By the time most stroke patients arrive at a hospital, the earliest biological changes are already underway, making these first moments elusive and hard to investigate.  

In the laboratory, researchers work with mouse models to study strokes, but existing techniques don’t allow them to continuously observe those first critical moments using advanced imaging technologies. The onset of stroke, the period that may ultimately determine how much brain tissue survives, has remained largely hidden from view.

Now, Penn Engineers and collaborators at the University of Maryland School of Medicine have developed a tiny inflatable device that is making those first moments visible.

Described in a study published in Advanced Materials, the team’s MRI-compatible elastomeric micro-balloon was designed to precisely and reversibly modulate cerebral blood flow in mice, allowing researchers to capture continuous MRI and two-photon microscopy images. The platform gives scientists an unprecedented look at the brain’s immediate response to ischemic stroke, the most common type of stroke caused when a blood clot blocks an artery. The technology could also help accelerate the search for treatments that must be delivered within minutes of stroke onset.

Led by Shu Yang, Joseph Bordogna Professor in Materials Science, and Jong Bin Kim, a postdoctoral researcher in the Yang lab, this breakthrough began not with neuroscience, but with a materials problem. 

“As materials scientists, we are always connecting the dots,” says Yang. “We start by asking what a material can do. Once we understand those fundamental properties, we can connect them to problems in completely different fields. In this case, techniques we had been developing for soft robotics became the key to answering a longstanding question in stroke research.”

The collaboration began when Yajie (Kevin) Liang, Assistant Professor in Diagnostic Radiology and Nuclear Medicine at the University of Maryland, approached Yang with an idea.

Inspired by Yang’s previous work on light-responsive liquid crystal elastomers (LCEs), materials that can change shape in response to external stimuli, Liang wondered whether similar materials could create a miniature device capable of controlling blood flow remotely during MRI imaging.

Eager to find the right fit, Yang suggested a pneumatically controlled and biocompatible silicone instead of the LCEs controlled by light to create an inflatable micro-balloon that would work with living tissue and MRI technology.

“The original idea wasn’t really applicable to the biological problem,” says Yang, “But we have a repertoire of materials with properties that would be better suited here. I immediately started thinking about what materials and fabrication strategies we already had that could solve this completely different challenge.”

And, the challenge at hand was formidable.

The device needed to be small enough to wrap around the common carotid artery without damaging surrounding tissue. It had to inflate repeatedly, hold different levels of expansion, remain completely free of metal so it wouldn’t interfere with MRI, and reliably return to its original shape after every experiment.

No existing device could do all of those things simultaneously.

“Researchers have developed several ways to block blood flow in animal models, but each comes with important tradeoffs,” says Kim. “Some devices have been designed on larger swine models and include metal components that aren’t compatible with MRI. Those also permanently block the vessel or only allow an all-or-nothing response, and many don’t let us precisely control or reverse blood flow while continuously imaging the brain. We aimed to build a device that could overcome all of those limitations.”

Shrinking an inflatable device to microscopic dimensions introduced an unexpected problem. At that scale, surface tension causes the liquid sheath to undulate and collapse, blocking the hollow core and trapping bubbles rather than forming a long, uniform tube needed for an inflatable balloon.

Kim turned to a natural source of inspiration in the very system they were studying: blood.

“Nature has already solved a similar problem in blood, which can behave like both a liquid and a solid depending on the forces acting on it,” says Kim. “We borrowed those same physical principles to design a material that could hold its shape during fabrication while still remaining flexible enough to become an inflatable micro-balloon.”

Inspired by the way blood can flow like a liquid or act like a solid when it begins to clot, Kim used microscopic silica particles dispersed throughout silicone elastomers to create a yield-stress material that behaves much like toothpaste, remaining solid enough to hold its shape until sufficient force is applied, allowing it to flow.

That unusual behavior stabilized the material during fabrication, preventing it from collapsing under surface tension while it was molded into microscopic hollow tubes.

The researchers then used a multi-step, air-jet bubble-casting process to create a layered structure with regions of different stiffness. One section remained highly elastic so it could inflate, while neighboring regions stayed rigid enough to direct where the balloon expanded.

The result was one of the smallest biocompatible elastomeric inflatable tubes ever created, with an inner diameter smaller than 200 microns.

After Penn Engineers fabricated the device, collaborators at the University of Maryland implanted the micro-balloon and connected it to water-filled tubing.

Researchers could gradually inflate the balloon, partially restricting blood flow, hold it at intermediate states, or completely block the artery before reversing the process, all while continuously imaging the brain.

“I won’t forget the first time we watched the balloon close the carotid artery inside the scanner,” says Liang. “Brain oxygenation fell as we inflated it and climbed back as we released it. Two-photon imaging showed flow in the surface vessels dropping drastically and recovering within seconds.”

 But the real surprise was how much the brain absorbs. 

“We expected blocking the artery to cause enough loss of blood flow that part of the brain would die, creating a stroke lesion,” says Liang. “It doesn’t. In some cases, the animal is able to compensate so well that even blocking both common carotid arteries does not reliably cause a stroke. So actually, this is not yet a stroke-inducing device. It is the first tool that produces controlled, graded, reversible cerebral hypoperfusion during continuous imaging.”

Measuring what happens in the brain when blood flow is variably restricted may provide more valuable insight than a device that shuts the flow off entirely.

“The hyperacute phase of stroke has largely been a black box because we haven’t had a way to continuously observe the brain from the moment blood flow begins to decline,” says Piotr Walzcak, Professor in Diagnostic Radiology and Nuclear Medicine at the University of Maryland and Co-director of PIGN (Program in Image-Guided Neurointervention) along with Miroslaw Janowski. “The ability to remotely and reversibly control blood flow during an MRI fundamentally changes what we can study. Instead of looking only at the aftermath of reduced blood flow, we can now observe how oxygenation and perfusion evolve in real time as the brain responds.”

The ability to capture those dynamics continuously opens doors to new questions previous mouse models could not achieve.

“Now that we can reliably control blood flow during imaging, we can begin asking what individual neurons, blood vessels and supporting cells are doing during the earliest stages of reduced perfusion,” says Jinghui Wang, co-first author and postdoctoral fellow at the University of Maryland.

“Medicine is full of important questions we can’t answer simply because the right tool doesn’t exist yet,” adds Liang. “This collaboration shows how advances in materials science can create those tools and open entirely new areas of discovery.”

The researchers are already exploring whether future versions of the device could actively deliver drugs while controlling blood flow, creating new possibilities for treating stroke rather than simply studying it.

But both Yang and Kim see the micro-balloon as another example of how advances in materials science rarely stay confined to a single field, a hallmark of the research philosophy in the Yang Lab.

The fabrication techniques developed for this project could improve miniature soft robots that move using tiny inflatable chambers. 

“When we hear the problems that arise in clinical settings, we’re always thinking about how to address them with our materials, devices and technologies,” Yang says. “Sometimes a technology developed for soft robotics becomes the solution for neuroscience. Then what we learn from that biomedical application can even come back and improve the original engineering technology.”

Learn more about the work being done in the Yang Lab here.

This work was supported in part by the National Institutes of Health under grant numbers R21AG077631, R03NS123733, R03NS128459, R21AG074978 and R01DA056739. It was also supported by the National Science Foundation through the Materials Research Science and Engineering Center program under grant number DMR-2309043, and by the Maryland Stem Cell Research Fund under grant numbers 024-MSCRFD-6363, 2022-MSCRFL-5893, 2022-MSCRFD-5886 and 2024-MSCRFF-6328.