How do scientists study the inner workings of human blood vessels?
Cardiovascular diseases are the leading cause of death globally, with an estimated 17.9 million people dying each year. So, preventing and treating them is one of the toughest challenges facing public health today.
The vascular system is made up of blood vessels – arteries and veins – that carry blood around our bodies to deliver oxygen and nutrients. As we age, the structure and function of these vessels declines, leading to damage to the heart, brain, kidneys, and other organs.
For instance, our blood vessels normally have the capacity, known as compliance, to respond to changes in blood pressure. When the pressure increases, they expand to increase the volume of blood they can hold, and when the pressure decreases the reverse occurs.
But blood vessel walls begin to lose this elasticity and become stiffer as we age. As a result, the heart needs to work harder. Vascular stiffening is a contributing factor in several cardiovascular diseases, as well as kidney disfunction, and vascular dementia.
Organ-on-a-chip technology, integrating biology and microfluidics, is revolutionising drug discovery.
Sara Baratchi
The preclinical approaches researchers use to develop drugs to treat these diseases rely primarily on animal models, which don’t reflect human physiology very well. Bigger animals, such as pigs, are a closer match but are expensive to use and have significant ethical considerations associated with them. Smaller animals, like mice and rats, are somewhat cheaper, but have physiologies very different from ours. They too come with ethical considerations.
But a new non-animal approach is changing the game in cardiovascular research: organ-on-a-chip technologies. These microscale devices simulate the activities, mechanics, and physiological responses of entire organs or organ systems.
“Organ-on-a-chip technology, integrating biology and microfluidics, is revolutionising drug discovery by presenting a powerful approach to mimic sophisticated tissue models in vitro and allowing better recapitulation of human physiology and pathophysiology,” Associate Professor Sara Baratchi, head of mechanobiology and microfluidics laboratory at the Baker Heart and Diabetes Institute and RMIT University, told Cosmos.
It is believed that in the future they will replace small animal models.
Sara Baratchi
“These models reduce the cost, and they can reduce the experimental time. Something that you would need six months to develop [with animal models] you might be able to get through in a week.
“It is believed that in the future they will replace small animal models.”
Baratchi and her team have developed a bioengineered model of a blood vessel and used it to identify a potential therapeutic target to slow vascular aging. A paper detailing their discovery has been published today in the journal ACS Applied Materials & Interfaces.
The team’s microfluidic device can mimic both the stiffness of young and aged human aortas, and the blood flow patterns inside them.
It contains a microfluidic channel – just 45 mm long, 3 mm wide, and 0.3 mm high – and, on a separate glass slide, an elastomer of varying levels of stiffness. These components are sandwiched together with mechanical clamps to impart varying stiffness levels to the microfluidic channels.
Then, human endothelial cells – which line blood vessels and control the development of tissue cells in the blood vessel wall – are cultured inside these microfluidic channels.
The device is hooked up to a pump that controls the force of liquid flowing on the cells on surface of the microfluidic channels. This force is called shear stress and it can be another major contributor to cardiovascular diseases, kidney dysfunction, and vascular dementia.
There are two main types of blood flow: laminar and disturbed. Laminar flow happens where the blood vessel is straight and uniform, whereas disturbed flow occurs at branch sites and curvatures.
In areas of disturbed blood flow there is also very low shear stress on the endothelial cells. Here, atherosclerotic plaque – thickening or hardening of the arteries due to the buildup of plaque – tends to develop.
“In blood vessels we have laminar flow – which is a really good flow and its atheroprotective – and then we have disturbed flow patterns which is atherogenic,” says Baratchi.
By culturing the endothelial cells in microfluidic channels that mimic the stiffness of young and aged aortas, and atheroprotective or atherogenic shear stress, Baratchi and her team identified that the protein Piezo 1, an external sensor expressed on endothelial cells, plays a critical role in how the cells sense, and respond to, shear stress and vascular stiffening.
Endothelial cells in a healthy state exhibit non adhesive properties similar to Teflon.
Sara Baratchi
“Piezo 1 allows the cells to sense changes in shear stress and stiffness and that contributes to endothelial aging (senescence) and inflammation under the aging vessels conditions,” she explains.
“Endothelial cells in a healthy state exhibit non adhesive properties similar to Teflon, preventing other cells such as immune cells from adhering to them.
“However, during senescence, which occurs with aging, they lose their non adhesive capacity. Consequently, endothelial cells become inflamed and adhesive, leading to the attachment of immune cells.”
Baratchi and her team believe that by identifying drugs to target Piezo 1, or other signalling pathways activated downstream from the protein, they could prevent or reverse vessel inflammation and arterial stiffness.
This could even alleviate endothelial dysfunction in aging adults, a coronary artery disease that Baratchi says affects more women than men and can cause severe chest pain.
“Endothelial dysfunction does not directly cause an obstruction, instead it can contribute to abnormal vascular tone. In the condition of endothelial dysfunction, the large blood vessels on the heart’s surface constrict, or narrow, as opposed to normal dilation or opening up,” she says
The beauty of the organ-on-a-chip technology is that it can be tweaked to study other forms of cardiovascular disease and improved upon to represent an even better model of human tissues. They aim to design even more complex vascular models that incorporate the 3 dimensional structures of the cell layers that make up the blood vessels.
According to Baratchi, the technology will also be useful for the development of personalised medicine and drug discovery for tackling vascular aging. This is because, unlike in animal models, the cells could be sourced directly from patients to study their specific conditions.
“We have the option to study specific donor samples. We can obtain stem cells from our patients and then differentiate them to different cell types, for example those found in blood vessels, and subsequently mimic specific conditions or test particular drugs,” she says.
“As well as offering pivotal tools for understanding cardiovascular pathologies, drug screening, and assessing therapeutic effects, organ-on-a-chip technology offers diverse study platforms for preclinical research, encouraging innovative approaches to mitigate cardiovascular diseases and ultimately improve patient outcomes.”
