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Seeing The Light, Nixing The Knife ; Cu Tissue Research May Eliminate Need For Some Surgeries

Posted on: Wednesday, 24 March 2004, 06:00 CST

Hearts will be reborn, knees rejuvenated, damaged or diseased nerve cells rebuilt - all without invasive surgery.

This is the future foreseen by pioneering engineers at the University of Colorado who are on the vanguard of a revolution in medical care.

Using already available materials - light, body cells, steroids and molecules - the scientists are designing and building replacement parts for the human body.

At the forefront is a 35-year-old workaholic who presides over a CU lab that bears her name.

"I believe that it will be routine in five to 10 years to see this procedure successfully working in human knees," Kristi Anseth, professor of chemical engineering at CU-Boulder, said last week in her lab.

Anseth's lab was the first in the world to use light-activated chemistry to develop an injectable, biodegradable scaffold to regenerate cartilage tissue.

Think of scaffold in the building sense - a framework that is assembled so that other structures can be formed. In the sense of Anseth's work, it's similar, but considerably more complicated.

Anseth tries to simplify:

"We make the scaffolds that re-create tissues and accelerate the healing process," she said. "The key is that we put in a molecule that absorbs the light - that starts the reaction that forms the biological material."

The scaffold is injected as liquid, but, when treated by light, becomes a somewhat solid gel - "like Jell-O or a contact lens," Anseth said.

"When you use light to make the scaffold it can be done in the presence of cells and tissues," she explained. Meaning that cells - cartilage-forming cells, for example - can be placed in the same solution that forms the liquid precursor to the scaffold. The entire solution can be injected by the surgeon into the knee's trouble spot.

The cells imbed on the scaffold, adhering to each other and, eventually, to the bone or remaining original cartilage.

Already, the CU lab has grown cartilage in mice, rats and one goat.

"We were able to repair the defect" in the goat, Anseth said. "They were very encouraging results."

Still, the work will stay mostly in the lab for months or years, as researchers simulate what will happen in the human body once the process is perfected.

Crossing boundaries

Anseth presides over more than a dozen undergraduate and graduate students who spend their off-class hours in the lab, putting stem cells into gel, accelerating DNA, building the delicate architecture.

Thousands of Americans die each year while waiting for available tissues and organs. Hundreds of thousands are sidelined from their favorite activities because their knees are short on cartilage, which can't repair itself.

Cartilage is a soft tissue that surrounds many of the body's joints, acting as a shock absorber. Its absence causes joint pain and arthritis, turning runners into cyclists, walkers into couch potatoes.

Tissue engineering already has created a skin substitute to treat burn patients. But more complex tissues and organs present bigger challenges.

CU's special interest is in creating better and more reliable scaffolds that can guide cells to organize in three-dimensional structures.

Anseth uses techniques from computer engineers and biologists, as well as from chemistry. Computer engineers use different scaffolds and patterns to design integrated circuits and tiny microelectronic devices. "We were one of the first to translate that and bring it into the medical community," she said.

For the cartilage scaffolding, she makes chains of molecules called polymers that contain chemical signals telling the cells what to do.

The aim is to encapsule the cells in the scaffolds and then modify the scaffolds so the cells adhere, proliferate and differentiate.

The ideal scaffold is also biodegradable, so that after the cells the scaffold supports cling to each other and fill in the gap, it disappears, letting the natural tissue do the job.

New hope for sports injuries

"It sounds very promising and definitely is in the direction we are trying to head," said Dr. Reed Bartz, a professor of sports medicine and shoulder surgery at the CU Health Sciences Center.

Currently, orthopedic surgeons rely on cartilage from cadavers or synthetic substitutes to strengthen weak knees. Those approaches can cause bone loss because of problems absorbing fluid. Also, the donor cartilage can be infectious, and availability is unreliable.

Bartz uses animal cartilage or the patients' own, if he or she has enough to spare in another part of the body. He's also had success with a procedure called microfracture in which holes are drilled in the bone to form blood clots, which help create an environment in which a type of cartilage can regrow.

"It's better than nothing," he said. But Anseth is working with a more durable type of cartilage that holds the promise of restoring function to sidelined athletes, added Bartz, who is a physician with the CU and DU sports teams.

Research centers have used several different polymer scaffolds to form cartilaginous tissue, but huge questions remain:

* How do you control the structure and mechanics of the scaffold to produce cartilage that can actually function in the body?

* How can the scaffold help accelerate the formation of tissue and help it meld with the body's tissue?

* How can the scaffold help the surgeon repair the knee without major surgery?

Anseth thinks the answers to all three of those questions is in the light, visible or ultraviolet, that turns the liquid scaffold solution into the cell-sustaining gel.

To accomplish this part of the process, the surgeon slides a tiny light through an arthroscope and shines it on the injected solution near the knee. The cells imbedded in the scaffold multiply and collectively form the shape of the scaffold.

"They won't grow beyond the scaffold, because they only grow where they can attach and where there is surrounding environment to support them," Anseth explained.

