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COAXING STEM CELLS TO REPAIR DAMAGED TISSUE

THE BALTIMORE SUN

In a car wreck, the dashboard crushes the driver's knees and takes a divot out of his cartilage. Or, on a battlefield, shrapnel tears flesh from a soldier's face and a slice from the cornea of his eye.

Surgeons will do their best to repair these injuries. But bioengineers are working toward a future in which a combination of surgery and new materials will coax stem cells and the body's own repair mechanisms to regenerate tissues that trauma has taken away.

Among those in the forefront of the research is Jennifer Elisseeff, an associate professor in the biomedical engineering department at the Johns Hopkins University in Baltimore.

Speaking this week at the 2009 World Stem Cell Summit in Baltimore, Elisseeff described how she and her colleagues have guided stem cells to patch up patients' damaged and deteriorating knee cartilage.

"And their function is better," she said. "They might not be star athletes, but they can go out and do something like playing doubles tennis," which their injuries had made impossible before treatment.

Stem cell research is poised for more such significant advances now that the Obama administration has lifted Bush-era restrictions on federal funding of research using new lines of stem cells derived from human embryos.

Maryland labs also compete for significant state funding. While appropriations from Annapolis have been smaller than originally proposed, the Maryland Technology Development Corp. signed a cooperative agreement this week with California that is designed to encourage scientific collaboration between researchers in the two states. California has the richest stem cell funding program in the world.

Elisseeff's lab is also working to perfect technologies that will enable stem cells to reconstruct fat and muscle lost to surgery or trauma. And researchers there are testing a sort of contact lens that can guide the patient's own stem cells to rebuild a damaged cornea.

It is hopeful evidence that after years of promises from stem cell pioneers, researchers might be getting closer to practical applications.

"People are working on the basic science of things and trying to understand how tissue develops but also at the same time developing practical technologies that can be used in the clinic today," Elisseeff said.

Directing stem cells

A central problem is getting stem cells to grow and become the kind of cells a patient needs, said Dr. Bartley P. Griffith, chief of cardiac surgery at the University of Maryland Medical Center, whose own research has focused on getting new cells to grow to repair damaged heart muscle.

"A cell in free space doesn't know what to do," he said. "It looks for a comforter to get under," a place that provides all the nutrients and chemical signals it needs to thrive and transform itself.

Bioengineers such as Elisseeff are constructing those comforters in the form of new biomaterials that provide physical scaffolds that the stem cells can colonize.

"We're thinking this is a real ally to the stem cell effort," Griffith said. "That's a huge leap for us."

Stem cells are immature cells that retain the ability to transform themselves into whatever type of tissue is needed to grow or repair body parts, from bones and blood to kidneys and nerves. Scientists who have worked for years to learn to extract and direct these cells to cure disease and heal injuries believe it is among the most promising fields in medical science today.

The Department of Defense recently allocated $250 million over five years to drive "regenerative medicine" research.

Elisseeff's work relies primarily on stem cells from the patient's own body, rather than from embryos or donors.

"It's going to be cheaper and easier to deliver to patients," she said. "We wanted something off the shelf, that the surgeon can grab when he needs it."

For example, working with Dr. Norman Marcus, an orthopedic surgeon and Hopkins graduate practicing in Virginia, Elisseeff's lab has tackled the problem of damaged knee cartilage, a familiar problem among athletes and soldiers.

When a piece of knee cartilage is lost or damaged, holes develop. Elisseeff calls them potholes. And, like potholes, they tend to grow.

"It will gradually get bigger and bigger, and you get a generalized arthritic process happening in the joint," she said. "You really want to treat them when they're a reasonable size."

Current treatment is called "micro-fracture." Surgeons essentially tap into the surrounding bone, allowing blood and stem cell-laden bone marrow to ooze out and, with luck, effect some repair in the cartilage.

"The problem is, it ends up making more scar tissue instead of the real cartilage, and it doesn't fully fill the defects" in the cartilage, Elisseeff said.

A healthy place to grow

To tackle the problem, her lab - in part with economic stimulus funds from the American Recovery and Revitalization Act - has developed a hydrogel derived from cow cartilage that provides the body's stem cells with a convenient and healthy place to grow.

The hydrogel is placed in the injured cartilage in a honey-like consistency, solidified with ultraviolet light, and attached to the tissue with a "glue" the lab developed. The porous material absorbs the blood and marrow and stem cells released from micro-fractures, guiding it into the shape needed to fill the hole and providing a fertile place to grow.

In a few months, the gel degrades, leaving - if things work out - new cartilage formed by the stem cells.

In their first clinical trial, conducted in Europe to take advantage of lower costs and easier regulatory hurdles, Elisseeff's team treated 15 adults who had at least a two-year history of knee cartilage injuries.

One year after treatment, the cartilage defects were still 89 percent filled on average, compared with the 50 percent expected with traditional treatments. And based on ratings of pain reduction and restored function, treatments using the new biogels and stem cells did twice as well as those getting micro-fracture treatments alone.

"They can get out and get around, versus not being comfortable or getting around at all," she said.

In another project, Elisseeff's lab has been working with a California company, Kythera Inc., to develop and test a technology for filling soft tissue with a biomaterial that cosmetic surgeons can shape using beams of light, filling wrinkles.

That work got Elisseeff thinking about the need for reconstructing soft tissue lost to surgery, such as breast lumpectomies, or trauma, such as combat injuries. She has begun to investigate using a new biomaterial that would serve as a skeleton, or a scaffold, where stem cells could settle and regrow missing fat and muscle.

"We make it from fat tissue," she said. "We take the fat and process it with chemicals. We take out the cells ... We don't want any foreign DNA in there. And we take out the lipids [fats]."

What's left is a scaffold of connective tissue: collagens and proteins. When you put stem cells on these biomaterials, or tissue blueprints, "you want to give them instructions on what to become," she said. "That's the underlying purpose of it."

The lab's next challenge is to provide the cells with the proper chemical signals to stimulate the desired transformation of the stem cells. That work is just beginning, she said, but "we're very excited about it."

A healing eye patch

Elisseeff's lab has also been at work developing a new biomaterial, derived from collagen, to serve as a healing eye patch, placed directly on the eyeball like a big contact lens.

In one form, it could be applied on the battlefield or at an accident scene to protect the damaged eye and to apply antibiotics or pain-killing drugs.

But Elisseeff would like to do more.

"Someone's stable now. They're in the hospital and have a corneal injury. How can we repair that? How can we rebuild that cornea?" she said.

The goal she's pursuing, with a five-year, $4 million Defense Department grant that began this week, is a biomaterial patch that would guide and nurture stem cells from the area at the eyeball's periphery where they form, onto the cornea.

Like skin, the cornea is constantly rebuilding itself, using stem cells that "crawl" from the edges where they form. With the right physical, chemical and biological signals implanted in the patch, Elisseeff said, "we can help these cells proliferate more and make it easier for them to crawl."

Preliminary studies with rabbits seemed to work well, she said.

Human tests are "a little ways away," she said. "But we're hoping that, working with the Defense Department, that ... these people who really have a strong need for this ... will help move the technology forward."

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