Revealing New Physiology with Brain In Vitro Models

Micro-engineered cell culture models, so-called Organs-on-Chips have emerged as a new tool to recapitulate human physiology and drug responses. Multiple studies and research programs have shown that Organ-on-Chips can recapitulate the multicellular architectures, vascular-parenchymal tissue interfaces, chemical gradients, mechanical cues, and vascular perfusion of the body can produce levels of tissue and organ functionality, as well as mimicry of human disease states, which are not possible with conventional 2D or 3D culture systems. Here we exploit the micro-engineering technology in a novel system-level approach to disintegrate the functions and coupling of neurovascular unit in to its individual cellular compartments while keeping the paracellular metabolic coupling. Using individual, fluidically connected, chip units we created a system modeling influx and efflux functions of the brain vasculature and interaction with the brain parenchyma. Based on proteomic and metabolic assessment we would conclude that this coupled system mimicked the effect of intravascular administration of the psychoactive drug methamphetamine observed in vivo. Moreover, this method revealed an additional metabolic role of the of the brain endothelium to neural cell metabolism. In addition to the well-established function of metabolic transport the brain endothelium secretes metabolites that are being directly utilized by neurons. This contribution is not possible to evaluate in conventional in vitro or in vivo measurements.