When knees can't take any more

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WE count on them to be strong and supportive, flexible and accommodating, willing to go the extra mile even when we load them down more than we should.

Our knees. We put them through their paces, so to speak, every day. No wonder that, every now and then, they fall down on the job.

Treatments for needy knees generally fit into three categories, says Dr. David Caborn, professor of orthopedic surgery at the University of Louisville: relief (treating the symptoms); repair (getting things back in working order, if not back to normal); and, most recently, restoration (trying to return a damaged knee to its original condition).

In particular, researchers these days are looking for ways to make damaged cartilage as good as new again -- and they're getting closer and closer to pulling it off.

Articular -- or hyaline -- cartilage is the firm, shiny, slick tissue that protects the ends of the thigh bone and the shin bone. Its nearly frictionless surface allows the bones to glide past each other smoothly even when the knee is carrying around a lot of weight.

But strong as it is, articular cartilage -- unlike the bones it safeguards -- has no blood supply of its own, leaving it helpless when it gets hurt. A cut in the skin will heal itself, but a tear in articular cartilage will not.

That's where scientists are stepping in to help.

"We're going through a very exciting time in the whole world of cartilage regeneration," says Dr. Bert Mandelbaum, vice president of the International Cartilage Repair Society and team physician for the U.S. soccer team and for Pepperdine University.

Advances are being made in three main areas: manipulating cartilage cells, or chondrocytes; developing scaffolds for new tissue to grow on; and using growth factors to hurry things along.

"The holy grail will be to have all three come together," Mandelbaum says. "We need to integrate all three into a lunar excursion module. That's how we'll get to the moon."

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Cell culture

In 2005, Miguel Rueff of Rialto would feel fine after his weekly softball and basketball games. But his left knee would swell up, and he felt some unidentified floating objects that didn't use to be there.

Those objects were broken-off pieces of cartilage that had left behind two lesions, or holes, says Rueff's doctor, Raffy Mirzayan, co-director of sports medicine and director of cartilage restoration and repair at Kaiser Permanente in Baldwin Park.

Mirzayan treated Rueff, now 28, with an autologous chondrocyte implantation, or ACI, using a method called Carticel, developed by Genzyme Corp. in Framingham, Mass.

In this procedure, a surgeon takes a raisin-size sample of healthy articular cartilage from a patient's knee and sends it to Genzyme's laboratory. There, the 200,000 to 300,000 chondrocytes originally contained in the sample are grown (using a proprietary process) until there are about 12 million.

The surgeon then injects these 12 million cells into the patient's lesion under a patch of tissue he makes from the periosteum, the lining of the patient's shin bone. The company says these cells "mature and eventually fill the defect with a durable cartilage with properties similar to original cartilage."

It's hard to check and see, of course. As Mirzayan says, patients aren't eager to have another surgery just for the sake of science.

But Rueff is happy with his results. "Last week was my first basketball game since the surgery," he says. "I actually felt great."

Genzyme introduced Carticel in 1995. TiGenix, a biomedical company in Belgium, now hopes to take such cellular technology to the next level with a new product called ChondroCelect that is not yet approved for use.

The idea behind ChondroCelect is not to settle for any old chondrocyte in the implantation procedure, but rather to select the chondrocytes most likely to be good hyaline cartilage when they grow up.

Gil Beyen, chief executive of TiGenix, says that when cultured chondrocytes multiply, they have a tendency to forget who they are. "They become more like stem cells" -- very susceptible to outside influences and apt to turn into the wrong kind of cells.

For example, if they're injected into muscle tissue, some of them will turn into muscle. Only the ones "with a mind of their own" will persist in becoming cartilage.

Beyen says ChondroCelect favors these strong-minded chondrocytes over the go-with-the-flow ones. "The way we culture the cells leads to better cartilage than other products like Carticel," he says.

Last month, TiGenix announced as yet unpublished results of a randomized clinical trial in which ChondroCelect outperformed a conventional treatment -- meant to repair, not restore -- called microfracture.

In microfracture a surgeon drills tiny holes into the bone, which gradually fill up with fibrocartilage, a kind of scar tissue. This may provide temporary relief, Mirzayan says, "but it's definitely different from the hyaline cartilage we're born with. The main difference is, it doesn't last as long."

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Plug the gap

One minute Jean Roso of Diamond Bar was carrying her dog downstairs after his bath. The next minute she was on her way to the emergency room.

