Microphysiological Human Brain and Neural Systems-on-a-Chip: Potential Alternatives to Small Animal Models and Emerging Platforms for Drug Discovery and Personalized Medicine

Abstract

Translational challenges associated with reductionist modeling approaches, as well as ethical concerns and economic implications associated with small animal testing, drive the need for developing microphysiological neural systems for modeling human neurological diseases, disorders and injuries. Here, we provide a comprehensive review of microphysiological neural systems on a chip (NSCs) for modeling higher order trajectories in the human nervous system. Societal, economic, and national security impacts of neurological diseases, disorders and injuries are highlighted to identify critical NSC application spaces. Hierarchical design and manufacturing of NSCs are discussed with distinction of surface- and bulk-based systems. Three broad NSC classes are identified and reviewed: microfluidic NSCs, compartmentalized NSCs, and hydrogel NSCs. Emerging areas and future directions are highlighted, including the application of 3D printing to design and manufacturing of next-generation NSCs, the use of stem cells for constructing patient-specific NSCs, and the application of human NSCs to ‘personalized neurology’. Technical hurdles and remaining challenges are discussed. This review identifies the state-of-the-art design methodologies, manufacturing approaches, and performance capabilities of NSCs. This work suggests NSCs appear poised to revolutionize the modeling of human neurological diseases, disorders and injuries.

In Vitro Blood–Brain Barrier-Integrated Neurological Disorder Models Using a Microfluidic Device

“…These models help in a reliable recapitulation of in vivo cytoarchitecture as opposed to the conventional 2D and animal models. There are two typical approaches that can be adopted for creating 3D neural models: brain organoids and brain-on-a-chip technology [74,75]. Recently, these technologies have been combined to generate a new 3D model of organoids-on-a-chip [76].…”

“…(c) A hydrogel free 3D neurospheroid-based AD model congaing concave microwell to generate a neurospheroid and study neurotoxicity of Aβ. Reproduced with permission from[75] copyright 2017, The Royal Society of Chemistry (RSC). (d) Neural outgrowth and formation of a human motor unit along with NMJ in a 3D ALS motor unit model and NMJs in microfluidic devices reproduced with permission from[79].…”

Microscale Architecture in Biomaterial Scaffolds for Spatial Control of Neural Cell Behavior

“…Lithographic patterning of grooves into biomaterial surfaces has been extensively shown to direct NC alignment, migration, and differentiation (Dos Reis et al, 2010;Haring et al, 2017). Astrocytes seeded onto a polystyrene mold patterned with channels that were 10-µm wide and 3-µm deep using photolithography, and subsequently coated with laminin, had elongated process extensions that aligned with the grooves (Recknor et al, 2004).…”

Modeling Alpha-Synuclein Pathology in a Human Brain-Chip to Assess Blood-Brain Barrier Disruption in Parkinson’s Disease

“…Recently, microengineered Organs-on-Chips 22,23 have been successfully developed for multiple complex organs, including intestine, lung, liver, heart, and brain [24][25][26][27][28][29] . Organs-on-Chips enable the recreation of a more physiological mircroenvironement, including coculture of cells on tissue-specific extracellular matrices (ECM), the application of flow to enable a dynamic microenvironment and in vivo-relevant mechanical forces such as fluidic sheer stress.…”