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Monday, August 18, 2008

Injured? Stem Cells may be the cure

Doctors might soon be able to regrow injured muscles, tendons and bones without invasive surgery, simply by injecting a person's own stem cells into the site of an injury. Veterinarians are already doing it with injured horses, and research into human applications is well under way.

The National Institutes for Health seem to think regenerating human muscle and bone using a person's own adult stem cells is nearly ready for prime time. Last week, the NIH announced to its staff that it's creating a bone marrow-stem cell transplant center within the National Institute for Arthritis and Musculoskeletal and Skin Diseases.

Researchers at the NIH labs in Bethesda, Maryland, are already growing human muscle, cartilage and spinal disks in vitro. The tissue isn't mechanically sound yet, says lead researcher Rocky Tuan, but that will come with further work.

"I have a piece of tissue that looks like a spinal disc, a sand bag, tough as nails on the outside and like sand on the inside," says Tuan, a Ph.D. and the senior investigator in the Cartilage and Orthopedics branch of the NIAMS. "The mechanical properties are lousy, but it's a beginning."

While the use of stem cells harvested from human embryos has been getting the most media attention, scientists and doctors have also been working with adult stem cells that also have the ability to become one with their environment and to replicate as cells of their adopted tissue. Using adult stem cells -- grown inside the body or in the lab -- has become accepted in the veterinary community, and horses have benefited greatly. Researchers are working to bring those same benefits to humans, but there are still hurdles left to clear.

The NIH project comes in part from what veterinarians have learned from injecting adult stem cells into valuable horses who've suffered injuries. In many cases, those horses' careers were saved when the stem cells regrew damaged tendons and ligaments.

Rodrigo Vazquez, a Southern California veterinarian, has been using adult stem cells to regrow damaged muscles in horses for several years. It's a fairly common procedure in the veterinary arena, and the results are impressive: One of Vazquez's patients is participating in this year's Olympics Dressage events; another is a prize-winning jumper.

The procedure is simple and straightforward. Inside a surgical suite at his equine hospital, Vazquez removes blood full of adult stem cells from the sternum of the anesthetized horse.

Then he rolls his stool to the other end of the horse, where ultrasound data has helped guide needles into the exact areas on the rear leg where the beautiful horse's ligaments are torn. He injects the stem cells into those spots.

"A few years ago, these injuries were career-ending," Vazquez says. Not any more. "In a month, the torn tissue will be completely regrown and healed."

Vazquez would like to put himself in his patients' place. He has had surgery several times for spinal injuries he incurred while lifting horses. Human medicine, unable to regrow or heal the injured spine, simply fuses the bone and tissue through a surgical procedure. At best, the surgery relieves some of the pain and restores some mobility. But it's not a true repair.

"I wish I could have had a procedure like this," Vazquez says of the treatment he gives horses. "This will lead to human treatments, but they can't move as fast as we can."

Tuan, who is using stem cells to cultivate experimental tendons and disks in his lab, thinks it's about time to look to treating humans.

An emerging body of scientific studies from all over the world -- including a cardiac study under way in Miami and a pediatric ACL (anterior cruciate ligament) study at the Harvard-affiliated Children's Hospital of Boston -- is showing that using a patient's own stem cells can prompt the growth of new muscle, from the knee to the heart. And the precursor step, using platelet-rich plasma for injuries, is on the verge of becoming mainstream.

Adult stem cells, particularly mesenchymal cells that come from muscle, bone and fat, are cells with a powerful ability to replicate and not a lot of personal identity. They easily take on the characteristics of surrounding cells and they tend to grow quickly once they get there. Ultrasounds of Vazquez's horses, for example, show regeneration of muscle in four to six weeks.

The final product is this cartilage-like tissue grown around the scaffolding by NIH scientists. Tuan says the tissue resembles the human version, but may not be mechanically sound -- yet.
Courtesy NIAMS

Adult stem cells can be found all over the body, in bone and marrow. Tuan says they're also found in tonsils and in the placenta and umbilical cord, which suggest that the discarded body parts can be stored for later use.

