 生物工程学报, 2025, 41, 4004.)
[21] Zhou C.; Li Z.; Xu J.; Yu D.; Xuan L.; Wang X. Bio-Des. Manuf.2025, 8, 930.
[22] Kim J.; Yoon T.; Lee S.; Kim P. J.; Kim Y.Lab Chip 2024, 24, 3347.
[23] Caragnano G.; Monteduro A. G.; Rizzato S.; Giannelli G.; Maruccio G.Biosensors 2025, 15, 338.
[24] Booth R.; Kim, H. Lab Chip 2012, 12,1784.
[25] Park T.-E.; Mustafaoglu N.; Herland A.; Hasselkus R.; Mannix R.; FitzGerald, E. A.; Prantil-Baun, R.; Watters, A.; Henry, O.; Benz, M.; Sanchez, H.; Ingber, D. E.; Park, T.-E.; Herland, A.; Herland, A.; Mannix, R.; Ingber, D. E.; McCrea, H. J.; Goumnerova, L. C.; Song, H. W.; Palecek, S. P.; Shusta, E.; Ingber, D. E.Nat. Commun. 2019, 10, 2621.
[26] Maoz B. M.; Herland A.; FitzGerald, E. A.; Grevesse, T.; Vidoudez, C.; Pacheco, A. R.; Sheehy, S. P.; Park, T.-E.; Dauth, S.; Mannix, R.; Budnik, N.; Shores, K.; Cho, A.; Nawroth, J. C.; Segre, D.; Budnik, B.; Ingber, D. E.; Parker, K. K.Nat. Biotechnol. 2018, 36, 865.
[27] Wang P.; Jin L.; Zhang M.; Wu Y.; Duan Z.; Guo Y.; Wang C.; Guo Y.; Chen W.; Liao Z.; Wang Y.; Lai R.; Lee L. P.; Qin J.Nat. Biomed. Eng. 2024, 8, 1053.
[28] Ahn S. I.; Sei Y. J.; Park H. J.; Kim J.; Ryu Y.; Choi J. J.; Sung H. J.; MacDonald, T. J.; Levey, A. I.; Kim, Y.Nat. Commun. 2020, 11, 175.
[29] Zhang M.; Wang P.; Wu Y.; Jin L.; Liu J.; Deng P.; Luo R.; Chen X.; Zhao M.; Zhang X.; Guo Y.; Yan Y.; Di Y.; Qin J.Nat. Commun. 2025, 16, 3701.
[30] Deosarkar S. P.; Prabhakarpandian B.; Wang B.; Sheffield J. B.; Krynska B.; Kiani M. F.PLoS One 2015, 10, e0142725.
[31] Adriani G.; Ma D.; Pavesi A.; Kamm R. D.; Goh E. L.Lab Chip 2017, 17, 448.
[32] Xu H.; Li Z.; Yu Y.; Sizdahkhani S.; Ho W. S.; Yin F.; Wang L.; Zhu G.; Zhang M.; Jiang L.; Zhuang Z.; Qin J.Sci. Rep. 2016, 6, 36670.
[33] Wevers N. R.; Kasi D. G.; Gray T.; Wilschut K. J.; Smith B.; Vught, R. v.; Shimizu, F.; Sano, Y.; Kanda, T.; Marsh, G.; Trietsch, S. J.; Vulto, P.; Lanz, H. L.; Obermeier, B.Fluids Barriers CNS 2018, 15, 23.
[34] Oddo A.; Peng B.; Tong Z.; Wei Y.; Tong W. Y.; Thissen H.; Voelcker N. H.Trends Biotechnol. 2019, 37, 1295.
[35] Kappings V.; Grün C.; Ivannikov D.; Hebeiss I.; Kattge S.; Wendland I.; Rapp B. E.; Hettel M.; Deutschmann O.; Schepers U.Adv. Mater. Technol. 2018, 3, 1700246.
[36] Kim J. A.; Kim H. N.; Im S. K.; Chung S.; Kang J. Y.; Choi N.Biomicrofluidics 2015, 9, 024115.
[37] Partyka P. P.; Godsey G. A.; Galie J. R.; Kosciuk M. C.; Acharya N. K.; Nagele R. G.; Galie P. A.Biomaterials 2017, 115, 30.
[38] Li Y.; Fu B. M.Cells 2025, 14, 456.
[39] Herland A.; van der Meer, A. D.; FitzGerald, E. A.; Park, T.-E.; Sleeboom, J. J. F.; Ingber, D. E.PLoS One 2016, 11, e0150360.
[40] Yu F.; Kumar N. D.O. S.; Foo, L. C.; Ng, S. H.; Hunziker, W.; Choudhury, D.Biotechnol. Bioeng. 2020, 117, 1127.
[41] Yue H.; Xie K.; Ji X.; Xu B.; Wang C.; Shi P.Biomaterials 2020, 245, 119980.
