Illustration shows silhouette of human head revealing outline of the blood-brain barrier that covers and protects the brain.

When blood meets brain: New lab models to explore role of blood in brain’s protective layer

Could bring improved diagnostics and treatments for dementia, stroke, brain trauma, and more

The blood-brain barrier has been called one of neurology’s greatest challenges. The thin, selectively permeable membrane acts almost like plastic wrap, protecting the brain tissue from dangerous pathogens and toxins in the blood. In short, it maintains the brain’s integrity and helps keep you alive. But the same barrier, which is made of an often impenetrable network of tightly bonded cells, has also proven effective at keeping out beneficial drugs that could treat brain-related diseases like stroke and dementia, and that could also help in the repair of traumatic brain injury caused by accidents or combat.

Researchers have spent decades trying to develop improved drugs that are capable of passing through the blood-brain barrier (BBB), and they’ve created animal models to mimic and understand how the complicated barrier works.  But these efforts have often fallen short, leaving in their wake a severe shortage of viable treatments for brain disease and injury.

This image illustrates blood flowing through the Blood-Brain Barrier landscape
Illustration shows blood flowing through the Blood-Brain Barrier landscape. Courtesy of Edward Neuwelt, M.D.., Oregon Health & Science University.

That could change with the recent launch of the Trans-Agency Blood-Brain Interface Program, a research program developed by the National Heart, Lung, and Blood Institute (NHLBI), in collaboration with the Department of Defense Joint Program Committee-6 (JPC-6), Combat Casualty Care Research Program.

Researchers in the new program have a big goal: They want to develop tiny, bioengineered models of the BBB that mimic the human counterpart more closely than current animal or lab-based models. And they want to use these new, more sophisticated versions to better understand crosstalk between the BBB and the blood—something that has not been attempted before on a large scale.

“The blood component has been a missing piece of the puzzle in blood-brain barrier research,” said Margaret Ochocinska, Ph.D., the program’s director from the NHLBI’s Translational Blood Science and Resources Branch in the Division of Blood Diseases and Resources. “Historically the focus on blood-brain barrier research has been on the brain or the barrier, but not the blood.”

This is mainly because blood is a complex system that is difficult to model. It contains a diverse pool of chemicals and cells that play wide-ranging roles in the body including nutrition, waste removal, disease-fighting, wound healing, and cell-to-cell communications. Likewise, blood flow and blood pressure impact the brain and organs and must be well-controlled for optimal health.

“The blood is not just a passive fluid that courses through our veins, but rather an active participant in the regulation of the blood-brain barrier or “interface” as it is more accurately described,” Ochocinska said. “It is key to understanding this protective barrier.”

Yet, the precise role of the blood in the blood-brain interface, particularly in the development of neurological disorders and brain injury states, is largely unknown and under-researched, as was pointed out by a group of blood-brain barrier experts who met in 2016 during a special National Institutes of Health workshop assembled to address challenges and opportunities in this area. The intent of the new program is to shed light on its role by melding the study of blood with neurovascular research into a new area of “neuro-vascular-blood science,” Ochocinska said.

The program will draw upon the expertise of multidisciplinary teams of scientists—blood experts, vascular experts, neuroscientists, circadian rhythm researchers, and BBB tissue chip developers. 

Together, she said, they will help build a next generation of BBB models that could help reveal disease mechanisms and identify new treatments. 

The $30 million program has already funded projects by four research teams and plans to fund up to six more by September 2021. Each project will have two phases—during the first 1 to 2 years, the researchers will develop models to study the role of blood and vascular components across the BBB; during the next 3 years, the researchers will try to characterize the role of individual blood components, including cells and molecules, on the function of the BBB.

The model BBBs represent the latest tissue-chip, or organ-on-a-chip, technologies that have been celebrated within research circles over the last decade. These tiny devices typically take the form of plastic chips or miniature boxes, some as small as two AA batteries. They are bioengineered to support human tissues and cells and mimic complex biological functions of organs and systems. For this reason, they are also called Microphysiological Systems (MPS) platforms. This small, controlled environment allows researchers to more easily and efficiently study disease components than larger, more complex animal models, and very importantly, all with human cells. Thus, MPS platforms can complement and extend on existing animal models.

This image shows a close-up of a 96-well plate, a rectangular lab dish containing multiple wells that serve as test tubes, that researchers are developing into a new and improved model of the blood-brain barrier.
A 96-well plate—a rectangular lab dish containing multiple wells that function as test tubes—that researchers are developing into a new and improved model of the blood-brain barrier.

In one of the funded projects, researchers will develop an MPS model to study Huntington’s disease, an inherited brain disorder that causes nerve cells in the brain to break down over time resulting in uncontrolled movements, emotional problems, and loss of thinking ability. Symptoms usually appear in a person’s thirties or forties and the condition has no cure.

“Evidence suggests that Huntington’s disease involves a malfunction of the blood-brain barrier and we would like to see how this occurs by recreating this malfunction in an MPS platform,” said Christopher C.W. Hughes, Ph.D., a researcher in the Department of Molecular Biology and Biochemistry at the University of California at Irvine and a principal investigator in the program along with Huntington’s Disease expert and UC Irvine professor Leslie Thompson, Ph.D. “Our model will very closely mimic the natural physiology of the human blood-brain barrier, including its blood flow, to help us understand this devastating disease.”

Hughes’ model is a palm-sized plastic box he calls a “Vascularized Micro-Organ Platform.” It consists of three layers. A microfluidics layer, containing the tissue, is sandwiched between a tissue culture plate and a transparent protective bottom layer. Microfluidic “arteries” and “veins” within the middle layer are connected to each other by a living human capillary network that has all the characteristics of BBB-type blood vessels in the brain. The vessels carry a blood mimic that feeds nerve cells growing around the vessels, just like in an actual brain. 

“We’re going to start off with normal brain cells and see how they interact with the blood-brain barrier, and later we’ll add brain cells containing the Huntington’s genetic defect to see what malfunctions might occur in the barrier cells,” Hughes said. “We’ll also look at how these barrier cells communicate or ‘crosstalk’ with each other, which is critical to the structure and function of the BBB. And, most importantly, we’ll also be looking at the role of blood in this process.” 

The life-like model could lead to the development of drugs that effectively target Huntington’s. It could also shed light on the role of the blood-brain interface in other neurological diseases, including Alzheimer’s, Parkinson’s disease, stroke, Multiple Sclerosis, and traumatic brain injury, Hughes said.

Other BBB models funded by the program will study how strokes form in people with sickle cell disease; examine the brain injury mechanisms behind the life-threatening hospital infection known as sepsis; and explore traumatic-brain injury caused by falls, accidents, battle wounds, and other sources of head trauma. Lessons learned from these models can be applied to other diseases that are affected by injury to the BBB, including COVID-19 and other viral-based diseases.

“In recent years researchers have learned a lot about the crosstalk between circulating blood cells and the endothelium – in particular in the context of inflammation following injury,” said W. Keith Hoots, M.D., director of the NHLBI Division of Blood Diseases. “However, less is known about how this crosstalk occurs in blood vessels at the blood-brain barrier and what is the downstream impact on the brain itself. This new initiative is designed to decipher this important mechanism in response to injury on the brain side and the blood side.”

And hopefully it will lead to better treatments for brain disease and injury, researchers say.