Blood-brain barrier research has long been one of the most difficult frontiers in drug development, and a team at Harvard University just made a significant leap forward. Scientists at the Wyss Institute for Biologically Inspired Engineering have created a blood-brain barrier chip that replicates the human blood-brain barrier with a level of fidelity never previously achieved in a laboratory setting. The breakthrough, published in Nature Communications, could transform how researchers develop and test drugs for brain cancer, neurodegeneration, Alzheimer’s disease, Parkinson’s disease, and other central nervous system conditions.<\/p>\n
The blood-brain barrier is a highly specialized structure that controls what enters the brain from the bloodstream. It consists of thin capillary blood vessels formed by brain microvascular endothelial cells, wrapped by supporting pericytes, and surrounded by star-shaped astrocytes. Together, these cells create a tightly sealed wall that blocks harmful substances while selectively allowing nutrients and essential metabolites to pass through.<\/p>\n
This protective function is critical for brain health. However, the same selectivity that protects the brain also prevents most drugs from reaching their targets inside it. The vast majority of potentially therapeutic compounds, including antibodies, chemotherapy agents, and other large molecules, cannot cross the blood-brain barrier in sufficient quantities to be effective. This is why treating brain tumors, neurodegenerative diseases, and CNS infections remains so difficult despite decades of research.<\/p>\n
In some brain diseases, the blood-brain barrier also breaks down locally, allowing neurotoxic substances, immune cells, and pathogens to leak into the brain and cause irreversible damage. Understanding and replicating the blood-brain barrier in the lab is essential to developing treatments that can either cross it safely or stabilize it when it fails.<\/p>\n
Researchers have historically relied on animal models, particularly mice, to study the blood-brain barrier and test drug transport across it. The problem is that the composition and transport functions of the blood-brain barrier differ significantly between mice and humans, making animal models unreliable predictors of how a drug will actually behave in human patients.<\/p>\n
In vitro models using primary human brain tissue cells have also fallen short. Previous laboratory systems were unable to adequately replicate the physical barrier function, selective transport capabilities, and drug and antibody shuttling activity of the real human blood-brain barrier, limiting their usefulness as drug development tools.<\/p>\n
The team led by Donald Ingber, M.D., Ph.D., Founding Director of the Wyss Institute, overcame these limitations using two key innovations: microfluidic organ-on-chip technology and a hypoxia-mimicking approach to cell differentiation.<\/p>\n
The researchers began by differentiating human induced pluripotent stem (iPS) cells into brain microvascular endothelial cells under low oxygen conditions, mimicking the environment in which the blood-brain barrier naturally forms during embryonic development. By reducing oxygen concentration from the standard 20 percent to just 5 percent, the iPS cells activated a developmental program very similar to that of the embryo, producing endothelial cells with significantly higher functionality than those generated under normal oxygen conditions.<\/p>\n
These hypoxia-induced endothelial cells were then transferred into a microfluidic organ-on-a-chip device: two parallel channels divided by a porous membrane and continuously perfused with fluid. One channel was lined with the blood-brain barrier endothelial cells; the other was populated with a mixture of primary human brain pericytes and astrocytes. Under the shear stress of flowing fluid, the cells organized into a structure that closely recapitulated the architecture and function of the real human blood-brain barrier.<\/p>\n
The resulting blood-brain barrier chip could be stably maintained for at least 14 days, far longer than previous human blood-brain barrier models, providing a more practical research and development tool.<\/p>\n
The hypoxia-enhanced blood-brain barrier chip demonstrated several critical capabilities that prior models could not match.<\/p>\n
First, the chip showed tighter barrier function than control models, with elevated numbers of selective transport and drug shuttle systems. Researchers were also able to reversibly open the blood-brain barrier for short periods by increasing mannitol concentration, mimicking a strategy already used in clinical settings to allow large drug molecules to temporarily pass through.<\/p>\n
Second, the chip accurately replicated efflux pump behavior. When researchers blocked P-glycoprotein, a key pump that normally removes drugs from the brain back into the bloodstream, transport of the anticancer drug doxorubicin from the vascular channel to the brain channel increased substantially, matching what has been observed in human patients.<\/p>\n
Third, the chip faithfully replicated receptor-mediated transcytosis, the process by which the brain selectively pulls in nutrients and specific molecules from the bloodstream. Using known transcytosis receptors including LRP-1 and transferrin receptors, the team demonstrated that the chip could be used to model the shuttling of therapeutic antibodies into the brain, a capability with enormous implications for CNS drug development.<\/p>\n
“Our approach to modeling drug and antibody shuttling across the human blood-brain barrier in vitro with such high and unprecedented fidelity presents a significant advance over existing capabilities in this enormously challenging research area,” said Ingber.<\/p>\n
Beyond drug transport studies, the hypoxia-enhanced blood-brain barrier chip can be used to model how specific brain diseases affect the blood-brain barrier itself. The authors note that the system is well suited for studying the blood-brain barrier changes associated with Alzheimer’s disease, Parkinson’s disease, and other neurological conditions. It can also be adapted for personalized medicine applications using patient derived iPS cells, potentially allowing researchers to study how an individual patient’s blood-brain barrier responds to specific drugs before treatment begins.<\/p>\n
The Wyss Institute has launched a dedicated Blood Brain Barrier Transport Program to build on these findings, with goals including the discovery of new shuttle targets on the vascular surface of brain endothelial cells and the development of fully human antibody shuttles with enhanced brain targeting capabilities.<\/p>\n
Advances in blood-brain barrier research directly shape the clinical trial landscape for neurological conditions. As new drug delivery strategies advance from the lab toward human testing, the demand for experienced research sites with access to neurology patient populations will grow significantly.<\/p>\n