Interfacial Morphology Shapes Endothelial Organization and Function in a Blood-Brain Barrier-on-a-Chip

Area of Science:

• Biomaterials Engineering
• Microfluidics
• Translational Medicine

Background:

• Organ-on-a-chip (OOC) systems, particularly those integrating hydrogels, offer advanced modeling of human physiology and disease.
• Current limitations in hydrogel mechanical stability and barrier interface integrity hinder reproducibility in OOC models like the blood-brain barrier (BBB).

Purpose of the Study:

• To develop a robust blood-brain barrier-on-a-chip (μBBB) model with enhanced interfacial stability.
• To investigate the impact of hydrogel interface morphology on endothelial cell behavior and BBB function.

Main Methods:

• Fabrication of a three-channel μBBB device incorporating an in situ photo-cross-linkable hydrogel system.
• Computational fluid dynamics (CFD) analysis to predict shear stress distribution based on interface morphology.
• Assessment of endothelial cell viability, invasion, BBB function, and transcriptomic profiles.

Main Results:

• Subtle variations in hydrogel interface morphology significantly alter local shear stress, with protruded interfaces favoring endothelial organization.
• The photo-cross-linkable hydrogel system stabilized the interface, improving endothelial cell viability and reducing matrix invasion.
• Enhanced BBB-associated functional readouts and a more quiescent endothelial phenotype were observed, indicated by reduced inflammation and sprouting pathways.

Conclusions:

• Hydrogel-cell interfacial stability is a critical factor for μBBB performance, impacting reproducibility and functional fidelity.
• The developed photo-cross-linkable hydrogel strategy offers a simple and adaptable method to enhance the reliability of hydrogel-integrated OOC systems.
• This approach facilitates the creation of more physiologically relevant in vitro models for drug discovery and disease research.