The 44-year-old hair stylist blames her teenage years filled with gymnastics and dance more than she blames Cooper, her 35-pound mutt.

"That was a lot of wear and tear on my poor knees," says Roso, now 44.

Mirzayan is Roso's doctor, too, but for her he used a different procedure, implanting a calcium sulfate plug into her damaged right knee.

It's not at all new to ream out a damaged section of a patient's knee and implant a plug, but in the past this was a plug made of actual cartilage and bone -- either from the patient (an osteochondral autograft) or from a cadaver (an osteochondral allograft).

But fitting that sort of plug perfectly can be very difficult. "Plus, an autograft is like robbing Peter to pay Paul," Mirzayan says. Although the plug is taken from a part of the knee that bears little weight, cutting it out still introduces a new hole, and thus a new weakness. With an allograft, on the other hand, there's the possibility of introducing disease or infection.

The calcium sulfate plug Roso received -- called a TruFit plug and made by the OsteoBiologics division of London, England-based company Smith & Nephew -- is based on quite a different idea: providing a scaffold for new cartilage and bone to grow into.

Again, this is a difficult claim to test. But the University of Louisville's Caborn, who in October 2003 was the first to perform one of these implants, has had several opportunities to do "second-look arthroscopies" and has been happy with what he's found: bone growing where there should be bone, and cartilage where there should be cartilage. And the tests he's performed have shown that, as desired, it's articular cartilage, not fibrocartilage.

Just the other day -- almost exactly a year after the surgery on her knee -- Roso took a couple of jogging steps on the way to her mailbox, and discovered, "I can actually run on it."

Researchers at the Cleveland Clinic in Ohio are experimenting with a different sort of scaffold: collagen from rat tails. As in the Carticel procedure, a doctor takes chondrocytes from a healthy part of a patient's knee. But in this ACI, the chondrocytes are grown in the rat tail collagen, which is then cut to fit the patient's lesion and implanted.

Because collagen is one component of articular cartilage, the scaffold can actually be incorporated into the tissue growth -- instead of dissolving, the way a TruFit plug does. And because the process is quicker than the Carticel process, the chondrocytes are used earlier in their lifespan, when they're more likely to remain true to cartilage form, says Dr. Anthony Miniaci, an orthopedic surgeon and head of the Cleveland Clinic's sports medicine department.

Both scaffolding techniques eliminate the need for the patch used in the Carticel procedure. This is a plus, not only because the patch can sometimes slip, and cells can sometimes leak out from under it, but also because sewing on the patch is very difficult.

"It takes 30 to 40 stitches about as thin as a hair," Mirzayan says.

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Studying growth factors

The third area of research into cartilage regeneration -- studying growth factors -- will take a big step in the next few months with the start of several clinical trials, one based in Santa Monica, Mandelbaum says.

Growth factors are substances that promote cell division. The trials will evaluate the role of growth factor BMP-7 (bone morphogenetic protein 7) in enhancing regeneration of cartilage and inhibiting degeneration of the knee joint.

Already, the three areas of research are starting to overlap, as Mandelbaum says they should.

The rat-tail ACI merges new scaffolding and cellular techniques. Beyen says his company plans to try seeding plugs with the "super-chondrocytes" produced by ChondroCelect. And Caborn says he's already had good results in experimenting with "seeding" TruFit plugs with chondrocytes. "And you could also seed the cells with growth factors," he says. "It's like adding fertilizer to a plug in your lawn."

But in all the excitement over these new knee procedures, Mirzayan sounds a reminder about a procedure that's been around the block a few times.

"Knee replacement surgery, if done in the right patient at the right time, is still one of the most successful operations we can offer as orthopedic surgeons," he says.

The right patient is older, probably over 60. At that point, damage to the knee is most likely caused by generalized arthritis. That means the new procedures couldn't even work, because they're only suited to very localized damage.

But just as the new procedures aren't suited to most older patients, knee replacements aren't suited to most younger ones.

"They don't last forever, only about 15 to 20 years," Mirzayan says. After that, the patient needs another, but each time the surgery is repeated it's less effective.

In his practice, Mirzayan only sees young people with early arthritis. "I try to do something before they end up needing knee replacement," he says. "The longer they can wait, the better the chances that they'll only need one."

Copyright © 2014, Los Angeles Times
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