Those who study human disease, and those of us who benefit from treatments developed by their research, owe a great debt to mice. The tiny animals get many of the same diseases as us and have very similar genetics and biological processes, making them a useful stand-in for understanding what goes wrong in our bodies and how we might respond to novel therapies. But as a surrogate for humans, mice aren’t perfect, says Assistant Professor of Mechanical Engineering Aditya Raghunandan, who started at UM-Dearborn in 2023. All you have to do, he says, is look at the thousands of human clinical trials for new treatments that showed promise in mice but failed to deliver similar results in humans. Experimenting on human cells in the lab offers a promising alternative, because researchers can theoretically study diseases more directly. But, like mice, this technique has limitations: Raghunandan says how cells behave, isolated from their neighbors and living in an artificial environment in the lab, isn’t necessarily how they behave in our bodies.
In his early days as a researcher, Raghunandan often speculated that there had to be a better way, and as luck would have it, his career intersected an era of bioengineering in which some transformative new methods were emerging. In the early 2000s, researchers from the Wyss Institute at Harvard University developed a novel technology they dubbed “organ-on-a-chip.” Like traditional cell culturing, the idea was to create an experimental environment for human cells in which researchers could subject them to all kinds of things — genetic engineering, toxins, new drugs, mechanical and chemical signals — and then see how they behave. But their technique promised several advantages. Traditional cell cultures typically contain just one or two cell types, living in some kind of media, but that environment isn’t particularly representative of how things work in our bodies. For one, Raghunandan says our cells don’t just float around statically in goo; they're constantly being subjected to things like fluid flow and mechanical forces, which greatly influence their health and regulate their function. Moreover, a key part of cell function is interacting with other cell types. If you’re just observing how one cell type reacts to something in a Petri dish, he says you’re only getting a small slice of the picture.
Organ-on-a-chip technology, which has been tweaked and improved in the decades since its invention, directly addresses these shortcomings. Raghunandan says you can sort of think of the difference between an organ-on-a-chip and a traditional static cell culture like the difference between a house and a studio apartment. In a traditional cell culture, there’s just one room and everything is just kind of thrown in that room. But with an organ-on-a-chip, you can put up to three or four different cell types in different rooms within the house. Just as walls divide the rooms of the house, membranes keep the cells where you want them, and by tweaking the porosity of the membranes, you can also facilitate different kinds of interactions between cell types. Most importantly, tiny microfluidic channels, smaller than the width of a human hair, function like hallways, connecting the rooms, allowing researchers to pump in fluids to mechanically and chemically stimulate the cells in very precise ways.
The setup much more closely resembles how things work in our bodies, Raghunandan says. For example, in his own lab, where he studies how fluid flow in the brain impacts protein aggregation, one of the factors linked to neural diseases like Alzheimer’s, he builds layered organs-on-a-chip that mimic the way that neural and blood vessel tissues are organized in our brains. “If we go from the bloodstream into your brain, the first barrier are endothelial cells. And then the next layer of cells are smooth muscle cells, then you have an empty compartment where you have fluid, and then you have astrocytes,” he explains. “So the brain is layered, and we can reproduce these compartments and membranes and fluid flow where everything can interact with each other.” You can breed a mouse to have a predisposition to develop a certain disease. But you can’t manipulate fluid flow in its brain in real time, he says. “I can do that just by turning a knob on a pump.”
Being able to manipulate fluid flow is extremely important for Raghunandan’s current research. During his recent postdoc at the University of Rochester, he worked with the teams of Mechanical Engineering Professor Douglas Kelley and Neuroscience Professor Maiken Nedergaard, where they discovered that the brain actually has a separate “plumbing system” that bypasses the blood-brain barrier and flushes away waste while we sleep — almost like an alternative lymph system that only exists within the brain. Raghunandan says about half of the waste is physically flushed away, the way your plumbing removes waste from your house. But the other half requires specialized enzymes that are secreted by specific brain cells, like smooth muscle cells, which chop up or digest waste proteins. What’s surprising, Raghunandan says, is that abnormal fluid flow can actually change these cells' behavior in ways that make them less effective. That is, fluid flow in the brain isn’t just a plumbing system. It’s a dynamic that, in itself, can directly change cells and how they function.
Raghunadan says the research teams made these initial discoveries using mice models. But to investigate the details of how abnormal brain fluid flow was impacting Alzheimer's patients — and potentially develop therapeutics — he knew he’d need a different platform. This led to a fruitful collaboration with University of Rochester Biomedical Engineering Professor James McGrath, who had developed a new organ-on-a-chip technology to study inflammation in the brain. Now, Raghunadan is adapting that technology in his own lab to expose brain cells to varying types of fluid flow and precisely measure the effects. That’s something he could never do in a static cell culture or with mice. Raghunandan and McGrath have also created their own custom organ-on-a-chip devices that are much faster to build. “With the original design, it took a long time to build them — maybe a couple days to build 10 devices, and not all of them were going to be successful,” Raghunandan says. “We’ve streamlined the design, so now you can put together the parts like Legos and it takes three minutes.” McGrath even started a company so other researchers can use the snap-together version in their work.
Raghunandan, who’s one of only two researchers that he’s aware of at UM-Dearborn currently using this technique, sees some big practical benefits if this technology is more widely adopted. First, he says you could test new drugs on human cells in an organ-on-a-chip device to get some preliminary indication of their efficacy before moving them to full-blown human clinical trials. Second, we could use organs-on-a-chip to do patient-specific modeling for drugs. “If you had a certain disease, we could biopsy your cells, build a ‘you-on-a-chip’ and then test a drug to see if it had the potential to be a useful therapy for you,” he says.
###
Story by Lou Blouin. Photos by Annie Barker.
