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Body Regenerate Thyself -- Stem cells become part of the treatment arsenal for orthopedic conditions
[September 03, 2007]

Body Regenerate Thyself -- Stem cells become part of the treatment arsenal for orthopedic conditions

(BioMechanics Via Thomson Dialog NewsEdge) A college football player on a sports scholarship who tears an anterior cruciate ligament at the beginning of the season could conceivably see his athletic career end. But stem cell-based treatments being developed may not only allow the athlete to return to his sport during the same season-and keep his scholarship-but also restore his previous level of performance.

"The potential is to heal injuries more completely and to possibly even reverse degeneration and musculoskeletal illness in the future," said David T. Dellaero, MD, an orthopedist with Triangle Orthopaedic Associates in Durham, NC, referring to the use of stem cells for treating orthopedic and sports medicine conditions.

Dellaero is conducting clinical trial research for Osiris Therapeutics of Baltimore, a developer and manufacturer of stem cell-based products.

"So far we are not looking at performance enhancement other than achieving more complete recovery after injury," he said.

Toward that end, the focus of stem cell-based therapies for orthopedic conditions is strictly biological.

"The objective is to use biological solutions instead of mechanical or metal ones," said Arnold Caplan, PhD, professor of biology and director of the Skeletal Research Center at Case Western Reserve University in Cleveland, OH, and a longtime orthopedic stem cell researcher.

They're not trying to put orthopedic surgeons out of business, he pointed out.

"We still need to have these things surgically implanted," he said.

While many of the stem cell-based orthopedic solutions being developed will require surgery, the goal is for the procedures to be minimally invasive, according to Caplan.

"Stem cell th erapy is a key approach to regeneration, which would completely restore the patient's tissue to its original form and function prior to injury," said Edward Schwarz, PhD, professor of orthopedics and associate director of the Center for Musculoskeletal Research at the University of Rochester Medical Center in New York.

Schwarz and his research team are developing ways to repair and regenerate bone, cartilage, ligament, and tendons.

"The treatments that we hope to develop range from adjuvants for sports injuries to the regeneration of entire limbs resulting from war wounds," Schwarz said.

Caplan notes that we may be able to regenerate structures like ligament, tendon, and bone 10 years from now, but an entire limb is unlikely, at least any time reasonably soon.

"The power of positive thought is wonderful, but it ain't going to happen in your lifetime," he said.

The potential performance-enhancing attributes of stem cells also have been promoted in the mainstream media, but how that would be accomplished remains unclear.

"We think there's a low probability of using mesenchymal stem cells for doping," said Michelle LeRoux Williams, PhD, vice president of development at Osiris Therapeutics. "However, they may help athletes who push themselves to the point of injury to recover faster."

She explained that mesenchymal stem cells, which are adult stem cells typically obtained from the bone marrow of donors, are activated only in the presence of injury or inflammation.

As political debate on the use of embryonic stem cells for medical research and treatments continues, other types of stem cells have begun to be used for orthopedic and sports medicine conditions. More therapies are under development and are predicted to become available in the next five to 10 years.

Only a limited number of stem cell-based orthopedic therapies are currently available commercially or through clinical trials. But that number is certain to grow as researchers further their understanding of stem cells and develop techniques for using them to heal injury and regenerate worn-out body parts. Much of the research at this point is being done in the laboratory or in animals.

For now, parents with the financial means-among them, professional athletes-are banking the umbilical cord blood of their newborn babies. Cord blood can be used to harvest stem cells, which in turn could be used to treat medical conditions in the baby or a close relative, like a parent or sibling. An article published in the New York Times in March told of the possibility of professional athletes one day using cord blood stem cells from their offspring to help combat potentially career-ending injuries.

Many of the potential uses of cord blood will likely be developed in the future and are not yet known, but some families are willing to bet on its benefits. Cord Blood Registry of San Bruno, CA, charges $1700 for initial processing, plus an annual storage fee of $125. The company educates expectant parents on the current uses of cord blood, which includes treating a wide range of blood diseases, genetic and metabolic disorders, immunodeficiencies, and certain types of cancer, said David Zitlow, the company's senior vice president of corporate communications.

He said that the company does not promote the orthopedic uses of cord blood because the research is still in its infancy. However, he did confirm that some of the company's clients include professional athletes who hope that if their children one day become athletes, they can benefit from banked cord blood.