Because researchers are using autologous cells -- from the patient's own body -- the research is not controversial. No one has challenged the ethics or funding of adult stem cell research the way embryonic stem cell studies have been challenged. And because adult stem cells are native to the patient's own body, the chances of a patient rejecting them are slim to none.

Tuan and his team have been able to coach adult stem cells to form muscle and disks using goo from the small intestine and a polymer scaffold to tell cells how to grow. But, he cautions, the primitive structures aren't ready to go into humans.

"After a few weeks (of lab growth), it will turn into something that resembles a tendon, but it has to be the mechanical equivalent and we don't know that we're there," Tuan says. "Stem cells are very promising, but what they do for horses may not work so well for humans because humans are the hardest animal to rebuild."

Once they're perfected, Tuan sees a day when the tendons will change the dreaded surgery for torn anterior cruciate ligaments that sideline up to a quarter-million people in the United States and Canada every year.

"Often, that injury is a complete tear -- the ligament is snapped in two and the ends ball up and even if you untangle them and pull them together, they won't heal," he says. "So they take part of the patella tendon, which is short and tough, and stretch it and staple it to the bones. So not only is your ACL not working too well and you have to stretch it out, but your knee hurts like crazy."

"If we can learn to grow a tendon that works right, or figure out how to make the ACL heal back together, we can save a lot of people a lot of pain," he says.

In fact, doctors are already treating people with adult stem cells. Bone marrow transplants for cancer patients are basically stem cell therapy. But the marrow often comes from other people, and its primary purpose is to boost a weakened immune system, not to generate tissue.

And treating with platelet-rich plasma -- a blood product made by spinning a patient's blood in a centrifuge to concentrate the platelets -- is already in limited use and is becoming more widely accepted as a safe therapy. PRP is routinely used in cardiac surgery, where applying it to a cut sternum before closing has been shown to cut the infection rate in half. The plasma has growth factors that also promote healing.

"PRP helps recruit stem cells to the injury," says Dr. Allan Mishra, who has used PRP on its own and as part of surgery in sports injuries -- including treating tennis elbow and getting Stanford football player James McGillicuddy's patellar tendon to heal after his second surgery. "The body knows how to heal itself -- we're speeding up and concentrating the process."

Last year, Mishra wrapped up a study where he used platelet-rich plasma to treat the 20 worst tennis-elbow injuries he'd culled from more than 100 volunteers. "Ninety-three percent got better with a single injection and stayed better for two years," Mishra says.

The treatments are about one-tenth of the cost of surgery, or about $2,000 to $2,500, he says. The patient's blood is drawn, centrifuged by a specialist called a perfusionist, and injected, all in one visit. "I will guess that five years from now, insurance companies won't authorize surgery until the patient has tried and failed at PRP."

The obvious next step is to isolate the stem cells and send them to work, both inside and outside the body, researchers say. "PRP is reparative. Stem cells are regenerative," says Angela Nava, a perfusionist who processes both animal and human blood for PRP, stem cell and other procedures.

But getting from animals to humans is going to take a lot more research, according to Dr. Thomas Rando, an associate professor of neurology at Stanford University School of Medicine. Rando studies the body's signaling systems that tell stem cells what to do.

"We don't always know how stem cells, when injected into some tissues, work their magic," Rando said. "Veterinarians don't go back and study the horse's tendons to figure out what the stem cells did to promote healing."

"There are all kinds of ways stem cells could work. If we could understand how they are actually promoting better function of the tissue, we might be able to further improve their therapeutic effects," he adds.

Stem cell treatment is not without risks, researchers say. The worst-case scenario is that the stem cells could cause cancer -- or become cancerous themselves.

"You're putting in cells that want to grow. That has to be under control," Rando says. "Or we can end up with cancer."

Tuan also says that researchers don't entirely trust stem cells and their ability to adapt and grow.

"There's a nagging feeling that there's a cancer stem cell, that when it's agitated by exposure to carcinogens or radiation or something, it goes nuts, and that we can't identify it from the other stem cells," he says. "How do you find this bad boy and pull him out?

"And there's a nagging worry it's the same cell. We only know these cells by what they've done, and by the time they've become cancer, it's too late."