The patient was clearly in pain. Doctors were not sure how Johnny, a middle-aged male, had hurt his left knee, but they wanted to assess the damage. So they reached for an arthroscope, a video camera on a flexible, pencil-thin tube, and inserted it into the joint through a small incision.
Although arthroscopic surgery is fairly routine for diagnosing and treating knee injuries, Johnny's procedure was anything but. That's because Johnny is a monkey: an 11-year-old mandrill at the Pittsburgh Zoo. There's no precedent, says Freddie Fu of the University of Pittsburgh School of Medicine, the surgeon who performed the operation in June. I think this is maybe the first time anyone has ever 'scoped a monkey knee.
What Fu found is that Johnny had partially torn his anterior cruciate ligament (ACL), a band of tissue that stabilizes the knee, particularly as it rotates. A torn ACL is one of the most common major injuries in the sports world, says Fu, who guesses that he has mended some 5,000 ligaments during his 30 years in the orthopedic business. Such knee injuries are not limited to professional athletes, however: they can befall just about anyone who is physically active, including weekend warriors, high school students and--as Fu discovered--middle-aged mandrills. Sources in the orthopedic industry estimate that physicians reconstruct about 200,000 ACLs every year in the U.S. alone; worldwide the number of reconstructions may reach up to half a million.
But the problem doesnt end there. Tearing an ACL--even if the ligament subsequently gets repaired--can set the stage for osteoarthritis, a condition in which the entire joint begins to deteriorate. According to one Norwegian study, 100 percent of women who tear their ACL are going to have arthritis in that knee by 20 years out, says Tim Hewett, director of the Sports Medicine Biodynamics Center at Cincinnati Children's Hospital.
Even without an obvious injury to trigger it, osteoarthritis of the knee affects 6 percent of adults older than 30 and 12.5 percent of those older than 60. This is an extremely common disease, says David Felson, a rheumatologist who specializes in osteoarthritis at the Boston University School of Medicine. Everyone is at risk. And treatment often involves complete replacement of the knee joint with a prosthetic device that, unfortunately, can also wear out over time.
Given those statistics, bioengineers and orthopedic surgeons are working to come up with new methods and materials for repairing worn-out ligaments and other joint components biologically--so that people in their 40s, 50s and even 60s can delay or avoid replacing their knees with metal or ceramic prostheses. In the clinic and in the lab, these researchers are exploring promising approaches to relieve pain, restore motion and encourage damaged joints to heal themselves.
Anatomy of an Injury
Every joint in the body is subject to damage, but the knee is the best studied, perhaps because it is often injured and reasonably easy to diagnose, says Stefan Lohmander, an orthopedist who specializes in osteoarthritis at Lund University Hospital in Sweden. Knee injuries send a large portion of the population limping to the physician with complaints of pain and reduced mobility in that joint--problems that Lohmander notes can make getting around, going shopping, seeing friends and participating in life difficult.
The ACL is not the only structure in the knee that can cave under pressure. A few people snap the posterior cruciate ligament, which crosses the ACL in the center of the joint (hence the term cruciate, for cross-shaped). Another structure that is subject to wear and tear is the articular cartilage, which covers the ends of the thighbone (femur) and shinbone (tibia) like a thick coat of paint. This slippery material (think of the white stuff on the end of a chicken drumstick) not only decreases the friction between the moving parts of the joint--allowing the bones to slide over one another--but serves as a cushion to evenly distribute the load that is introduced with each step. Lose this cartilage, and bone will rub on bone. Additional shock absorption in the knee comes from the meniscus, a washerlike wedge of cartilage that rests between the femur and the tibia. This structure--really a pair of structures, one on the outer half of the knee, one on the inner half--can also be damaged or torn by injury. When the meniscus is damaged, the articular cartilage underneath it can begin to wear; this combination of injuries can pave the way for osteoarthritis, with its associated inflammation and pain.
Any sport that involves body contact, jumping, landing, pivoting or zigzagging raises the players risk of injury and osteoarthritis, particularly when athletes get back in the game before a damaged joint heals. Most at hazard are those who play soccer, football, basketball or tennis and those who perform gymnastics.
Women are particularly susceptible to tearing an ACL [see box on page 65]. Women's gymnastics has as high a rate of ACL injuries as men's spring football, which is when collegiate teams practice and play scrimmage games, says Jennifer Hootman, an athletic trainer and epidemiologist with the Centers for Disease Control and Prevention. In Norway, which often takes home the trophy in women's team handball competitions, Hewett says something like one in five women who play that sport tears her ACL.
Gimme a Graft!
For torn ACLs, treatment generally involves trying to connect the knee back together in some way, Fu says. In the 1950s surgeons tried to stitch together the torn ends of the ACL. Unfortunately, that didnt work too well, says Martha Murray, head of the sports medicine research laboratory at Children's Hospital Boston. Patients with sewn-up ACLs would eventually find that their knees were as unstable and prone to buckling as before the repair.
Of course, not everyone with a torn ACL needs surgery. If you are not very active, if your lifestyle is such that you go swimming and walking but dont engage in activities that require sharp changes in direction--like basketball or tennis--you may be able to live without surgery, Fu says. Such individuals might be able to get by merely with physical rehabilitation to strengthen their leg muscles and help stabilize the joint.