The future is now

Much of the research on orthopedic applications for stem cells has focused on adult mesenchymal stem cells, which are obtained from donors. Some research has been done, particularly in the past, on the use of autologous adult stem cells, a process in which patients are their own donors. But such procedures are generally labor intensive and cost prohibitive, Caplan said.

Other types of stem cells, such as those taken from amniotic fluid obtained during amniocentesis and from umbilical cords, placenta, and adipose tissue, are also receiving attention in studies. Academic researchers, start-ups, and established medical product companies are busy developing new techniques, products, and methods.

Cytori Therapeutics of San Diego has commercialized its Celution System, which it says standardizes and automates the process of obtaining stem cells from adipose tissue and returning the cells to the patient. DePuy Orthopaedics of Warsaw, IN, a Johnson & Johnson company, markets the Cellect device, which uses a minimally invasive approach for harvesting autologous bone marrow stem cells.

Genzyme of Cambridge, MA, first made Carticel, an autologous chondrocyte implant product, available to surgeons in 1995. Used in the repair of symptomatic cartilage defects of the femoral condyle due to acute or repetitive trauma, patients must already have undergone surgery with an unsatisfactory result before being treated with it. Implantation is a two-step procedure in which healthy cartilage tissue is obtained (from either another procedure or one performed solely for this purpose) and cells are then cultured and grown for up to five weeks. At that point, the second surgical procedure is performed to implant Carticel.

Osiris Therapeutics, which was founded by Caplan and his colleagues at Case Western Reserve, is awaiting results of a combined phase I/II clinical trial on another treatment designed to be used in combination with surgery. In the trial, Chondrogen, a mesenchymal stem cell product, is injected into a patient's knee one week after a meniscectomy for repairing damaged meniscus tissue and preventing osteoarthritis. Fifty-five patients at seven sites received either this treatment or a placebo, which was an injection of Chondrogen without the stem cells.

Following up with the patients after six months, the investigators found that the product was safe and that although Chondrogen appeared to have prevented progression of further cartilage and joint damage, it had not promoted regeneration, Williams of Osiris said. The patients will continue to be monitored for two years using magnetic resonance imaging.

Another Osiris mesenchymal stem cell product, Osteocel, has been available since 2005. Designed to promote bone growth, it is implanted during spinal fusion and surgery following trauma. The company also is studying Prochymal in clinical trials for graft-versus-host disease and may investigate the product for the treatment of rheumatoid arthritis.

Back in the 1980s

As to when potential stem cell-based therapies in development will become available, Caplan, who has been conducting stem cell research since the 1980s, says it is hard to predict.

"It is a long time frame until therapies can get through clinical trials and reach the marketplace," he said.

It took 20 years before people accepted mesenchymal stem cells as potential orthopedic treatments, he said, and it might be another 10 years before products become available. Ten years ago, according to Caplan, large companies were not funding this research. Today, because of greater interest, research funding is flowing to universities, start-ups, and larger established companies.

One of the most important discoveries from Caplan's research was that mesenchymal stem cells differentiated into specialized roles for bone or other structures; they were immunosuppressive and trophic, that is, they had rejuvenating qualities. Mesenchymal stem cells were also found to be more plentiful in younger people compared with older people, who have more difficulty repairing, let alone maintaining, their skeletal tissues. These findings suggested the possibility of taking stem cells from healthy young adults and having them supply stem cell doses for thousands of people. Caplan's research on using mesenchymal stem cells from bone marrow to form cartilage, tendon, or bone in animals was rolled into Osiris, he said. (Caplan is no longer involved with Osiris.)

His research group at Case Western Reserve is now working on the use of mesenchymal stem cells for orthopedic indications, such as resurfacing damaged cartilage and repairing bone.

"The long-term goal is for a 60-year-old to be able to repair skeletal structures the way a six-year-old does," Caplan said.

He said complete limb regeneration was theoretically possible, particularly in a young person, based on the fact that young children have been known to regenerate parts of fingers, including joints; some amphibians also are known to regenerate limbs, as are starfish.

Regeneration fascination

Newer players to this area of research are trying their hands at discovering better ways to promote healing of orthopedic and sports medicine injuries and conditions.

