In medicine, collagen from animals, principally cows, is used to
rebuild tissue destroyed by burns and wounds. Commonly, it is employed
in plastic surgery to augment the lips and cheeks of starlets and
others seeking perpetual youth.

Catgut, the biodegradable sutures made from cow or horse intestines
and used in surgery to minimize scarring, is also a form of collagen.

But for such a commonplace and useful protein, collagen has defied the
efforts of biomedical researchers who have tried mightily to synthesize
it for use in applications ranging from new wound-healing technologies
to alleviating arthritis. The reason: Scientists were unable to
synthesize the human protein because they had no way to link the easily
made short snippets of collagen into the long, fibrous molecules
necessary to mimic the real thing.

But now a team of scientists from the University of
Wisconsin-Madison, writing this week (Feb. 13, 2006) in the Proceedings
of the National Academy of Sciences (PNAS), reports the discovery of a
method for making human collagen in the lab.

The work is important because it opens a door to producing a material
that can have broad use in medicine and replace the animal products
that are now used but that can also harbor pathogens or spark
undesirable immune responses. What’s more, the new work may also lay
the foundation for applications in nanotechnology — such as microscopic
sensors that could be implanted in humans to confront the effects of
disease — because it gives scientists a way to precisely manipulate the
lengthy molecules and add elements to collagen that confer new

Ronald T. Raines“We can make collagen that duplicates nature exactly, but we can
diverge from that when it is desirable,” says Ronald T. Raines, a
UW-Madison professor of biochemistry who, with postdoctoral fellow
Frank W. Kotch, authored the new PNAS study.

Scientists have been seeking a way to make synthetic collagen for at
least 30 years. In clinical settings, human collagen would be preferred
over bovine collagen because the material now gleaned from cows can
prompt an unwanted immune response in patients and it can harbor animal
pathogens that might infect humans.

The Wisconsin team discovered a way to make the long, slender
collagen molecules, in essence, by having the protein assemble itself.
What was required, Raines explains, was a way to give the collagen
snippets that scientists could easily make a way to “self assemble”
into the long, thin fibers of native collagen. The Wisconsin team was
able to modify the ends of the snippets so they could fit together and
stick to form long collagen fibers.

“Now we can make synthetic collagen that’s longer than natural
collagen,” says Raines, who previously authored a paper in the journal
Nature that demonstrated how to make synthetic collagen that is
stronger than natural collagen. “We just don’t have to take what nature
gives us. We can make it longer and stronger.”

In medicine, synthetic human collagen could be used as “solder” to
speed healing of large wounds. In the context of nanotechnology,
collagen has appeal as a type of nanowire because it is thin — thinner
even than the vaunted carbon nanotubes hailed by nanotechnologists —
and long.

Coated with gold or silver, human collagen could form the basis of
implantable electric sensors. By attaching certain biological molecules
to the wire, it would be possible to create sensors that might, for
example, quickly alert a diabetic to falling insulin levels. Similarly,
equipped with molecules to recognize specific pathogens, such a sensor
could stand perpetual guard in the body and provide instant warning of
invading viruses or bacteria.

“We can have total control of what goes on these very thin extended
fibers,” says Raines. “We are able to build these molecules up one atom
at a time and we can manipulate them in very precise ways.”

The new Wisconsin study, which was supported by grants from the
National Institutes of Health, lays a foundation for bringing human
collagen to the clinic, says Raines. But he notes there is still some
work to be done to perfect the technology.

For example, while the new work enables the researchers to make
collagen molecules that are long and strong, ways to precisely control
the self-assembly of collagen to molecules of a specified size remain
to be worked out, according to Raines.

Collagen comprises 1/3 of the protein in humans and 3/4 of the
weight of human skin. Collagen abnormalities are associated with a wide
variety of human diseases. The long-term objective of our research on
collagen is to obtain an atomic-level understanding of collagen
structure and conformational stability.

Each polypeptide chain of collagen is composed of repeats of the sequence: Xaa-Yaa-Gly, where Xaa is often a (2S)-proline (Pro) residue and Yaa is often a (2S,4R)-4-hydroxyproline (4R-Hyp) residue. The hydroxyl groups of the 4R-Hyp
residues contribute greatly to the conformational stability of
triple-helical collagen. A long-standing paradigm had been that this
stability arises from hydrogen bonds mediated by networks of bridging
water molecules. We have disproved this paradigm using collagen in
which Yaa is a (2S,4R)-4-fluoroproline (4R-Flp) residue. The side chain of this residue cannot form hydrogen bonds. Yet, a collagen triple helix containing 4R-Flp residue in the Yaa position is far more stable than one containing 4R-Hyp
residues. We have also demonstrated that 4S-Flp residue in the Xaa
position enhance stability. These results, which are the first to
demonstrate a stereoelectronic effect on protein stability, could are
leading to the creation of collagen mimics with important therapeutic

Source : University of Wisconsin-Madison