Researchers take up challenge of reviving cartilage

Stanford orthopaedists are researching ways to predict and track damage to articular cartilage to find new approaches to repair it.

- By Sara Wykes

Several Stanford researchers are working to predict and track the damage to articular cartilage and find new ways to treat it.

Jon Han

Constance Chu was a medical student observing a surgery performed by her teacher when she caught her first glimpse of human articular cartilage, the smooth, glistening coating that covers the ends of bones as they meet at the ankle, knee and hip.

“You only have one chance at this,” her teacher, Henry Mankin, MD, chief of orthopaedic surgery at Massachusetts General Hospital, told her. “If you damage this cartilage, it doesn’t grow back.”

This was the early 1990s, and Mankin was considered one of the 20th century’s leaders in research on cartilage — especially articular cartilage, which is thought to be incapable of recovery from injury because it lacks nerves and blood, the body’s two most important tools for healing. Its basic metabolism was believed to be so slow that the tissue was considered nearly inert. With that set of characteristics, the only hope for damaged joints was to replace them with something artificial.

Now a Stanford professor of orthopaedic surgery, Chu treats the kind of cartilage and ligament injuries that typically lead to joint replacement. She is convinced, however, that articular cartilage can heal itself. She and several Stanford colleagues are researching ways to predict and track the damage to this all-important bone protector, to find new treatments and to stem the rapidly rising flood of people whose joints are wearing out.

“The next generation of orthopaedic devices,” said William Maloney, MD, professor and chair of orthopaedics at Stanford, “is going to be biologic in nature: protein and cells, not metal and plastic.”

Cartilage research has only recently gained wider interest. In fact, when she was a young researcher looking for ways to grow cartilage from stem cells and to capture images of articular cartilage behavior, Chu said, “people were acting like I was crazy. Now everybody wants to be able to do it.”

Main driver of knee and hip replacements

Understanding articular cartilage is at the heart of that next generation of orthopaedic devices, pushed by a rapidly rising need for joint replacement. Many people — 27 million of them in the United States — are familiar with the pain caused by damaged articular cartilage, otherwise known as osteoarthritis. That condition is the primary impetus for the knee and hip replacements already given to more than 7 million Americans. Osteoarthritis is distinctly age-related, so the aging of the baby boomers will push even higher the numbers who suffer from osteoarthritis and the joint replacements that usually follow.

Just last year, another 800,000 knees and hips were replaced. Joint replacement numbers are rising so fast that the American Academy of Orthopaedic Surgeons projects that by 2030 the combined demand for hip and knee replacements may outstrip the availability of surgeons to perform the procedures.

The current plastic and metal replacement parts are good but not perfect, and don’t function as well as a normal joint. Ultimately, many of the implants must themselves be replaced. The metal alloys in implants can corrode; plastics, too, will wear out. And metal particles shed by some implants can destroy healthy tissue or cause poisoning.

Cost is also a driver. In 2005, orthopaedic-implant costs in the United States were $5 billion, double what they had been in 2002. Now, nearly half of Medicare’s annual $20 billion tally for implanted medical device coverage is spent on orthopaedics. Effective prevention or earlier biologic treatment might reduce the rate of replacements and the subsequent cost of those surgeries.

‘Mother Nature did a brilliant job’

Orthopaedists are aiming their work at the key puzzle of how bones and articular cartilage behave. Articular cartilage is perhaps the most challenging component of developing new biologic devices for joints. Most of us might look to our bones as the workhorse of our skeleton, but it is articular cartilage that, ounce for ounce, does the most with the least. Generally no thicker than a dime, it helps our joints remain strong against forces that with each step can add up to three times our body weight.

No small job, that. The average adult takes 1.2 million steps annually. Stair climbing triples the load that joints bear. Mankin and two co-authors of a 2005 lecture on articular cartilage called it the biggest contributor to the “extraordinary functional capacities” of the joints it protects, allowing those joints to move with a level of friction less than any artificial substitute.

 The five zones of articular cartilage’s internal architecture are a marvel of functional design — a series of distinctively different cellular arrangements that control and direct water, the main component of articular cartilage. That water acts as the primary weight-bearing element in the cartilage. The cartilage’s layers — some horizontal, some vertical and some in random array — work with the cells’ biochemical reactions to manipulate water within cartilage. “Mother Nature did a brilliant job of engineering,” said Jason Dragoo, MD, associate professor of orthopaedic surgery at Stanford, “to the point that it is difficult to recreate. This is one of the body’s most complex tissues.”

The next generation of orthopedic devices is going to be biologic in nature: protein and cells, not metal and plastic.

If researchers succeed in recreating articular cartilage, it won’t be the first time that a natural substance has been chosen to replace a damaged joint. The first experiments in joint replacement began in the late 19th century with a German physician who used ivory to replace a young woman’s knee. In the 1930s, an American doctor tested a tempered glass called Pyrex before finding a chrome-cobalt alloy to be more stable.

