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The Blood-Brain Barrier (BBB) is a selective barrier that shields the brain and Central Nervous System (CNS), maintaining a stable environment. It comprises endothelial cells, pericytes, glial cells, and the extracellular matrix, ensuring integrity. Dysfunction in the BBB, linked to diseases like Alzheimer’s and Parkinson’s, allows harmful substances into the CNS. Advanced BBB models now enable better study of these diseases by developing targeted therapies, and identifying potential neurotoxic xenobiotics, representing a significant step forward in neuroscience and pharmacology (1,2).
Traditional methods for studying the blood-brain barrier (BBB), like transwell assays, and animal models, face limitations like oversimplification, poor physiological relevance, and cross–species differences.
An ideal in vitro blood-brain barrier (BBB) model should replicate the key characteristics of the in vivo BBB, including:
One of the most challenging aspects of mimicking the BBB in vitro is accurately replicating the native BM, which plays a critical role in processes such as cell differentiation, homeostasis, tissue maintenance, and structural support. Ideally, an artificial BM should be fabricated from biocompatible materials and have a thickness of approximately 100 nm.
This μBBB design features an upper and lower polydimethylsiloxane (PDMS) channel separated by a porous membrane. Polycarbonate membranes with pore diameters ranging from 0.2 to 3 μm are typically used, resembling the transwell system. Endothelial cells are generally seeded in the upper channel, while pericytes, astrocytes, or other brain cells are cultured in the lower channel.
Alternative transparent membranes, such as polytetrafluoroethylene, enable high-resolution imaging and real-time biomolecule transport and cell growth monitoring. Additionally, reversing the cell seeding configuration, and culturing endothelial cells (ECs) in a 3D vessel-like structure in the lower channel while seeding pericytes and astrocytes in the upper channel, enhances the observation of cell-cell interactions.
Two horizontally aligned channels are separated by a PDMS microchannel array, replacing traditional polycarbonate membranes with a PDMS-based micropillar ‘membrane’ (3-μm gaps). This design enables co-culture with astrocytes or brain tumor cells and simplifies assembly by removing the need for extra chemical modifications. The planar layout improves cell interactions and imaging.
The device features a central tissue compartment flanked by two vascular channels with flow access, assembled on a microscope slide with plastic tubes for channel access.
Photolithography typically produces PDMS-based μBBB models with rectangular microchannels, but this can cause uneven flow and shear stress, impacting endothelial cell behavior. To address this, some μBBB systems use cylindrical microchannels for uniform shear stress. For example, 3D collagen-based microvascular tubes (75–150 μm) are created with microneedles, allowing precise diameter adjustment through fluid flow rates, and are integrated into μBBB devices.
Blood–brain barrier (BBB) models are employed to investigate how vascular glioma-initiating cells; key players in brain tumor invasion-interact within their environment. Moreover, using in vitro BBB systems enables a clearer understanding of the mechanisms behind brain tumor metastasis. By integrating patient-derived glioblastoma spheroids into microfluidic systems, these models provide a highly efficient platform for screening drugs with strong tumor-killing capacity.
The inflammatory response in neural disease lesions results from the aggregation and migration of immune cells, including neutrophils, glial cells, and astrocytes. In models of neurological disorders, such as Alzheimer’s disease, neuroinflammation is driven by the activation of microglia and astrocytes. Activated immune cells release inflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-1. During this response, cytokines and immune cells contribute to the disruption of the blood-brain barrier (BBB), often causing blood to infiltrate the brain and leading to irreversible brain tissue damage.
Controlling the microenvironment around neuronal cells, including cell–cell and cell–extracellular matrix (ECM) interactions within microfluidic platforms, enables the creation of an in vivo-like niche for neural stem cells to differentiate into components of the nervous system.
By integrating microfluidic technology with neurobiology, several technical challenges in the field can be addressed, such as culturing central nervous system (CNS) neurons, isolating axons, patterning cultured neurons, directing neurite outgrowth to model axonal injury, and studying processes like local protein synthesis in axons, axonal regeneration, and axonal transport.
BBB-on-chip systems provide advanced platforms for assessing drug permeability across the blood-brain barrier under dynamic and physiologically relevant conditions, addressing limitations of traditional in vitro models. They enable the evaluation of drug-loaded nanoparticles, including receptor-mediated transcytosis and nanocarrier optimization for CNS-targeted delivery. By replicating the cellular complexity of the BBB, these models facilitate testing neuroprotective agents and antibodies under disease-specific conditions. Integrated sensors offer insights into drug toxicity, neuronal activity, and synaptic behavior. Using patient-derived cells, they support personalized drug screening and disease-specific studies (5).
Multi-organ chips provide an advanced platform to study interactions between the brain and other organs in the context of diseases and drug development. They enable the investigation of complex conditions such as brain metastasis of lung cancer, where dynamic processes can be replicated and studied in detail.
These chips also help unravel the communication pathways in the microbiota-gut-brain axis, shedding light on how gut health impacts neurological diseases. By simulating interconnected organ systems, such as the liver-brain axis in hepatic encephalopathy or immune modulation via the brain-spleen axis, multi-organ chips offer an integrated approach to understanding systemic diseases. Their ability to mimic dynamic physiological environments facilitates groundbreaking research in inter-organ communication and therapeutic development.
X. Chen ; C. Liu ; L. Muok ; C. Zeng and Y. Li, Dynamic 3D On-Chip BBB Model Design, Development, and Applications in Neurological Diseases, Cells, 2021
Easy-to-use instrument package for extended BBB on a chip research.
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