"It's fast . . . takes seconds or minutes," Anseth said of the process that is accelerated by light. "You also have spatial control of the process, so you can make complex shapes and patterns."

'Exciting but also frustrating'

Students use sophisticated equipment to measure the stiffness of the scaffold, learning how to design the ideal template. A three- dimensional microscope examines how well the scaffold is forming.

"It's very interesting chemistry," said Charles Nuttelman, a doctoral candidate in chemistry. "Not a lot is being done in this. It's very exciting, but also frustrating."

One section of Anseth's lab is devoted to making the scaffolding materials, in collaboration with chemists.

Anseth and the students start with a molecule - usually something synthetic, but occasionally a natural molecule such as riboflavin, that can absorb the light, which starts the chain reaction that builds the scaffold to which the cells cling.

The scaffold is made up of repeating chains of complex molecules called polymers. These polymer chain reactions greatly accelerate growth.

The tissue will grow into cartilage or a ligament, a heart valve or a bone, whatever the engineers have instructed it to become.

Because the tissue cells grow along with the scaffold, the students working with cells team closely with those working with scaffolds.

In the sterile lab, students and biologists isolate cells in a device called bioreactors, then grow them in cultures with the scaffolds. Through the windows of incubators, they can watch how tissues grow.

They use a machine that reads DNA to ensure that what they are making is what they want to make. If they see the bands that express the gene for collagen, they know they're making cartilage, for example.

Some of the cells haven't quite committed to being a bone or collagen, so they're thrown out. Others have followed the instructions perfectly and are retained.

Future matter of the heart

Anseth also is collaborating with CU colleagues and students to bioengineer human heart valves.

Currently, the only two options for someone with a bad heart valve are mechanical valves that require the person to take anticoagulants, or pig valves, which eventually deteriorate.

The heart valve engineering involves stem cells, not from embryos, but from bone marrow. Stem cells are immature cells that haven't yet changed into cells with a particular function. By feeding steroids to the stem cells, the engineers can instruct them to become tissues that form bones, cartilage, valves, whatever the goal. With stem cells and the complex heart valve design, the challenge is to provide an environment within the scaffold that allows the cells to communicate with each other, Anseth said.

In addition, Anseth is involved in clinical trials going on now at the CU Health Sciences Center that involve injecting stem cells into human brains in an attempt to treat Parkinson's disease and other neurological diseases.

"This is a very tricky procedure," said Anseth, who is also a professor of surgery at the center. "Only about 5 percent of the injected stem cells survive, but we think we know how to get them to better survive and form functioning neurons."

The approach is to use her scaffold techniques and to deliver signaling molecules to the precise spot in the brain where they are lacking.

Great challenges ahead

The most challenging problem facing Anseth and the tissue- engineering field is to regenerate organs such as hearts, livers or kidneys.

There are more than 40,000 people in need of heart transplants in the United States annually, but only 2,000 to 3,000 donor hearts are available for such transplants.

To translate clinical science - including the regeneration of tissue to restore damaged organs - into human medicine will require close collaboration among several disciplines.

The new tissue that Anseth's lab is creating is classified as a hybrid product and will need Food and Drug Administration approval.

"We hope it will be picked up by a company and taken to clinical trials," she said. One company purchased the license for the patent, but went bankrupt. Smith & Nephew, a medical device company headquartered in suburban Boston, now owns the license, "and we hope they'll pick it up" for commercial use, Anseth said. She presented her findings on CU's tissue-forming process at the annual American Association for the Advancement of Science last month in Seattle.

Anseth got her doctorate in chemical engineering from CU in 1994 when she was 26. Since then, 10 of her students have earned their doctorates.

When she is not working, she jogs or watches the CU basketball and volleyball teams. But mostly she is working - usually 60 to 80 hours a week.

It's not a burden, she said, because "it's such a dynamic and stimulating environment."

It's the vanguard of a revolution.

INFOBOX 1

Glossary of terms

* Bioreactor: a vessel that supports a cell culture in which a biological transformation can take place

* Polymer: a giant molecule formed when thousands of small molecules bond to each other to form chains or networks

* Scaffold: the template or carrier system for the cells that make new tissue; gives the new tissue its size and shape

* Stem cell: a primitive cell that can differentiate - sometimes with prodding by scientists - into a specific kind of cell.

INFOBOX 2

Regrowing cartilage

The process involves using ultraviolet light to make repeating chains of complex molecules called polymers into degradable, three dimensional scaffolds, along which cartilaginous cells multiply to form new tissue. The scaffolds, which can be injected into the knee as a fluid, become gel-like when exposed to light, then dissolve after the tissue regenerates.

Why cartilage:

Cartilage is a soft tissue that surrounds many of the body's joints, acting as a shock absorber. Lack of it causes joint pain and arthritis.

The importance of light: If light can flood the polymers inside' the body, the cells form more naturally, perfectly filling the space of the missing cartilage. A surgeon will slide a tiny light through the arthroscope and shine it on the injected solution at the knee. The light will catalyze the molecules, so they turn into the three- dimensional scaffolds needed for the cells to grow into tissue.

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