In Vitro Human Blood Brain Barrier

Technology

The iBBB is constructed using a three-dimensional scaffold seeded with human brain endothelial cells (BECs), human pluripotent-derived pericytes, and astrocytes. The cells self-assemble into a physiologically relevant arrangement, with the BECs forming a capillary-like network, the pericytes aligning to the apical vessel surface, and the astrocytes dispersed throughout the matrix. The resulting iBBB demonstrates structural and functional properties that closely mimic in vivo blood-brain barrier tissue, including relevant gene expression profiles and reduced molecular permeability. This system enables functional assays such as screening compounds for their ability to inhibit Aβ peptide production by exposing the BEC-formed vessels to test compounds and comparing Aβ levels in the presence and absence of the candidate inhibitor.  

Problem Addressed

The blood-brain barrier (BBB) is a critical physiological structure that regulates molecular exchange between the central nervous system and the periphery. Cerebrovascular Aβ accumulation can impair BBB integrity and function, leading to neurodegeneration and cognitive deficits. Traditional BBB models have typically been two-dimensional or based on larger vessel geometries, limiting their utility for disease modeling and drug development. The present iBBB is human-derived, three-dimensional, and scaled to resemble human capillaries, enabling physiologically relevant, genotype-specific research. A proof-of-concept study demonstrated that targeting the calcineurin/NFAT signaling pathway in the context of the APOE4 genotype can yield measurable therapeutic effects, validating the model’s potential for Aβ inhibitor screening.  

Advantages

• Enables high-throughput screening of combinatory compound libraries for Aβ inhibitors
• Human-relevant physiology with relevant structural and functional BBB properties
• Genotype-specific modeling reveals how genetic variants influence cerebrovascular pathology
• Novel therapeutic link established between the APOE4 genotype and calcineurin/NFAT pathway inhibitors