By RON WINSLOW  Wall Street Journal
February 12, 2007; Page A1

Five soldiers at a military base in Texas are about to participate in a
remarkable test to see if they can regrow portions of fingers they lost
in the war in Iraq.

Doctors plan to treat them with a fine powder called extracellular
matrix, harvested from pig bladders. The material, found in all animals,
is the scaffolding that cells latch onto as they divide and grow into
tissue and body parts. In the human body, it was long thought to be
inert. But scientists have discovered that it appears to activate latent
biological processes that spur healing and regenerate tissue.

Medical researchers have been making intriguing progress in the field
of regenerative medicine. The pilot test in Texas shows how doctors are
trying to apply their recent discoveries to a pressing challenge:
helping thousands of Americans returning from Iraq to recover from
wounds that would have killed soldiers a generation ago.

Scientists have long been enthralled by the ability of animals such as
salamanders, starfish and deer to regrow body parts lost due to injury
or other causes. Cut off a salamander's leg and a new one grows back
within weeks. A deer sheds its antlers annually, then regenerates
another set -- adding a new "point" each year.

But in humans and most other complex life forms, healing is primarily
about survival, not regeneration. Serious wounds produce scar tissue,
which besides being unsightly, doesn't function as well as normal
tissue.

In the womb, though, humans have a remarkable ability to develop and
grow new parts -- and to recover from injury or fetal surgery. A
prevailing theory is that this ability begins to wane in humans about 16
weeks into gestation, when the immune system and its infection-fighting
apparatus kick in, and that it eventually goes dormant after birth.
Advances in stem-cell research, genetics and tissue engineering are
convincing scientists that it may be possible to reignite this
capacity.

"Fetuses can regenerate just about everything," says Stephen Badylak, a
researcher at University of Pittsburgh's McGowan Institute for
Regenerative Medicine. "If those signals are there, how can we turn them
back on?"

Importance of Matrix

Extracellular matrix, which scientists say harbors signaling molecules
that help direct the development of cells into tissue, may hold part of
the answer. In the 1980s, while working as a researcher at Purdue
University, Dr. Badylak stumbled onto the importance of matrix during an
experiment in which he used a portion of a dog's intestine to fashion a
makeshift aorta for its heart. Not only was the dog's tail wagging the
morning after the surgery, but months later, an examination revealed
that the transplanted intestine part had morphed into a vessel that
looked much like an aorta. Somehow, it had sensed where it was in the
body and had remodeled itself to take on the structural traits of an
aorta. There was hardly any scarring.

"We've been spending the last 20 years trying to understand how that
happened," Dr. Badylak says.

The quest led initially to a layer of intestinal lining called the
submucosa, a form of extracellular matrix. Dr. Badylak's team found that
extracting the submucosa from the intestine and putting patches of it at
injury sites triggered a novel healing response: As the implanted matrix
material broke down, healthy living tissue, not scar tissue, repaired
the damage. Matrix from bladders, liver and other organs induced a
similar reaction.

"When cells die, they release their contents [into surrounding tissue],
and the body responds with inflammation and scar tissue," Dr. Badylak
explains. By contrast, as matrix degrades, it "instructs cells to
divide, migrate and organize, the way they do in a developing fetus." In
the process, stem cells move to the site of the injury -- the same type
of cells responsible for structural development of the fetus; the
inflammatory response retreats.

The research revealed an added benefit: Wounds healed with the help of
matrix almost never got infected. And instead of rejecting matrix as
foreign, the immune systems of animals accommodated the treatment -- a
phenomenon Dr. Badylak attributes to the lack of cells in the material.

The work has resulted in some 100 peer-reviewed journal articles and
more than 40 patents in which Dr. Badylak is a primary or co-inventor.
Most of the patents are held by Purdue. In the early 1990s, DePuy Inc.,
now a unit of Johnson & Johnson, licensed the technology from Purdue for
orthopedic uses. In 1999, a Stanford University surgeon implanted the
first matrix patch in a patient -- to help repair a torn rotator cuff in
the shoulder.

The material, considered a medical device by the Food and Drug
Administration, is now commonly used in rotator-cuff procedures and
Achilles-tendon repairs. Other orthopedic-products companies have
developed similar technology that they market as an alternative or
adjunct to conventional orthopedic procedures.