"Tissue engineering and stem cell research are innovative fields that have emerged during the last decade or so," said Dan Gazit, PhD, DMD, a professor of dental medicine and head of the Skeletal Biotechnology Lab at Hebrew University of Jerusalem in Israel, and director of the Stem Cell Therapeutics Research Lab at Cedars-Sinai Medical Center in Los Angeles.

"The goal is to generate tissue substitutes that would not be made from synthetic materials but rather from the body's own repair cells-adult stem cells. To this end there are several groups around the world that use different approaches for the repair of injured skeletal tissues," he said.

Gazit and his colleagues have developed a technique for repairing tendons using mesenchymal stem cells. Results of some of this research, which has been conducted in rats, were published in the Journal of Clinical Investigation in April 2006.

"Our unique approach is to genetically modify adult stem cells with specific genes and thus enhance their capability to regenerate damaged tissues in a rapid manner," Gazit said. "Our research has shown that engineered stem cells were able to regenerate a partial defect in a tendon within five to seven weeks."

Gazit has also published studies on the use of engineered mesenchymal stem cells for nonhealing fracture repair and for the treatment of spine disorders.

"Synthetic implants provide a solution for a short period of time but tend to fail in the long run," Gazit said. "Stem cell-based therapies would actually regenerate the damaged tissue and allow the athlete to regain the tissue properties that he or she had prior to injury, helping athletes to return to competition faster and to have longer careers. In severe cases, it might even save their careers from ending due to serious injuries."

Scott Rodeo, MD, an orthopedic surgeon at the Hospital for Special Surgery and an associate professor of orthopedic surgery at Weill Cornell Medical College, both in New York, and an associate team physician for the New York Giants, is conducting research on the use of stem cells to better repair torn anterior cruciate ligaments and rotator cuffs. His research involves the use of stem cells transfected with DNA for a particular gene that provides instructions to overproduce a particular protein.

Studies conducted in rats have produced encouraging results, Rodeo said, with the technique stimulating new tissue proliferation. The results have been presented at various meetings but have not yet been published.

Rodeo estimated that these techniques may be tried in human patients in three to five years. In the meantime, he and his colleagues are trying to figure out the best way to apply stem cells to injured tissue. He hopes that the techniques they are developing will speed healing, allow patients to return to sports activities more quickly, and potentially prolong athletic careers.

When Schwarz of the University of Rochester isn't fantasizing about growing limbs, he sees the potential for stem cell-based therapies to improve long-term outcomes for sufferers of cartilage or meniscus injuries.

"Although current orthopedic treatments for most sports injuries are excellent, several of them suffer from poor long-term outcomes after 10 years or longer," he said. "These include arthroscopy for cartilage and meniscus injuries that lead to osteoarthritis and rotator cuff repairs that often fail."

Schwarz also is president of LAGeT of Rochester, NY, a biotech company involved in light-activated gene therapy. His current research involves applying techniques developed by the company to stem cells in order to heal articular and meniscal cartilage using recombinant adeno-associated viruses and stem cells to revitalize structural bone grafts.

Parts is parts

Schwarz says he's also serious about the use of stem cells for limb regeneration. He cites statistics that show that less than 3% of U.S. military casualties in the Middle East are fatal, owing to advances in body armor and battlefield critical care.

"However, a high percentage of those injured become amputees. So we bring back healthy 20-year-old veterans without limbs," Schwarz said. "While limb regeneration is science fiction now, the U.S. Department of Defense is committing serious resources to this end, based on this current reality."

Through his role as chair of media relations for the Orthopaedic Research Society, Schwarz is spearheading a campaign that touts, "Prosthetics were the solution for the 20th century. Regeneration is the solution for the 21st century."

Caplan imagines that stem cells will be able to improve athletic performance, but with major limitations.

"There may be aspects of stem cell biology that can optimize your genetics," he said. "It turns out that your body parts and athletic performance are genetically controlled. You can only optimize to a certain extent."

But he suggested that we may not yet have any idea about the eventual orthopedic applications of stem cells and how they will be administered.

"The approaches we use today are not the ones that will work tomorrow," Caplan said. "Twenty years ago we were pretty clever in predicting that mesenchymal stem cells could differentiate into bone or cartilage, but we couldn't have imagined their incredibly powerful activities in terms of trophic activity and immune system suppression."

Copyright 2007 CMP Media LLC. All rights reserved.

Copyright 2007 CMP Media LLC

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