When doctors diagnose a torn ligament, it’s usually because they can see ruptures in the ligament’s collagen fibers, which are visible on a variety of different scans. However, doctors also often treat patients who have symptoms of a tear, but whose ligaments don’t show this kind of damage.
Penn engineers are using network science—a discipline that historically analyzed computer systems and social dynamics—to gain new insights into these “subfailure” injuries.
Such injuries can lead to pain and dysfunction despite the lack of obvious physical evidence; the mechanisms that lead to these symptoms happen on a microscopic level and can’t be detected by existing clinical tools.
In a recent study, the researchers put human ligament samples to the test, stretching them until they tear, while looking at these microscopic features. The research was conducted by Beth Winkelstein, professor in the departments of bioengineering in the School of Engineering and Applied Science and neurosurgery in the Perelman School of Medicine; Sijia Zhang, a graduate student in the Winkelstein lab; and Danielle Bassett, the Skirkanich Assistant Professor of Innovation in Engineering.
Earlier work in the Winkelstein lab showed microscopic evidence of the first tears appearing in a ligament as it was put under strain. These visible ruptures are often initiated by disorganization of ligament fibers, which amount to a few pixels on an optical scan.
Zhang was interested in adding more context to the picture, hoping to explain the incidence of pain by showing how this collective rearrangement of collagen fibers prefigured visible damage.
“Our hypothesis was that the cells embedded in the collagen matrix are being stretched during ligament loading, affecting cell behaviors, so we set out to see how the matrix is being reorganized under strain,” Zhang says.
Zhang was enrolled in Bassett’s introductory class on network science, a discipline that investigates how individual elements of complex systems interact to determine the system’s overall behavior. There, Zhang brought in data obtained from experiments in the Winkelstein lab in which stretched ligament samples were imaged with a system that uses polarized light. Much like how polarized sunglasses work by blocking all light aligned at a particular angle, this system can show the orientations of the fibers by measuring how much light they allow through.
By using analysis techniques she learned in Bassett’s class, Zhang was able to show the degree to which concerted reorientation prefigured the spots where failure first occurred.
“Network science offers a fundamental explanatory mechanism for subfailure damage, a process that we think may lead to pain,” Bassett says. “If a single fiber is turning, a tear is unlikely, as is the activation of pain fibers; but when there is a coordinated change in many fibers, pain and tears may be more likely.”
The team’s findings raise the possibility of particularly injury-prone “domains,” the presence and location of which might explain why different people respond to the same type of injury with different outcomes.
Their network-science-based analysis is also being pursued in experiments in which Zhang is using synthetic tissues she has designed to test theories of failure in a more systemic way.
“Since we have hypotheses based on the networks, we can now examine those relationships between ligament and cells and the grouping of both,” Winkelstein says. “By controlling them in the lab by making them in vitro to specification, we could start to actually test how failure happens and what that means on the cellular level.”