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<p>The blood–brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) are critical interfaces that protect the central nervous system (CNS) from the surveilling immune system in the body. However, they also pose challenges for drug delivery and disease modeling. Over the past decade, organ-on-a-chip technology has revolutionized in vitro modeling of these barriers by incorporating microfluidic flow, three-dimensional (3D) architectures, and human stem cell-derived cells, which has helped better recapitulate the in vivo physiological environment. This review summarizes the evolution of BBB and BCSFB models from traditional <i>static</i> Transwell systems to <i>dynamic</i> micro-engineered platforms, highlighting key engineering advancements in microfluidics, 3D tissue engineering, and the use of induced pluripotent stem cell (iPSC)-derived neurovascular tissues. Then, we discuss the need for integrating BBB and BCSFB components into unified “brain barrier” chips, investigating how these holistic models could accurately simulate the CNS physiology. Despite significant improvements, major challenges still remain to faithfully reproduce in vivo brain barrier functions. Key hurdles include achieving a physiological level of shear stress, enabling proper cellular crosstalk among endothelial, glial, and immune cells, and creating biomimetic basement membranes that surround brain barriers. To address this, we also highlight how current studies tackle those issues and emphasize the need for standardization of barrier model characterization metrics across platforms​. Finally, we explore future directions: incorporating artificial intelligence (AI) for data analysis and model optimization, establishing standardized protocols for model validation, and advancing clinical translation of barrier-on-chip systems for drug screening and personalized medicine. This comprehensive review seeks to provide an insightful guide for neuroscientists, bioengineers, and Organ-on-Chip developers, offering a timely overview of the state-of-the-art in BBB and BCSFB on-chip models and their potential impact on clinical research and therapeutic development.</p>

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Integrating the Blood–Brain Barrier and Blood-CSF Barrier Organ-on-Chip Models: Development and Future Directions

  • 期刊论文

  • 发表日期：

    2026年1月5日

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  • Sehoon Jeong,
  • Kwang-Min Kim

摘要

The blood–brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) are critical interfaces that protect the central nervous system (CNS) from the surveilling immune system in the body. However, they also pose challenges for drug delivery and disease modeling. Over the past decade, organ-on-a-chip technology has revolutionized in vitro modeling of these barriers by incorporating microfluidic flow, three-dimensional (3D) architectures, and human stem cell-derived cells, which has helped better recapitulate the in vivo physiological environment. This review summarizes the evolution of BBB and BCSFB models from traditional static Transwell systems to dynamic micro-engineered platforms, highlighting key engineering advancements in microfluidics, 3D tissue engineering, and the use of induced pluripotent stem cell (iPSC)-derived neurovascular tissues. Then, we discuss the need for integrating BBB and BCSFB components into unified “brain barrier” chips, investigating how these holistic models could accurately simulate the CNS physiology. Despite significant improvements, major challenges still remain to faithfully reproduce in vivo brain barrier functions. Key hurdles include achieving a physiological level of shear stress, enabling proper cellular crosstalk among endothelial, glial, and immune cells, and creating biomimetic basement membranes that surround brain barriers. To address this, we also highlight how current studies tackle those issues and emphasize the need for standardization of barrier model characterization metrics across platforms​. Finally, we explore future directions: incorporating artificial intelligence (AI) for data analysis and model optimization, establishing standardized protocols for model validation, and advancing clinical translation of barrier-on-chip systems for drug screening and personalized medicine. This comprehensive review seeks to provide an insightful guide for neuroscientists, bioengineers, and Organ-on-Chip developers, offering a timely overview of the state-of-the-art in BBB and BCSFB on-chip models and their potential impact on clinical research and therapeutic development.