Brain-on-a-chip devices create an interface between neuroscience and microfluidics by: 1) improving culture viability; 2) supporting high-throughput screening; 3) modeling organ-level physiology and disease in vitro/ex vivo, and 4) adding high precision and tunability of microfluidic devices. Brain-on-a-chip devices span multiple levels of complexity in terms of cell culture methodology. Devices have been made using platforms that range from traditional 2D cell culture to 3D tissues in the form of organotypic brain slices.
Organotypic brain slices are an in vitro model that replicates in vivo physiology with additional throughput and optical benefits, thus pairing well with microfluidic devices. Brain slices have advantages over primary cell culture in that tissue architecture is preserved and multicellular interactions can still occur. There is flexibility in their use, as slices can be used acutely (less than 6 hours after slice harvesting) or cultured for later experimental use. Because organotypic brain slices can maintain viability for weeks, they allow for long-term effects to be studied. Slice-based systems also provide experimental access with precise control of extracellular environments, making it a suitable platform for correlating disease with neuropathological outcomes. Because approximately 10 to 20 slices can be extracted from a single brain, animal usage is significantly reduced relative to in vivo studies. Organotypic brain slices can be extracted and cultured from multiple animal species (e.g. rats), but also from humans.
Microfluidic devices have been paired with organotypic slices to improve culture viability. The standard procedure for culturing organotypic brain slices (around 300 microns in thickness) uses semi-porous membranes to create an air-medium interface, but this technique results in diffusion limitations of nutrients and dissolved gases. Because microfluidic systems introduce laminar flow of these necessary nutrients and gases, transport is improved and higher tissue viability can be achieved. In addition to keeping standard slices viable, brain-on-a-chip platforms have allowed the successful culturing of thicker brain slices (approximately 700 microns), despite a significant transport barrier due to thickness. As thicker slices retain more native tissue architecture, this allows brain-on-a-chip devices to achieve more "in vivo-like" characteristics without sacrificing cell viability. Microfluidic devices support high-throughput screening and toxicological assessments in both 2D and slice cultures, leading to the development of novel therapeutics targeted for the brain. One device was able to screen the drugs pitavastatin and irinotecan combinatorically in glioblastoma multiform (the most common form of human brain cancer). These screening approaches have been combined with the modeling of the blood-brain barrier (BBB), a significant hurdle for drugs to overcome when treating the brain, allowing for drug efficacy across this barrier to be studied in vitro. Microfluidic probes have been used to deliver dyes with high regional precision, making way for localized microperfusion in drug applications. Microfluidic BBB in vitro models replicate a 3D environment for embedded cells (which provides precise control of cellular and extracellular environment), replicate shear stress, have more physiologically relevant morphology in comparison to 2D models, and provide easy incorporation of different cell types into the device. Because microfluidic devices can be designed with optical accessibility, this also allows for the visualization of morphology and processes in specific regions or individual cells. Brain-on-a-chip systems can model organ-level physiology in neurological diseases, such as Alzheimers disease, Parkinsons disease, and multiple sclerosis more accurately than with traditional 2D and 3D cell culture techniques. The ability to model these diseases in a way that is indicative of in vivo conditions is essential for the translation of therapies and treatments. Additionally, brain-on-a-chip devices have been used for medical diagnostics, such as in biomarker detection for cancer in brain tissue slices.
Brain-on-a-chip devices can cause shear stress on cells or tissue due to flow through small channels, which can result in cellular damage. These small channels also introduce susceptibility to the trapping of air bubbles that can disrupt flow and potentially cause damage to the cells. The widespread use of PDMS (polydimethylsiloxane)  in brain-on-a-chip devices has some drawbacks. Although PDMS is cheap, malleable, and transparent, proteins and small molecules can be absorbed by it and later leech at uncontrolled rates.
Despite the progress in microfluidic BBB devices, these devices are often too technically complex, require highly specialized setups and equipment, and are unable to detect temporal and spatial differences in the transport kinetics of substances that migrate across cellular barriers. Also, direct measurements of permeability in these models are limited due to the limited perfusion and complex, poorly defined geometry of the newly formed microvascular network.