[42] Galpayage Dona, K. N. U.; Ramirez, S. H.; Andrews, A. M.Bioengineering 2023, 10, 817.
[43] Paone L.S.; Benmassaoud M. M.; Curran A.; Vega S. L.; Galie, P. A.Biofabrication 2024, 16, 015005.
[44] Bell R. D.; Zlokovic B. V.Acta Neuropathol. 2009, 118, 103.
[45] Lee S. W.L.; Campisi, M.; Osaki, T.; Possenti, L.; Mattu, C.; Adriani, G.; Kamm, R. D.; Chiono, V.Adv. Healthc. Mater. 2020, 9, 1901486.
[46] Phan D. T.T.; Bender, R. H. F.; Andrejecsk, J. W.; Sobrino, A.; Hachey, S. J.; George, S. C.; Hughes, C. C. W.Exp. Biol. Med. 2017, 242, 1669.
[47] Hajal C.; Offeddu G. S.; Shin Y.; Zhang S.; Morozova O.; Hickman D.; Knutson C. G.; Kamm R. D.Nat. Protoc. 2022, 17, 95.
[48] Wang F.; Zhao L.; Guo G.; Wang X. Prog. Chem.2024, 36, 840 (in Chinese).
(王芳田, 赵亮, 郭广生, 汪夏燕, 化学进展, 2024, 36, 840.)
[49] Bang S.; Lee S. R.; Ko J.; Son K.; Tahk D.; Ahn J.; Im C.; Jeon N. L.Sci. Rep. 2017, 7, 8083.
[50] Campisi M.; Shin Y.; Osaki T.; Hajal C.; Chiono V.; Kamm R. D.Biomaterials 2018, 180, 117.
[51] Winkelman M. A.; Kim D. Y.; Kakarla S.; Grath A.; Silvia N.; Dai G.Lab Chip 2022, 22, 170.
[52] Jiang L.; Xu S. J. Bryol.2025, 42, 80 (in Chinese).
(江林, 徐索文, 生物学杂志, 2025, 42, 80.)
[53] Davies, P. F. Physiol. Rev. 1995, 75, 519.
[54] Koutsiaris A. G.; Tachmitzi S. V.; Batis N.Microvasc. Res. 2013, 85, 34.
[55] Chavarria D.; Abbaspour A.; Celestino N.; Shah N.; Sankar S.; Baker A. B.Biomicrofluidics 2023, 17, 044105.
[56] Eigenmann D.E.; Xue G.; Kim K. S.; Moses A. V.; Hamburger M.; Oufir, M.Fluids Barriers CNS 2013, 10, 33.
[57] Deli M. A.; Papademetriou I.; Vedula E.; Charest J.; Porter T.PLoS One 2018, 13, e0205158.
[58] Mazhar N.; Islam M. S.; Raza M. Z.; Mahin S. M.K. H.; Islam, M. R.; Chowdhury, M. E. H.; Al-Ali, A.; Agouni, A.; Yalcin, H. C.Bioengineering 2024, 11, 1116.
[59] Guarino V.; Perrone E.; De Luca, E.; Rainer, A.; Cesaria, M.; Zizzari, A.; Bianco, M.; Gigli, G.; Moroni, L.; Arima, V.Adv. Healthc. Mater. 2025, 14, e2401804.
[60] Walter F. R.; Valkai S.; Kincses A.; Petneházi A.; Czeller T.; Veszelka S.; Ormos P.; Deli M. A.; Dér, A. Sens. Actuators B2016, 222, 1209.
[61] Iakovlev A. P.; Erofeev A. S.; Gorelkin P. V.Biosensors 2022, 12, 956.
[62] Ma H. L.; Urbaczek A. C.; Zeferino Ribeiro de Souza, F.; Bernal, C.; Rodrigues Perussi, J.; Carrilho, E.Int. J. Pharm. 2023, 634, 122629.
[63] Wang W.; Cui J.; Guo Y.; Kang X.; Liu H.; Hao Z. Lab Chip2025, 25, 6504.
[64] Birtek M. T.; Atceken N.; Tasoglu S.Lab Chip 2025, 25, 5506.
[65] Yang H., Ma Y., Li Z., Zhang J.Acta Chim. Sinica 2025, DOI: 10.6023/A25070250 (in Chinese).
(杨皓琛, 马颖超, 李自远, 张隽佶, 化学学报, 2025, DOI: 10.6023/A25070250.)
[66] Hirth E.; Cao W.; Peltonen M.; Kapetanovic E.; Dietsche C.; Svanberg S.; Filippova M.; Reddy S.; Dittrich P. S.Lab Chip 2024, 24, 292.
[67] Zhang X.; Bao Y.; Liu Y.; Pei Y.; Oseyemi A. E.; Lv F.; Hibara, A. Sens. Actuator A-Phys.2025, 396, 117182.
[68] Martier A.; Chen Z.; Schaps H.; Mondrinos M. J.; Fang J. S.Front. Physiol. 2024, 15, 1425618.
