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

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Biomechanics Magazine August 2007

http://www.biomech.com/showArticle.jhtml?articleID=201800350

Body Regenerate Thyself - Stem cells become part of the treatment

arsenal for orthopedic conditions

By: Lori Rochelle Roniger

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 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 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 LeRoux , 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 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 &

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, 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.'

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.'