A Human Brain-Chip for Modeling Brain Pathologies and Screening Blood-Brain Barrier Crossing Therapeutic Strategies

Area of Science:

• Neuroscience
• Translational Medicine
• Biotechnology

Background:

• Preclinical models often fail to translate to human patients due to species differences in brain and blood-brain barrier (BBB) function.
• There is a critical need for advanced models that elucidate brain pathogenesis, cell-specific contributions, and cell-cell interactions.
• Human microphysiological systems (MPS), like Organ-Chips, offer a promising solution for modeling human brain diseases.

Purpose of the Study:

• To develop and validate an advanced human Brain-Chip model that recapitulates the human cortical parenchyma and BBB.
• To incorporate diverse human cell types, including induced pluripotent stem cell (hiPSC)-derived neurons, endothelial cells, microglia, astrocytes, and pericytes.
• To assess the model's utility in studying neuroinflammation and predicting therapeutic interventions.

Main Methods:

• Utilized a combination of primary human cells and hiPSC-derived cells (neurons, endothelial-like cells, microglia, astrocytes, pericytes).
• Emulated neuroinflammation using Tumor Necrosis Factor alpha (TNFα) to analyze cell-specific responses.
• Evaluated the Blood-Brain Barrier (BBB) crossing efficiency of therapeutic agents, including antibodies and adeno-associated viruses.

Main Results:

• The Brain-Chip model successfully recapitulated in vivo-relevant responses to neuroinflammation, including microglia-derived reactions.
• Demonstrated the model's sensitivity in capturing cell-specific contributions to human disease pathology.
• Achieved successful in vitro/in vivo correlation for predicting Blood-Brain Barrier (BBB) crossing of therapeutic agents.

Conclusions:

• The developed Brain-Chip serves as a reliable, time-efficient model for advancing brain disease therapeutics.
• The model provides valuable mechanistic insights into brain pathogenesis and drug response prediction.
• Highlights the significant potential of microphysiological systems (MPS) in translational research and drug discovery for neurological disorders.