[69] Li M.; Zhong Y.; Zhu M.; Pang C.; Xiao L.; Bu Y.; Li H.; Diao Y.; Yang C.; Liu D.Analyst 2024, 149, 3980.
[70] Kim J.; Lee K. T.; Lee J. S.; Shin J.; Cui B.; Yang K.; Choi Y. S.; Choi N.; Lee S. H.; Lee J. H.; Bahn Y. S.; Cho S. W.Nat. Biomed. Eng. 2021, 5, 830.
[71] Wang, P.; Liu, J.; Zhang, M.; Yang, J.; Lian, P.; Cheng, X.; Qin, J. Adv. Sci (Weinh). 2025, 12, e02356.
[72] Lino M.; Persson H.; Paknahad M.; Ugodnikov, A. Farhang Ghahremani, M.; Takeuchi L. E.; Chebotarev O.; Horst C.; Simmons, C. A. Lab Chip2025, 25, 1489.
[73] Wei W.; Cardes F.; Hierlemann A.; Modena M. M.Adv. Sci. 2023, 10, e2205752.
[74] Tricinci O.;De Pasquale, D.; Marino, A.; Battaglini, M.; Pucci, C.; Ciofani, G.Adv. Mater. Technol. 2020, 5, e2000540.
[75] Palma-Florez, S.; Lopez-Canosa, A.; Moralez-Zavala, F.; Castano, O.; Kogan, M. J.; Samitier, J.; Lagunas, A.; Mir, M.J. Nanobiotechnol. 2023, 21, 115.
[76] Prabhakarpandian B.; Shen M. C.; Nichols J. B.; Mills I. R.; Sidoryk-Wegrzynowicz, M.; Aschner, M.; Pant, K.Lab Chip 2013, 13, 1093.
[77] Sticker D.; Rothbauer M.; Ehgartner J.; Steininger C.; Liske O.; Liska R.; Neuhaus W.; Mayr T.; Haraldsson T.; Kutter J. P.; Ertl P.ACS Appl. Mater. Interfaces 2019, 11, 9730.
[78] Sellgren K. L.; Hawkins B. T.; Grego S.Biomicrofluidics 2015, 9, 061102.
[79] Bryan T. M.; Reddel R. R.Crit Rev Oncog. 1994, 5, 331.
[80] Nair A. L.; Groenendijk L.; Overdevest R.; Fowke T. M.; Annida R.; Mocellin O.; de Vries, H. E.; Wevers, N. R.Front. Molec. Neurosci. 2023, 16, 1250123.
[81] Cerneckis J.; Cai H.; Shi Y.Signal Transduct. Target. Ther. 2024, 9, 112.
[82] Vatine G. D.; Barrile R.; Workman M. J.; Sances S.; Barriga B. K.; Rahnama M.; Barthakur S.; Kasendra M.; Lucchesi C.; Kerns J.; Wen N.; Spivia W. R.; Chen Z.; Van Eyk, J.; Svendsen, C. N.Cell Stem Cell 2019, 24, 995.
[83] Brown J. A.; Faley S. L.; Judge M.; Ward P.; Ihrie R. A.; Carson R.; Armstrong L.; Sahin M.; Wikswo J. P.; Ess K. C.; Neely M. D.J. Neurodev. Disord. 2024, 16, 27.
[84] Holzreuter M. A.; Segerink L. I.Lab Chip 2024, 24, 1121.
[85] Wang Y. I.; Abaci H. E.; Shuler M. L.Biotechnol. Bioeng. 2017, 114, 184.
[86] Chang Y.; Chen T.; Geng S.; Wang Y.; Zhang W.; Hu Q.; Zhao Y.; Pu Q.; Liu Z.; Guo G.; Wang X.Anal. Chem. 2025, 97, 3816.
[87] Ceccarelli M. C.; Lefevre M. C.; Marino A.; Pignatelli F.; Krukiewicz K.; Battaglini M.; Ciofani G.Lab Chip 2024, 24, 5085.
[88] Sun J.; Song S.Microfluid. Nanofluid. 2024, 28, 44.
[89] Liang J.; Qi H.; Zhu F.; Chen S.; Liu B.; Sun C.; Wang Y.Sens. Actuators B 2024, 408, 135567.
[90] Zeng Y.-L.; Du Y.; Xu X.-X.; Wang Y.-J.; Yu S.-X.; Liu T.; Luo S.; Xiang X.-W.; Liu W.; Chen Y.-C.; Huang H.; Gao H.; Shen Y.; Luo Y.; Bao C.; Liu Y.-J.Nano Today 2023, 52, 101947.
[91] Yates A. K.; Murray H.; Kjar A.; Chavarria D.; Masters H.; Kim H.; Ligocki A. P.; Jefferson A. L.; Lippmann E. S.Fluids Barriers CNS 2025, 22, 73.
[92] Lee S.; Chung M.; Lee S. R.; Jeon, N. L. Biotechnol. Bioeng.2019, 117, 748.