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What if the earliest signs of vascular disease could be observed as they unfold—inside lab-grown human blood vessels that mimic real-life conditions? The research Ranganath Maringanti performed during his PhD, brings this possibility closer to reality. By developing 3D “vessels-on-a-chip”, his work has taken important steps toward modelling complex cardiovascular and renal diseases. Ranganath successfully defended his PhD on August 25.

Driven by a mission: reducing animal experiments

Cardiovascular and kidney diseases are among the world’s leading causes of death. These are very complex diseases, and because of that, researchers still often depend on animal models to study them. Ranganath came to Utrecht determined to find alternatives to study them without depending on animal experiments. “During my master’s, I worked extensively with animal models. That experience motivated me to look for ways to reduce the need for them,” he explains.

Building life-like vessels with multiple cell types

“My main focus of my PhD was to create a vessel-on-a-chip model (organ-on-a-chip) to study atherosclerosis. We wanted to build a model that closely mimics the complex human biological environment of blood vessels,’’ Ranganath says. In the body, multiple types of cells interact to maintain blood vessel health. To replicate this, his team developed a 3D co-culture system, bringing together different human cells in a single microfluidic chip. After much effort to optimize this system, the team successfully recreating functional vessels, what Ranganath calls  ‘’vascular avatars’’.

In his new model, Ranganath used four types of human cells involved in atherosclerosis. These miniaturized vessels, exposed to realistic blood flow and inflammation, reproduced the earliest signs of disease with remarkable accuracy. The chip made it possible to observe immune cell infiltration and fat buildup in real time—processes that drive the first steps of plaque formation.

The power of collaboration

Ranganath’s PhD project shows the strength of collaboration. “My PhD was a joint project between UMC Utrecht and Erasmus MC. I relied on the team in Utrecht for their biofabrication expertise, while the team in Rotterdam provided valuable feedback and insights with their expertise in animal models to bridge the gap,” he explains. This collaborative approach has resulted in innovative models that offer promise for drug testing, personalized therapy development, and reducing reliance on animal experiments.

Broadening the scope with sophisticated experiments

Beyond modeling atherosclerosis, Ranganath applied his models to study other cardiovascular diseases, like aortic aneurysms, as well as kidney diseases, such as chronic kidney disease (CKD). These models allowed genetic manipulation of the cell types and revealed how different cell types communicate when they are exposed to forces like blood flow and vessel stretch during disease development. Ranganath also studied how a genetic risk locus linked to chronic kidney disease affects DNA regulatory elements. He used gateway cloning and CRISPR-Cas methods to investigate these genetic changes, opening new avenues for the treatment.

Resilience in research

Despite the impressive work he accomplished, Ranganath admits that his PhD journey wasn’t without its challenges. “The COVID-19 pandemic disrupted our work, forcing us to delay many experiments. We had to plan everything from home and only go to the lab to run essential experiments. But despite the setbacks, we kept pushing forward,” he recalls. His advice to future PhD students: “Stay calm and resilient.”

Looking ahead

Ranganath has already begun his postdoctoral research at Texas A&M ľ�ϸ���Ӱ��. “In my postdoc, I continue working on atherosclerosis, but now with a focus on mRNA-based therapies for long-term treatment,” he says. “We are using iPSC-derived vascular cells combined with advanced biofabrication techniques to create even more sophisticated vessel models.” techniques to create even more sophisticated models.”