Mechanical engineer Ovijit Chaudhuri is fascinated by the physical forces that regulate human cells, a phenomenon that can become a matter of life or death when the talk turns to breast cancer.
For instance, researchers know that normal breast tissue is soft while malignant breast tissue is stiff. What interests Chaudhuri is that when he puts normal breast cells into a stiff environment, the cells will begin to behave like cancer cells, growing wildly and becoming invasive and migrating, as occurs during metastasis.
“We see this really striking effect, just by increasing stiffness,” he says. “This is inherently a mechanical phenomenon.”
There is much still to be learned about exactly why this phenomenon occurs. Understanding how enhanced stiffness changes cell behavior might yield profound insights into how cancers develop, grow and metastasize, and suggest new ways to treat cancer.
Chaudhuri’s research explores not only the cells themselves, but also the scaffolding between the cells, known as the extracellular matrix. This gel-like protein lattice is for soft tissues, the equivalent of the steel infrastructure of a skyscraper. As scientists study the matrix more closely, they are finding that it is not merely a framework, but a critical factor in tissue development, providing biological and mechanical signals to help cells grow, the way a gardener will stake tomato plants to improve yield.
“It turns out that it’s not just what’s inside the cell that matters; what’s outside the cell matters as well,” Chaudhuri says.
As researchers learn more about the matrix, they are coming to understand that the nanoscale pushing and pulling that goes on between cells and this external scaffolding helps determine how cells form, grow and function. It would be as if the steel infrastructure of a skyscraper helped determine who occupies its offices, what they do for a living and how they behave on a daily basis.
The notion that mechanics may play a role in everything from stem cell differentiation to cancer metastasis has become a guiding principle of cell biomechanics, a field whose practitioners include not just medical researchers and biologists but also mechanical engineers. Decades ago, engineers helped invent ways to study small-scale mechanical forces. In the manufactured world, they apply these skills to understanding the complex, atomic-level forces at play in materials such as those that make up automobile engines and airplane wings. Increasingly now, they are applying their understanding of small-scale mechanical forces to studies in human biology.
Chaudhuri is taking advantage of advances in biomaterials and microscopy to explore such things as how cells multiply and migrate and, especially, how these processes go awry during disease. His study of the effect of mechanical stiffness on cancer progression is one example. Other tendrils of his work explore how cancer cells move through the extracellular matrix during metastasis and how a dividing mother cell creates room for two daughter cells in already crowded microenvironments, such as a tumor.
“As engineers, we can design really amazing, incredibly complex machines like spaceships and cars, yet we still have limited understanding of how something as fundamental as a cell moves within tissues,” Chaudhuri says. “You have this solid, porous extracellular matrix with holes that can be 100 to 1,000 times smaller than the cells themselves. Yet during metastasis, somehow the [cancerous] cells are able to crawl through the matrix.”
Chaudhuri is also interested in how mechanics can be harnessed for tissue engineering and guiding stem cell differentiation, the biological term that describes how cells specialize to become bone or muscle or other tissue types. In particular, his group is investigating the use of viscoelastic hydrogels for these applications. Contact lenses and gelatin desserts are everyday examples of hydrogels. The term viscoelastic refers to the mechanical response of a material. Some materials are elastic, like rubber bands. Stretch them and they snap back into place when the tension is released. Others materials, such as Silly Putty, are viscoelastic. That is to say they have some fluid-like characteristics and flow in response to force.
Chaudhuri says if you push or pull on Silly Putty, there is some resistance initially, as the Silly Putty will try to hold its shape, but over time the resistance is relaxed as the Silly Putty flows. Over long times, the Silly Putty is also malleable, as the Silly Putty will become molded into the shape of whatever container it is placed in, be it an egg-shaped plastic container or a square-cornered box. It turns out that stem cells and cartilage cells are sensitive to the relaxation, flow and malleability of the hydrogel biomaterials that they are placed in, he says.
His group has found that by culturing cartilage cells in highly viscoelastic hydrogels, improved artificial cartilage constructs are formed, which may be useful as a potential cure for osteoarthritis. Chaudhuri thinks that these viscoelastic hydrogels might be useful in a variety of other applications as well.