Related Experiment Video
Updated: Jun 23, 2026
Generation of Human Brain Organoids for Mitochondrial Disease Modeling
Published on: June 21, 2021
Human BBB-brain organoid on a millifluidic plate for modeling brain parenchymal pathology-induced barrier dysfunction
Lili Zhu1, Wen Zhao1, Min Shen2
1Tissue Engineering and Organ Manufacturing (TEOM) Lab, Department of Biomedical Engineering, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan 430071, China; State Key Laboratory of Metabolism and Regulation in Complex Organisms, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China; Brain Research Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
Introduction:
The blood-brain barrier (BBB) maintains brain homeostasis, and its dysfunction is a critical pathological mechanism for many neurological disorders. However, current BBB models lack functional brain parenchyma, hindering mechanistic studies of BBB-parenchyma interactions and limiting drug evaluation for barrier penetration and neural targeting.
Objectives:
To develop an integrated human blood-brain barrier-brain organoid-on-a-chip (BBOC) model that replicates physiological interaction and pathological disruption between the BBB and brain parenchyma.
Methods:
A bioengineered BBB model was constructed on a millifluidic plate using human brain microvascular endothelial cells and pericytes under dynamic flow. Human brain organoids (hBOs) derived from pluripotent stem cells were co-cultured to form the BBOC model. Parenchymal pathology was induced by Aβ42 oligomers (Aβ42O) to examine their effects on BBB function and integrity.
Results:
Conditioned medium and dynamic flow improved endothelial cell viability. Co-culture with hBOs significantly enhanced the engineered BBB function, increasing TEER values and reducing molecular permeability. Aβ42O-treated hBOs exhibited the pathological phenotypes of brain parenchyma, including notable neurite loss, impaired stem cell proliferation, increased cell apoptosis, and transcriptional upregulation of cytokine genes. The pathological hBOs disrupted the BBB, including decreased tight junction protein expression, increased barrier permeability, and impaired barrier integrity.
Conclusion:
The BBOC model reproduced physiological and pathological interactions between parenchyma and the BBB, collectively confirming that brain parenchymal states can modulate BBB integrity. Functionally, hBOs strengthened endothelial barrier integrity, indicating that parenchymal-derived signals actively promote the BBB maturation and stability. In contrast, pathological hBOs induced pericyte degeneration and tight junction disruption of BBB, demonstrating that pathological brain environments can impair BBB function. By bridging neurobiology and bioengineering, the BBOC model will facilitate investigations into neurological mechanisms and drug discovery for barrier penetration and neural targeting.
