IQ-MPS Affiliate perspectives on blood-brain barrier microphysiological systems: Progress and challenges ahead

The endothelial cells of the capillary network in the brain, in conjunction with pericytes and astrocyte end feet, form the blood-brain barrier (BBB). This highly selective cellular barrier helps to protect and maintain brain homeostasis. This barrier function must be circumvented to deliver therapeutics to the brain, a growing need owing to the increasing incidence in neurological disorders in progressively aging populations. Animal models may exhibit species-specific differences in response, ultimately leading to problems with predicting efficacy of treatments in humans, and conventional in vitro models of the BBB face challenges of reproducing cell-cell interactions, the human brain microenvironment, and transporter abundance and type. Microphysiological systems (MPS) and other complex in vitro models aim to address these challenges by combining engineered shear forces coupled with cell biology advancements to create models with greater predictive power, thereby contributing towards the replacement, reduction and/or refinement of animal use (3Rs). Here, we provide an industry perspective on the application of MPS to test drug delivery to the brain, including on newer modalities such as targeted protein degraders, biologics, nanoparticles, and viruses. We also highlight important considerations for MPS model qualification centered on cell sourcing, technological platform, and qualification of functionality. This commentary from members of the Innovation & Quality Microphysiological Systems Affiliate also aims to highlight areas where developers and suppliers can help address gaps in model development.