Bridging barriers: advances and challenges in modeling biological barriers and measuring barrier integrity in organ-on-chip systems

Biological barriers such as the blood-brain barrier, skin, and intestinal mucosal barrier play key roles in homeostasis, disease physiology, and drug delivery - as such, it is important to create representative in vitro models to improve understanding of barrier biology and serve as tools for therapeutic development. Microfluidic cell culture and organ-on-a-chip (OOC) systems enable barrier modelling with greater physiological fidelity than conventional platforms by mimicking key environmental aspects such as fluid shear, accurate microscale dimensions, mechanical cues, extracellular matrix, and geometrically defined co-culture. As the prevalence of barrier-on-chip models increases, so does the importance of tools that can accurately assess barrier integrity and function without disturbing the carefully engineered microenvironment. In this review, we first provide a background on biological barriers and the physiological features that are emulated through in vitro barrier models. Then, we outline molecular permeability and electrical sensing barrier integrity assessment methods, and the related challenges specific to barrier-on-chip implementation. Finally, we discuss future directions in the field, as well important priorities to consider such as fabrication costs, standardization, and bridging gaps between disciplines and stakeholders. Biological barriers play key roles in homeostasis, disease physiology and drug delivery, highlighting a need for representative in vitro tools. We discuss advances and challenges in modeling and measuring barrier integrity in organ-on-chip systems.