Development of Microvascular Network in Microfluidic Brain-on-a-Chip Models In Vitro: A Multidisciplinary Review

Microfluidic brain-on-a-chip and angiogenesis-on-a-chip models have been employed by leading research groups around the world. These models have great potential, but they have not yet been used in the context of personalized medicine and diagnostics, nor have they been widely adopted for testing drug candidates. The reproduction of a physiologically relevant in vitro brain-on-a-chip model with essential similarity to in vivo structural and functional characteristics, including integrity and complexity of the brain tissue, limited and controlled permeability of barriers, and plastic changes induced by brain stimulation or injury, is a highly challenging task that requires a comprehensive approach and a tour de force in advanced biomedical engineering and living soft matter physics. This approach necessitates not only the combination of well-established chip production technologies and cell biology protocols but also the integration of knowledge from neuroscience, (bio)physics, hydrodynamics, material science, (bio)chemistry, electronics, and soft matter physics. This review covers current understandings of the establishment of microvascular network formation in the active brain in vivo, as well as analysis of novel approaches to reconstruct the basic mechanisms of cerebral angiogenesis and barrier genesis in a physiologically relevant brain-on-a-chip model. The novel concept, which employs the application of an external electric field to stimulate vasculogenesis/angiogenesis on a chip, demonstrates how a synergistic approach may help to solve this non-trivial problem and to establish the vascularized brain tissue sensitive to various stimuli and suitable for the high-precision analysis of its functional activity and plasticity.