In 1995, closely held Cook Group Inc. of Bloomington, Ind., formed a
biotech unit to pursue other uses of intestinal matrix. Using licenses
under Dr. Badylak's patents, the unit now markets more than 100 products
to treat problems ranging from urinary incontinence to chronic wounds.
To repair hernias, for example, patches of matrix can be placed
internally against a torn muscle wall to promote the formation of new
tissue.

More than 500,000 people world-wide have had matrix-based treatments
since 1999, according to Johnson & Johnson and Cook. Other potential
uses are in development. No significant side effects have been linked to
the treatment, Dr. Badylak says.

That a single substance can be used to treat such different conditions
reflects matrix's capacity to adapt to its environment. In the shoulder,
for example, it promotes the formation of tendon tissue, in the lower
urinary tract, the formation of bladder or urine-channel tissue, and in
a diabetic ulcer, of normal skin.

"People used to think it was Buck Rogers science to talk about
regenerating tissues," says Scott Bruder, world-wide vice president of a
newly formed Johnson & Johnson unit, Regenerative Therapeutics LLC.
"This is the new wave."
[Alan Spievack]

How did fingers come into the picture? As an undergraduate at Kenyon
College in the 1950s, Alan Spievack did a research project on the
salamander's regenerative powers that helped him win a Fulbright
scholarship and admission to Harvard Medical School. He didn't realize
until many years later, when he heard Dr. Badylak give a lecture on
tissue engineering in 1996, that what he'd learned might apply to other
animals.

That insight spurred him to look in the bladders of mammals for a form
of extracellular matrix called epithelial basement membranes. He found
it, just a couple of layers above the submucosa. In his first human test
of the membrane, he spread it on a poison-ivy rash on his own leg. He
says it quickly healed.

The experience led to an informal research collaboration with Dr.
Badylak. Dr. Spievack was more interested in commercializing the
technology than in doing academic research on it, and in 1999, he
launched a company called ACell Inc. With so much science already behind
Dr. Badylak's inventions, he talked to Purdue about licensing some of
the Badylak patents related to matrix from sources other than the
intestine.

Patent Dispute

Initially, he says, Purdue encouraged his interest. But no agreement
was reached. Dr. Spievack then filed a patent on his basement-membrane
matrix. By late 2002, his closely held company was making matrix patches
and powder from pig bladders. Veterinarians began using it to treat
problems such as tendon injuries in horses and urinary incontinence in
dogs. The following year, the FDA cleared a human-grade version.

When Purdue learned about Dr. Spievack's patent application, it argued
that Dr. Badylak and his laboratory had had a role in the invention and
that the patent should be assigned to the university. That kicked off a
complex dispute in which Purdue faulted Dr. Badylak for his handling of
the work with Dr. Spievack. Purdue fired Dr. Badylak, ending his 25-year
career there and disbanding his 29-person lab. Dr. Badylak subsequently
accepted a post at Pittsburgh's regenerative-medicine program.

Purdue and Cook sued the two doctors and ACell for patent infringement
in U.S. District Court in Lafayette, Ind. A jury ruled in favor of
Purdue and Cook, but last August, a federal appellate court overturned
the verdict and upheld the validity of Dr. Spievack's patent. Mark
Bleyer, president of Cook's biotech unit, declines to discuss the
matter, except to say details about what happened remain in dispute and
that some litigation is ongoing.

Joseph L. Bennett, vice president for university relations at Purdue,
says Dr. Badylak was terminated "for multiple causes that had
accumulated over an extended period." He wouldn't elaborate. He says
Purdue's tissue-engineering researchers remain productive. And he says
Purdue is pursuing a case with the U.S. Patent Office claiming that Dr.
Spievack's patent should include inventors from Dr. Badylak's
laboratory.

In 2005, Dr. Spievack's brother, Lee, who runs a hobby shop in
Cincinnati, accidentally lopped about three-eighths of an inch off the
top of his middle finger on the propeller of a model airplane. He
decided against the skin graft recommended by a hand surgeon and
consulted his brother. Dr. Spievack sent him a vial of matrix powder.

