08 December 2016

BBB on a chip

A fully functional model of the hemato-encephalic barrier has been developed

Anna Stavina, XX2 century

An interdisciplinary team of researchers from the Vanderbilt Institute for Integrative Biosystems Research and Education, led by biophysicist John Wikswo, announced the completion of the development of a microfluidic device that bypassed the limitations of previous models of the hemato-encephalic barrier (BBB).

Diagram of the hemato-encephalic barrier on a chip 
(from Vanderbilt University press release Blood-brain barrier on a chip sheds new light on “silent killer")

Scientists have already started using a new device to study the inflammatory process in the brain, dubbed the "silent killer" because it does not cause pain, but contributes to the development of diseases such as Alzheimer's disease and Parkinson's disease. Recent studies have shown that inflammation can underlie many mental disorders, ranging from cognitive impairment to depression and schizophrenia.

The BBB model development project is part of the extensive Tissue Processor for Drug Testing Program (Tissue Chip for Drug Testing Program), which has a budget of $70 million. The program is funded by the National Center for Advanced Translational Sciences National Institutes of Health (National Institutes of Health). Its goal is to develop models of human organs on chips for faster, cheaper and more reliable study of the safety and effectiveness of new drugs.

In recent years, the study of the principles of the BBB has become a priority task, as scientists have found that this formation is associated with various disorders of the brain – from stroke and Alzheimer's disease to the consequences of traumatic brain injury, Parkinson's disease and brain inflammation.

Despite the importance of the task, scientists have faced serious difficulties in developing reliable laboratory models of a complex system that protects the brain. The first devices were either static – and could not be used to study circulatory disorders – or they lacked some types of cells present in the human BBB.

BBB on a chip

The new device, called the NeuroVascular Unit, is devoid of the mentioned disadvantages. The NeuroVascular Unit has a small cavity less than 1 mm thick. Its dimensions are 5 mm in length, 2.5 mm in width, and in volume it is comparable to one millionth of a human brain. The cavity is divided by a thin porous membrane into an upper chamber – it reproduces the side of the BBB facing the brain, and the lower one – simulating a blood vessel. Both cameras are connected to separate microchannels equipped with micro pumps, which allows you to fill the cameras and study their operation independently of each other.

In the process of creating a BBB model, scientists first turned the NeuroVascular Unit so that the chamber modeling the blood vessel was on top, and injected human endothelial cells into the device. The researchers found that endothelial cells, if there is a stable fluid flow through the chamber, independently line up parallel to the direction of this flow. This orientation of cells in space, characteristic of natural BBB, was absent in many previous models.

A day or two later, when the endothelial cells joined the membrane, the scientists turned the device over again and injected two more types of cells involved in the formation of the BBB into it. Along with astrocytes and perivascular cells wrapping around endothelial cells, neurons responsible for regulating the barrier were placed in the NeuroVascular Unit. All these cells were located in the "brain" chamber, which was now on top. The porous membrane allowed the new cells to establish a physical and chemical connection with endothelial cells – just as they would have done in vivo.

"This is one of the most exciting projects I've participated in," said co–author Diana Neely, associate professor of pediatrics at Vanderbilt University Medical Center. "Although the project is still in diapers, its potential is huge."

According to another participant of the project, Aaron Bowman, associate professor of pediatrics, neurology and biochemistry from the same center, one of the possible applications of the NeuroVascular Unit will be the development of chips containing cells of a particular patient, thanks to which it will be possible to predict an individual reaction to various drugs.

The device passed the tests for "excellent"

"Having completed the development of the NeuroVascular Unit, we subjected it to a series of tests. The device passed all the tests perfectly, which gives us the opportunity to claim that we have created a fully functional BBB model," says Jacquelyn Brown, an employee of the Vanderbilt Institute for Integrative Research of Biological Systems and Education, who is also the first author of the article "Recreating the physiology and structure of BBB on a chip: a new neurovascular microfluidic bioreactor". (Recreating blood-brain barrier physiology and structure on chip: A novel neurovascular microfluidic bioreactor), which was published in Biomicrofluidics.

"We have reached the point where we can start studying various drugs and compounds," explains one of the project participants, Donna Webb, associate professor of biology, interested in studying the effect of various substances on synapses. – We must definitely find out how various chemical compounds affect the thinking process. A lot of surprises are waiting for us!"

The first image of the inflammatory process in dynamics

A group of researchers has already used the NeuroVascular Unit to overcome the main limitations of previous work on the study of the inflammatory process in the brain. In early studies, this process was represented by separate "snapshots" of various stages. Since the reactions going on in the NeuroVascular Unit can be observed continuously, the device was able to provide scientists with a dynamic display of the BBB reaction to systemic inflammation.

The results of the work were described in the article "Metabolic consequences of inflammatory destruction of the BBB on the model of an organ on a chip of a human neurovascular unit" (Metabolic consequences of inflammatory disruption of the blood-brain barrier in an organ-on-chip model of the human neurovascular unit), accepted for publication in the Journal of Neuroinflammation.

Scientists have introduced into the device two different compounds known for their ability to cause an inflammatory process in the brain: large molecules of lipopolysaccharide located on the surface of a certain bacterium, and a "cocktail" of small proteins combined under the name "cytokines" – they play an important role in the formation of an immune response.

"One of the most unexpected discoveries for us was that in response to contact with these compounds, the BBB began to actively synthesize proteins," Brown noted. "Now we need to find out what these proteins are and what their function is."

Scientists also found that in response to inflammation, metabolic processes in the blood vessels of the BBB accelerated, while the metabolism of brain cells slowed down. According to Brown, this may indicate that "the circulatory system is trying to react, and the brain is trying to protect itself."

The hemato-encephalic barrier (BBB) is a network of specialized cells that surrounds the arteries and veins located in the brain. This barrier forms a kind of gateway that provides brain cells with the necessary nutrients and protects them from dangerous compounds.

Portal "Eternal youth" http://vechnayamolodost.ru  08.12.2016

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