John Slater, an assistant professor of biomedical engineering at the University of Delaware, has received a National Science Foundation (NSF) Career award to develop a tissue-engineered model of ischemic microstroke.

The grant, which is expected to total $530,000, started on March 15, 2018 and will last until February 28, 2023.

Slater develops three-dimensional, biomimetic models that mimic the microenvironment of human cells and can be manipulated to induce desired cellular traits. For this project, he is modeling microstrokes—small, temporary blockages in brain blood flow that affect an estimated 50,000 Americans per year. These brain attacks, which can induce mild symptoms or even none at all, can damage brain tissue and increase their victims’ risk of dementia later in life.

Most ischemic microstrokes are caused by clots that form in one or more of the brain’s tiny blood-carrying capillaries. To model brain blood flow during microstrokes, Slater will induce a clot in a vascular system made from healthy brain cells and a hydrogel that mimics tissue. Blood clots form when an enzymatic cascade converts the blood protein fibrinogen into fibrin, which polymerizes and hardens. Slater will blend fibrinogen and a photo-crosslinked hydrogel, which will allow him to control the formation—and dissolution—of the clot. He will utilize laser-based hydrogel degradation to generate brain mimetic vascular networks in tissue-engineered hydrogels with short pulses of light and quantify how the clots induce cellular damage.

Slater was inspired to start this project after he met Andy Shih, an assistant professor of neuroscience at the Medical University of South Carolina, at a research retreat. Shih studies microstrokes in rodents using an imaging method called two-photon microscopy, and Slater was intrigued by his work. While animal studies can reveal some information about how microstrokes form and dissolve, they have limitations. For example, it is difficult to control the formation and removal of clots in animal experiments. Slater suspected that he could use tissue engineering to induce and remove clots, yielding additional insights.

“There are things that cannot be measured in animals that could be measured in vitro,” Slater said. “We hope to learn more about the intracellular processes involved in microstrokes, and we plan to conduct imaging tests that would be extremely difficult to do otherwise.”

It will likely take Slater three to four years to get his model up and running and another year or more to validate it. He aims to pair the insights from his model with the results of Shih’s rodent studies to develop a more holistic view of how microstrokes form and dissolve and their impact on brain tissue.

Complementary effort

Slater’s expertise in biomaterials complements Shih’s work.

“His experience with biomaterials may yield powerful tools to form and remove clots on-demand in the live animal’s brain,” Shih said. “This will make way for some very elegant experiments that reveal the resilient and fragile aspects of the brain microvasculature. In return, we are able to inform some of the in vitro models he is generating. Building a flowing replica of a brain blood vessel in a dish is not trivial. It involves overcoming many challenges including harnessing vascular cells to grow properly and applying the right flow and pressures to mimic flow in the living brain. We are able to provide these benchmarks for his research, so he can build more accurate models.”

Slater is applying his tissue engineering expertise to microstrokes for the first time with this project.

“From my standpoint as an engineer, it poses interesting and difficult engineering challenges,” Slater said. “No one else is working on fluidized in vitro microstroke models, so if we can make this work, we may open up a whole new avenue of research on microstrokes.”

Slater hopes this work will eventually open the door for research on new stroke treatments and strategies to regrow brain tissue damaged during strokes. Only one drug has been approved by the FDA for acute stroke treatment, although hundreds of hopefuls have been tested.

“We don’t yet know enough about how strokes work to make effective drugs for prevention or repair,” Slater said.

In addition to Shih, Slater is collaborating with Kelvin Lee, Gore Professor of Chemical and Biomolecular Engineering at UD, on this project. Lee and John Ruano-Salguero, a doctoral student in chemical engineering at UD, are developing blood brain barriers from induced pluripotent stem cells that will aid in forming brain mimetic vasculature.

Cindy Farino, a doctoral researcher in biomedical engineering at UD, will help Slater conduct experiments for this project. Sylvie Lorthois, Director of Research at the Institute of Fluid Mechanics of Toulouse in France, will lend expertise in computational fluid dynamics to assess flow and transport through the model.

The grant will also fund outreach through UD’s annual Art in Science program and exhibit, which Slater is the faculty director for.

The NSF Career Award is among the most prestigious grants for junior faculty members.

“I feel honored to receive it and look forward to developing and validating this new model,” Slater said.

In January 2018, Slater was named a “Rising Star” by the Biomedical Engineering Society’s Cellular and Molecular Bioengineering group.

UD’s College of Engineering has had 34 NSF Career Award recipients since 2000.

“We are proud of John Slater’s NSF Career Award,” said Dawn Elliott, chair of the biomedical engineering department at UD. “His novel methods to study how cells respond to physical and chemical cues will have important impacts in tissue engineering and in developing drug screening models.”