The surgery has evolved since the first total knee replacement in 1968. Surgeons make a long incision from about 2 inches above the knee to about 2 inches below. The surgeon cleans and prepares the ends of the thighbone and the top of the shinbone to accommodate the replacement parts. The thighbone is capped with a metal covering that mimics its old, rounded end. Into the top of the shinbone, surgeons insert a stem that will support a circular, plate-shaped metal covering. On top of that covering rests a similarly shaped layer of plastic whose upper surface is curved inward to accept the rounded end of the thighbone. The back of the kneecap is fitted with a metal or ceramic button. With those components in place, the thighbone is rotated around on the shinbone’s tray, with the patella in place to cover the joint.

Cell-based cartilage repair

The great hope is that insight into the biology of cartilage will allow damaged cartilage to revive, making such drastic intervention unnecessary.

Clinical trials are taking place around the world to test implants made of materials designed to stimulate new bone and cartilage formation. Many of these materials, however, are created from cadaver tissue, which isn’t easy to come by. Treatments that rely on the patient’s own cells to make replacement cartilage are also plentiful, though not very successful so far, Maloney said. It will take another decade before cell-based cartilage repair will protect joints well enough for any activity that stresses our knees and hips beyond basic movement, he added.

Later this year, Dragoo plans to start testing a knee joint repair treatment that uses stem cells from the fat pad under the kneecap as a repair material. He will harvest those cells using minimally invasive instruments, put them in a centrifuge to concentrate them, add biologic glue made from blood, and insert that mix into the cartilage defect. “We’re taking an immature cell and supplying it with the right environment in the hopes that it stays a cartilage cell,” he said.

Even more reliable, Dragoo said, will be the ability to instruct a 3-D printer to re-create articular cartilage. That may be possible in a couple of years on a small scale to test as a repair for the pothole version of cartilage defects. “And when we can treat potholes,” Dragoo said, “then we can resurface the whole street.”

Preventing cartilage damage 

Other Stanford researchers are focused not only on better understanding how to work with transplanted forms of cartilage replacements, but also on how to prevent and predict cartilage damage. Marc Safran, MD, professor of orthopaedic surgery, has years of experience treating athletes’ cartilage injuries. He and Garry Gold, MD, a professor of radiology, are studying the knees of marathon runners using imaging to capture what the stress of running does to cartilage, and to investigate ways to prevent such damage. Safran has also been identifying the anatomic differences that make someone more vulnerable to joint damage. “If we can prevent this damage from happening, that will be the real key,” he said.

That kind of research is valuable because articular cartilage can be damaged by more than just the aging process. If the contact points of the knee joint are altered, then the cartilage’s protective barrier no longer makes contact properly. And the most-often damaged element of that arrangement is the anterior cruciate ligament, or ACL. Young athletes who tear their ACLs set in motion a deterioration of cartilage that can lead to early osteoarthritis and the need for joint replacement.

Cartilage and the discs between vertebrae in the spine have many similarities. Another professor of orthopaedic surgery, Serena Hu, MD, has focused on the discs of the spine, searching for new ways to preserve disc strength and function. “Understanding more about the genetics of disc degeneration will help us determine who will benefit from early intervention,” Hu said. She has also seen in her research that movement of the spine reduces deterioration. “I’ve always believed that you should stay active,” she said.

When Chu started her career, she was one of only a few researchers working on articular cartilage, but now she has plenty of collaborators. In fact, the International Cartilage Repair Society, formed in 1997, now has more than 1,300 members in 64 countries. At Stanford, Chu and Tom Andriacchi, PhD, a professor of mechanical engineering and of orthopaedic surgery, are studying how abnormal movement patterns damage articular cartilage. She is working with Gold, the radiologist, on the next generation of MRI techniques to detect cartilage behavior. And she is collaborating with Bill Robinson, MD, PhD, an associate professor of medicine, to develop a blood test “to give us an idea of what is going on with articular cartilage without having to do imaging,” she said.

But her longest-running project, funded since 2006 by the National Institutes of Health, seeks a way to diagnose osteoarthritis noninvasively before joints start hurting. The current method for diagnosis, arthroscopy, is a surgical procedure in which a camera is inserted inside the joint. 

So Chu is thrilled by the results of one of her recent experiments, published this summer. The study examined the ability of a new imaging technique called ultrashort echo time MRI mapping to assess cartilage health. It was a small study of 42 subjects: 31 with ACL tears, and 11 without. It showed that the MRI method was able to detect damage, and something far more exciting: that articular cartilage could recover. It took time, but after a new type of ACL reconstruction and a year of rest, most of the subjects’ injured cartilage did heal.

(A longer version of this story appeared in the summer 2014 issue of Stanford Medicine magazine.)

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