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ANN ARBOR --- As scientists work to develop engineered tissues that someday may be used to replace diseased or damaged body parts, they face some daunting challenges. Even when tissues are successfully grown in the lab, the engineered tissues are not as strong as the ones that nature makes. But new research by a University of Michigan team suggests ways of enhancing the mechanical properties of engineered tissues. The work is described in the October issue of Nature Biotechnology.
By repeatedly applying strain while engineered tissues were developing, the researchers were able to increase both the expression of key structural protein genes and the organization of the cells making up the tissues. This, in turn, led to significant enhancement of the tissues' strength.
The approach was a logical one, explains David Mooney, associate professor of dentistry and engineering who directed the project. It has long been known that mechanical forces influence development of many natural tissues in the body---bone and cartilage, for example. Other research groups have shown that engineered smooth muscle responds to mechanical stimuli as well. But the U-M research provides a clearer understanding of exactly how mechanical stimulation leads to increased strength.
"The major contribution of this paper is that it demonstrates an interaction between the chemistry and the mechanics," Mooney explains. "It was not a great leap on our part to say that strain would alter the development of tissue. What was novel was that we were able to demonstrate that mechanical signals must come through certain molecules to which the cells attach. Both from a basic science perspective and as a potential application, that's very important."
The engineered smooth muscle tissue used in the experiment was created by seeding cells onto sponge-like "scaffolds" made of a biodegradable material. As the cells multiplied, they filled in the open spaces, eventually building their own framework as the scaffold degraded. As the tissues were developing, the researchers clamped them to devices that repeatedly exerted a gentle pull similar to what natural blood vessel tissue experiences as blood pulses through the vessel. Tissues that were exposed to this strain for five to 20 weeks showed increased production of the structural proteins elastin and collagen, but only when grown on a specific type of scaffold. In other words, explains Mooney, "the type of molecule to which a cell was attached dictated its response to the mechanical signal."
The researchers also examined the alignment of cells within the engineered tissues to see whether mechanical strain altered the tissue's structure. They found that being exposed to repeated strain for 10 weeks resulted in a more orderly arrangement.
The tissues were then tested with a machine that measured the force needed to tear them apart. Those that had been subjected to strain as they developed were better able to withstand the force. Although the engineered tissues still were not as strong as natural smooth muscle tissue, the results suggest it may be possible to further improve their strength, an essential step in developing tissue to be used in repairing or replacing blood vessels, intestines and bladders. The method could also be used to investigate how mechanical stimuli contribute to disease in natural tissue, says Mooney. In blood vessels, for example, changes in shear forces have been associated with atherosclerosis (sometimes called hardening of the arteries).
Though the work focused on smooth muscle, the conclusions may have broader implications, says Mooney. "The idea of chemistry determining how a tissue responds to a mechanical signal is an important idea that potentially applies across all tissues, whether you're talking about bone, cartilage or muscle."
Other members of the research team were Jeffrey Bonadio, adjunct associate research scientist in the Department of Pathology, Medical School; chemical engineering graduate student Byung-Soo Kim and biomedical engineering graduate student Janeta Nikolovski. The study was supported by the National Science Foundation.
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