The brain is protected by the blood-brain barrier (BBB), a highly selective interface that controls the passage of substances from the bloodstream into the neural environment. To better study this gateway, scientists developed “BBB-on-a-chip” technology. This innovation uses micro-engineering to create a miniature, living model of the barrier for detailed investigation in a controlled laboratory setting.
Constructing a Miniature Barrier
The foundation of a BBB-on-a-chip is a polymer block, such as flexible polydimethylsiloxane (PDMS), containing minuscule, hollow channels that mimic the brain’s vascular system. One channel is the “blood” side, while an adjacent channel represents the “brain” side. The two are separated by a thin, porous membrane that acts as a scaffold for living cells.
To bring the model to life, human cells fundamental to the barrier’s structure are seeded onto the membrane. Brain endothelial cells, which form the inner lining of blood vessels, are the primary component. They are cultured alongside pericytes and astrocytes, two other cell types that provide support and contribute to the barrier’s integrity. This co-culture method helps recreate the complex cellular interactions of the actual BBB.
A defining feature is the ability to simulate blood flow. The microfluidic system pumps a nutrient-rich liquid through the vascular channel, creating a force known as shear stress. This mechanical pressure influences the behavior of endothelial cells, making the model more dynamic and physiologically accurate than static alternatives.
Overcoming Traditional Research Hurdles
BBB-on-a-chip technology addresses shortcomings of previous research methods. Animal models, such as mice and rats, have long been used, but considerable biological differences between their BBB and that of humans mean that drugs effective in animals often fail in human trials.
Traditional static cell culture systems also present challenges. These models lack the ability to replicate the brain’s dynamic microenvironment because cells are grown without fluid flow. The absence of shear stress results in a barrier that is often “leaky” and does not accurately represent the tightness of the human BBB.
By using human-derived cells and incorporating simulated blood flow, BBB-on-a-chip systems provide a more faithful replication of human physiology. This allows researchers to study the human BBB with greater accuracy and reduces the reliance on animal testing.
Applications in Medicine and Disease Research
BBB-on-a-chip technology has extensive uses in drug development and disease research. Pharmaceutical companies use these chips to test if a drug for a brain condition, like a tumor or neurodegenerative disorder, can cross the barrier. This allows for early screening of drug candidates to identify which compounds are most likely to reach their target.
The technology is also applied for toxicity screening. A drug intended for another part of the body might have harmful effects if it crosses into the brain. By introducing the drug into the chip’s vascular channel, scientists can observe if it compromises the barrier’s integrity or harms brain cells, providing safety data to prevent neurotoxicity.
These chips also serve as platforms for modeling diseases. Researchers can recreate the conditions of neurological disorders to study their effects on the BBB. For example, reducing oxygen levels can simulate a stroke to observe its impact on permeability. They can also introduce inflammatory molecules associated with Alzheimer’s disease to investigate how these elements disrupt the barrier.
Advancing Brain Research
The future of BBB-on-a-chip technology is moving toward more complex and personalized applications. A significant advancement is using a patient’s own cells to create a custom model. By taking a skin or blood sample, scientists can generate induced pluripotent stem cells (iPSCs) and then guide them to become the specific cell types of the BBB. This creates a personalized chip reflecting an individual’s biology, allowing doctors to test which drugs are most effective for that person.
Researchers are also connecting BBB chips with other organ-on-a-chip systems. Linking a BBB model to a liver-on-a-chip can provide insights into how a drug is metabolized by the liver and how those byproducts affect the brain. This integrated approach allows for the study of complex, multi-organ interactions not possible with isolated models.
Scientists are also increasing the biological complexity within the models by incorporating additional cell types, such as immune cells like microglia or neurons. This inclusion enables more detailed investigations into processes like neuroinflammation and the communication between different cells within the brain’s neurovascular unit.