Blood Vessel-on-a-Chip To Understand Vascular Malformations

60,000 miles of intricate pipelines make up our bodies, and they are essential for distributing nutrition, removing waste, and replenishing our organs with new oxygen and blood. A category of uncommon hereditary diseases known as vascular malformations (VMs) is characterized by the aberrant creation of veins, arteries, capillaries, or lymphatic vessels at birth. By generating obstructions, poor drainage, the growth of cysts, and tangles, VMs can obstruct the functions of our priceless pipes.

William Polacheck, Ph.D., an assistant professor at the UNC-NCSU Joint Department of Biomedical Engineering and the Department of Cell Biology and Physiology, and his group from the UNC School of Medicine have created a model that mimics VMs that are specifically brought on by a mutation of PIK3CA—a gene that has been linked to numerous forms of lymphatic, capillary, and venous malformations—in order to fill a need for additional research.

Science Advances published their research.

“There are a number of ‘chicken and the egg problems’ of the PIK3CA mutation,” said Polacheck. “Is it causing something else to go wrong? Or is there something else in the environment that’s causing the mutation to have more severe effects? Working in a much more controlled environment, such as a microfluidic model, allows us to isolate and figure out how the genetics of the disease relate to what is happening in the cells.”

Gene mutations that control how the body’s vasculature develops throughout the body are the source of VMs. One of the genes is PIK3CA, short for phosphoinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha. In a figurative sense, it is a “hotspot” for mutations that lead to abnormalities in the smaller blood arteries, which result in blood pooling under the skin.

Little research has been done on this particular type of vascular abnormality, which is typically seen at birth. Some illnesses begin when the baby is still developing. At this stage of the child’s development, there are a lot of changes occurring, making it challenging for researchers to study.

Developing a Team

A new strategy to simulate the illness, which affects the majority of her patients, was required, according to Julie Blatt, MD, a professor of pediatric hematology-oncology in the UNC Department of Paediatrics.

Dr. Blatt picked up the phone and cold-called Polacheck, who is a biomedical engineer by profession, to ask whether he could develop a microfluidic model of PIK3CA0-specific vascular malformations. Dr. Blatt is interested in repurposing cancer medications to treat young patients with vascular anomalies.

Wen Yih Aw, Ph.D., was simultaneously completing her postdoctoral degree at UNC Catalyst, a research team at the Eshelman School of Pharmacy devoted to researching uncommon diseases. Aw eventually began working with the Polacheck lab using basic science on different projects.

In addition to Blatt and Aw, the lab has collaborated with Boyce Griffith, Ph.D. in the Department of Mathematics and the Computational Medicine Program, who is helping with analyzing the structures of the networks.

“All those pieces, I think were necessary to complete the work,” said Polacheck. “It does say something about UNC because there were multiple colleges and departments working together. There were no barriers whatsoever to working together on this project.”

A Microfluidic Model’s Operation

Microfluidic models are tiny, three-dimensional objects that can be used to imitate or manipulate the environment inside the body. They are only a millimeter in size. In this instance, the device’s interior is centered with a little chunk of healthy blood vascular tissue. From there, the scientists can modify the model by adding particular chemicals and mechanical forces to mimic bodily situations. The PIK3CA mutation is then started by them.

The researchers needed to carry out a pharmacological efficacy study to determine whether or not their model accurately depicts the disease’s appearance.

Rapamycin and alpelisib are two medications that are now being utilized to treat vascular malformations. The FDA has approved the latter, a recently identified PIK3CA-specific inhibitor, to treat select forms of breast cancer and the PIK3CA-related overgrowth spectrum. Pre-clinical research in people and rodent models has so far demonstrated that alpelisib is more successful in correcting vascular malformation abnormalities.

Polacheck and Awe chose the two medications and then treated their equipment. The research was successful.

“The blood vessel used to be really dilated and large,” said Awe, who was the first author of the study. “With the treatment, the drug was able to shrink it and, more or less, revert it back to a normal shape and function. We were very excited to be able to replicate some of the results in vitro with the model that we built.”

Moving forward, Awe and Polacheck are looking to replicate the finding in tissues from vascular malformation patients, especially those who don’t have the PIK3CA mutation or don’t have clear genetic information. Their model can now be used to evaluate new medications or to perform synergistic drug studies.

Several Paths for Future Research

Wen and Polacheck intend to utilize their model to investigate the temporal dynamics aspect of the mutation as well as how the mutation impacts lymphatic tissue abnormalities now that they have proven that it is accurate.

A single cell that develops the PIK3CA mutation initially causes the disease. The effects of the mutation in that one cell then spread to the other cells, much like a chain reaction, until the deformity is completely developed. The lab is now unable to replicate that natural process with its model.

Wen, though, is already developing a fresh strategy for a microfluidic model. She wants to develop a system that will let them begin with healthy cells, “flip on” the mutation and watch it spread across the target region. In the end, it will aid in their understanding of how the mutation might impact other cells and travel over space.

In lymphatic tissue, vascular malformations can also happen. Unlike blood veins, lymphatic tubes serve as a superhighway for immune cells to reach infection sites while recycling extra fluid throughout the body.

“The outputs are slightly different because the function of the lymphatics is different from blood vessels,” said Polacheck. “By comparing and contrasting what happens on the blood side and the lymphatic side, we will also be able to learn something about the basic biology of those two types of tissues.”

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