About a year ago, the world’s smallest hammer came into being. Developed at UCSB, it was designed to apply impact loads to cultured human neural stem cells, which could then be studied to better understand the effects of traumatic brain injury (TBI) at the cellular level. After a year of testing the device, cells are now being hammered and studied by the team, which includes UCSB mechanical engineering professors Kimberly Foster and Megan Valentine; Neuroscience Research Institute professional researcher and lecturer Adele Doyle; PhD students Luke Patterson and Jennifer Walker; and industry partner Owl Biomedical, Inc. in Goleta.
As is true of any collaboration, this one didn’t just happen. It took effort, communication, awareness, planning, dedication, and a touch of serendipity. There was no single starting point.
The kernel of the idea came to Foster as she thought about the fruits of some consulting work she had done for Owl Biomedical, which developed micro-fluidic cell-sorting technology. Foster found herself wondering what else she could do with similar technology “that would be fun and exciting and make it possible to do something that currently could not be done.”
A self-described “applied mechanician by training” who focuses on “building little tiny machines that you either can’t see or can barely see,” Foster had been interested for some time in finding biomedical applications for her work.
Cool project: PhD student Sarah Grundeen (electrical and computer engineering) removes neural stem cells from a cryostorage tank, to be hammered in an experiment. Grundeen is co-advised by Adele Doyle and electrical and computer engineering professor Luke Theogarajan. Photograph by Matt Perko
The origin story of this collaboration includes the fact that, as an athlete and former bicycle racer who had seen many of her favorite athletes get knocked unconscious, Foster had long been interested in TBI. Despite the fact that about 1.7 million TBIs occur every year in the United States, she says, “We have remarkably limited understanding of TBI at the cellular level — which cells are affected and why, what exactly happens to affected cells, and which system is responsible for the associated loss of function and should therefore be the target for therapy.”
That interest was present as an undercurrent during Foster’s occasional meetings with Valentine, who was studying molecular mechanisms of neurological diseases. They began to discuss how their research might be mutually beneficial and which funding agencies they might want to target.
“Even before there was a discussion of the micro-hammer, I had the desire to tap in to the micro-tool area,” says Valentine, who came to UCSB in 2008, attracted partly by the university’s strength in micro-bioelectronics.
Foster describes the decision to include Valeninte on the team as a “no-brainer,” saying, “I really like the style of Megan’s work. She’s interested in the link between force and function in cells, and she’s working at a very fine scale.”
“My prior training that really impacts this study is expertise in cell mechanics,” Valentine says. “How do cells respond to force, what are their elastic properties, what are their viscous properties, how do those cellular properties depend upon the constituents, and what’s the relationship from molecular features up to cell-level responses?”
Valentine’s lab group has developed techniques useful in studying mechanics and applying loads to cells. But, she notes, “We were never able to push the envelope to achieve strains and loading rates that were relevant to brain trauma.” With Foster, she adds, “We eventually identified this question of what happens when cells are experiencing really high loads and high impacts, and what are the tools that might allow us to study that?”
Against that background of dovetailing interests came PhD student Luke Patterson. Having majored in physics and mechanical engineering as an undergraduate at Westmont College, he entered UCSB in 2014 knowing that he wanted to do collaborative research and was interested in the nervous system and going in a biomedical direction.
He was given office space with Foster’s group, and while looking for possible projects, she described her idea for the micro-hammer. Together, Foster and Patterson designed the prototype hammer as an unfunded project, hoping to acquire the proof-of-principle data required by funding agencies.
Once they had built the device, Foster began thinking about which cells she should hammer with it. “It was an interesting question,” she recalls, “and I spent a lot of time talking with people in biology, even outside of UCSB, about what would be interesting to hammer with this mechanism.”
Serendipity then occurred when Bridget Queenan was hired as the associate director of the UCSB Brain Initiative (BRI), and over an introductory lunch one day, Foster shared the micro-hammer idea with her. Queenan then mentioned the hammer to her colleague Adele Doyle, and encouraged her to contact Foster. She thought that Doyle’s expertise in measuring mechanosignaling at high-throughput using techniques she had developed for reading genetic expression in single cells would be a good fit for the project.
“Bridget ended up seeing connections that we had not necessarily observed in each other,” Doyle recalls.
Right around that time, Foster saw an article about President Obama’s nascent federal brain initiative and a call for proposals for team research on ideas for neuro-engineering. She set out to formalize the team.
Hard-hitting team (from left): Megan Valentine, Kimberly Foster, and Adele Doyle. Photograph by Matt Perko
With Patterson already on board, Foster asked Valentine and Doyle to join. Queenan helped to write the proposal, and six months later, the project Foster originally thought of as a long shot was funded.
The group decided to use neural stem cells because they flow well through the device, and the researchers could study whether force affected the cells’ unique capacity to become other types of cells.
“Since TBI patients also suffer increased risk for Alzheimer’s disease and dementia years after the initial injury, a current roadblock to patient care is understanding how regenerative cells in the body, such as neural stem cells, respond to external brain impact,” says Doyle. “We wanted to define this and then help design improved clinical treatments.”
Foster and PhD candidates Patterson and Jennifer Walker have spent the past year working to refine the hammer to make sure it functions correctly, while also working with their faculty PIs on design and parameters for experiments they could run when it was ready to go. The student researchers also collaborated with counterparts in the Valentine and Doyle labs to learn about microscopy and molecular measurement techniques, respectively, that could be useful for the experimental work.
With the device now operating, the researchers are hammering , collecting, and culturing cells and applying their techniques to investigate various states of interest they observe.
“I’m really excited by the micro-hammer project,” Valentine says. “I think we’re one of the few groups who can get into this range of very high forces and very rapid force impacts. And the fact that we can do that on thousands of cells in a single experiment and then collect the cells and track them over time — that’s incredibly unique.”
Watch for further collaborations as the research evolves.