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.