CHAMPAIGN, Illinois — Scientists have developed a tiny mechanical probe that can measure the inherent stiffness of cells and tissues, as well as the internal forces the cells generate and exert on one another. Their new “magnetic microrobot” is the first probe of its kind that can quantify both properties, the researchers report, and will help to understand cellular processes involved in development and disease.
They describe their results in the journal Science Robotics.
“Living cells generate forces through protein interactions, and measuring these forces is very difficult,” said Ning Wang, a professor of mechanical and engineering engineering at the University of Illinois Urbana-Champaign who led the research. “Most probes can either measure the forces actively generated by the tissues and cells themselves, a property we call traction, or they can measure their stiffness — but not both.”
To measure cell stiffness, researchers need a relatively rigid probe that can compress, stretch, or twist the tissue and quantify how robustly it resists. But to measure the contractions or expansions produced by the cells themselves, a probe needs to be relatively soft and pliable.
Like other scientists, Wang and his colleagues had already developed probes to measure each of these properties individually. But he said he wants to develop a more universal probe that can address both at the same time. Such a probe would make it possible to better understand how these properties affect diseases such as atherosclerosis or cancer, for example, or how an embryo develops.
To address this challenge, Wang and graduate student Erfan Mohagheghian looked for ways to alter a probe’s mechanical properties after it was injected into the tissue of interest. They used hydrogels made from polyethylene glycol, a material already approved for use in humans.
For the new study, the team developed a precise method for embedding a magnetic “microcross” into a rigid PEG hydrogel. Study co-author Kristi Anseth, a professor of chemical and biological engineering at the University of Colorado, Boulder, had already developed a method to use ultraviolet light to break down and soften the hydrogel.
In a series of experiments, the researchers injected their probes into lab-grown 3D tumor masses and into zebrafish embryos. By exposing these tissues to an electromagnetic field, the scientists activated the probes to apply various stresses to the tissues and measure tissue stiffness. By exposing the tumor mass or the embryos to UV light, the probes’ PEG matrix softened, allowing the probes to measure the forces generated by the cells in the tissue.
The probes provided accurate information on both tissue stiffness and traction, showing for the first time that while malignant tumors can stiffen in response to surrounding tissue, cancer cells do not alter their traction regardless of their proximity to soft or stiff materials. Wang said this challenges a common perception that the physical properties of the underlying tissue cause changes in the internal forces of cancer cells that allow them to metastasize.
“People thought that the rigidity of the substrate was the driving force behind cancer progression,” Wang said. “Our results do not support this claim.”
The probes also captured the pushing and pulling of cells during embryonic development, which could provide new insights into how such vibrations correspond to the patterning of organs, tissues and limbs as animals develop from single cells to complex tissues, Wang said. The embryonic work was carried out by researchers from the Chinese Academy of Sciences and Huazhong University of Science and Technology in Wuhan, China.
“We believe that the large force oscillations detected in the embryos are very important in driving the early developmental stages,” Wang said.
Wang is also a professor of bioengineering and a member of the Carle Illinois College of Medicine, the Beckman Institute for Advanced Science and Technology, and the Carl R. Woese Institute for Genomic Biology at the U. of I.
The National Institutes of Health, the National Science Foundation, and the National Natural Science Foundation of China supported this research.