Lee Spievack applied it every other day for 10 days, until he ran out.
By that time, he recalls, "I could already see the finger was starting
to regenerate itself." In four weeks, the wound was healed. In four
months, he says, except for a tiny scar, "it was like the finger I
always had." Winter, he says, has revealed one difference: "The finger
is only about 2 years old, whereas the rest of me is 68. In the cold
weather, all my finger tips have cracked except this one."

Back at the McGowan Institute in Pittsburgh, Dr. Badylak and others are
collaborating with the military on a variety of tissue-engineering
projects. One of them, funded by a multimillion-dollar grant from the
Pentagon's Defense Advanced Research Projects Agency, or Darpa, has a
long-term goal of enabling soldiers to regenerate lost limbs.

As a first step, Dr. Badylak has assembled a team of five other
scientists from around the U.S. to attempt to induce a mouse to form the
same kind of stem-cell-rich structure that forms when a salamander loses
its leg. In the salamander, that structure, called a blastema, forms at
the site of the missing leg and orchestrates the formation of a new one.
One aim is to understand the role of extracellular matrix in the
process.

Early Stages

The project reflects growing interest by labs around the world in
seeing if humans can be induced to form blastemas that would lead to
regrowth of lost limbs. The research is in its early stages, with a host
of unanswered questions, and any success could be many years away, Dr.
Badylak says.

Military officials learned of the episode involving Mr. Spievack's
finger and saw before and after pictures of the digit. That, coupled
with Dr. Badylak's matrix research, led to the upcoming pilot test,
which will use ACell's product.

"This isn't fly-by-night," says Col. John B. Holcomb, commander of the
U.S. Army Institute of Surgical Research at Fort Sam Houston in San
Antonio, where the test will take place.

The Army institute is both a research enterprise and the principal
burn-treatment unit for the entire Defense Department. Part of its
mission is to improve battlefield medicine to enhance soldiers' chances
of surviving serious wounds. Surgeons from Col. Holcomb's unit rotate in
and out of Iraq to help provide emergency treatment and to speed the
transfer of badly injured soldiers back to the 450-bed Brooke Army
Medical Center in San Antonio.

During the Vietnam War, it often took a few weeks for a wounded soldier
to make it from the battlefield to that hospital, says Col. Holcomb.
From Iraq, it typically takes three days.

Many of the gravest wounds involve severe burns caused by booby traps,
grenades and other so-called improvised explosive devices. Doctors are
also starting a test of whether ACell's matrix will speed the healing of
parts of the body from which healthy skin is removed for grafting onto
burn wounds.

Severe hand burns often cost soldiers parts of their fingers. While
losing fingers might not seem as debilitating as losing an arm or a leg,
"if you can't grab anything, if you can't pick up a pen or a toothbrush,
the world is a pretty difficult place," says David Baer, manager of the
Army unit's bone and soft-tissue program.

Mr. Baer says the research unit hasn't yet told potential candidates
for the finger test about the project, in part for fear of raising false
hopes among soldiers desperate for good news.

In the test, which is expected to begin late this spring, surgeons will
reopen the skin around what's left of the soldiers' fingers. Matrix will
be applied three times a week for at least two weeks. During each
application, researchers will look for new tissue and for complications.
If any fingers get longer, researchers will measure them for
sensitivity, test hand function, and X-ray them to check for bone
growth. If no problems arise in the first five soldiers, the doctors
will treat five more, then assess the procedure thoroughly. They hope to
know within a couple of months after treatment begins whether it works.

No one expects the treatment will regrow complete fingers, with joints,
knuckles and fingernails. "We'd love to see bone," says Mr. Baer, "but
we don't know." The hope is for maybe an inch of soft tissue, with blood
vessels and nerves, that soldiers can pinch their thumbs against and
restore some function.

Mr. Spievack's experience is one anecdote. Injuries to the soldiers'
fingers are much more severe. There is no guarantee it will work, Dr.
Badylak says. But without any new tissue, the hands of some injured
soldiers are like paddles -- they can't write with a pencil, zip their
pants or eat with a fork.

"The opposable thumb is what makes us human," says Col. Holcomb. "To an
18-year-old with no fingers, this would be a life-changing event."

Write to Ron Winslow at ron.winslow@wsj.com