Of course, allografts dont grow on trees. Although they do not need to be matched the same way a transplanted organ does, graft tendons must be healthy and strong, and thus they tend to come from donors somewhere between 18 and 35 years old. Lack of a suitable graft can sometimes postpone surgeries for weeks or months. To get around those problems, Kevin Stone, an orthopedic surgeon in San Francisco, is turning to pigs. Pig ligaments are similar to human ligaments, and we can get them young, healthy and strong every time, he says. He and his colleagues have developed a method for stripping the porcine tissue of the proteins that would trigger rejection and have shown that the grafts are safe for use in humans. One individual in their initial safety study went on to win the Canadian masters downhill ski championship--three times.
A Longer, Better Surgery?
But Fu argues that the current approach only does half the job, because the human ACL is actually made of two bundles: one that stabilizes the knee as it bends; the other that stabilizes the knee as it rotates. To restore normal anatomy--and range of motion--Fu says surgeons need to connect A to A and B to B.
Convincing his colleagues, however, has been an uphill battle--in part because a double-bundle replacement takes longer to perform. Fifteen years ago I would do an ACL in 30 minutes: bang, bang, bang, no problem, Fu notes. But looking back, I see that what I did before this double-bundle procedure was quite crude.
Odd as it might seem, Fu's curiosity about the function of the human knee is what led him to operate on Johnny the mandrill. Fu was probing the monkey's knee for insight into the anatomy and mobility of animal ACLs, information that he hopes will help surgeons see that different parts of the ligament serve different purposes--and that all parts need to be restored for the joint to function properly. Johnny's ACL, it turns out, has three bundles, which give his knee an even greater ability to rotate--a feature that Fu thinks might come in handy when the monkey is reaching for a tree branch to get to some ripe fruit or running from a bigger monkey.
Enter the Bioreactor
An ACL, once torn, cannot spontaneously mend itself--in part, Murray says, because there's no structure for the cells in the stumps to crawl into to build a new ligament. So some researchers are trying to come up with materials that can bridge that gap, allowing the ACL to regrow. Murray is betting on the blood cells called platelets. She has produced a platelet-rich gel that she squeezes into the space that remains when a torn ACL is sewn back together. The mixture forms a clot, which promotes the formation of scar tissue--the same way platelets help to heal a cut in the skin. In experiments with pigs--published in the Journal of Orthopaedic Research in January 2007--Murray reports robust healing: at four weeks the repair has regained 40 to 50 percent of the strength of an intact ACL. Preliminary results for later in the healing process show blood vessels growing into the new tissue and cells dividing and producing collagen--one of the main components of a ligament.
The results are particularly encouraging, considering the patients. The pigs feel good enough within a couple days that theyre up walking around and standing on their repairs, Murray says. Yet despite the lack of couch time and crutches, the pigs ligaments appear to heal. That makes us hopeful that when we get to clinical trials, where we have more control over the patients, the results will be even better, she says. Although with some of my teenage patients, Im not sure how much control I really have.
Greg Altman, president and CEO of Serica Technologies in Medford, Mass., is taking a similar approach, co-opting the body's natural repair capabilities to mend a wrecked knee. In studies with goats, instead of sewing the loose ends back together, Altman and his colleagues remove the damaged ACL entirely and replace it with a scaffold made of silk. This material is strong enough to support the growth of a new ligament, and the researchers have treated the fiber so that the body degrades it over time, leaving a strong new ACL in its place. The results of Altman's studies--presented at the annual meeting of the American Orthopaedic Society for Sports Medicine in July 2007--look good: the ACL regrows, the repaired joint is stable and, after 12 months, the researchers see no signs of arthritis. We observed a very calm, intact joint, says Altman, who is initiating a clinical study in Europe to test the safety and effectiveness of the grafts in patients.
Best of all, the silk graft needs no special storage or refrigeration, so a surgeon should be able to size a patient's joint and literally pull a replacement off the shelf. Avoiding the need for harvesting grafts from the patient's own knee was an important consideration in the development of the silk scaffold, says Altman, who tore his own ACL as an offensive lineman during his senior year at Tufts University and received a graft from his patellar tendon to take its place. My ACL was pretty good, he recalls, but my patellar tendon was killing me. The experience drove Altman to enroll in graduate school--initially so that he could play a fifth year of football but also so he could help other people recover better from ACL injury.
Green Tea on the Knee
Athletes like Altman who have torn an ACL are perhaps 10 times more likely to develop osteoarthritis than folks in the general population, according to Lohmander. But theyre not the only ones at risk. Arthritis tends to run in families, so genes play a role. So does obesity and even aging itself. Currently no treatments cure the disease. We have drugs, like painkillers and anti-inflammatory agents, that alleviate the symptoms, Lohmander says. But there's nothing that really stops or slows down the development of osteoarthritis once it starts.
Unfortunately, as the disease progresses, the damage mounts, and many people with osteoarthritis wind up having a knee replacement. The substitution relieves pain and restores mobility, making it one of the most successful operations in medical history, says Joseph Buckwalter, an orthopedic surgeon and researcher at the University of Iowa Hospitals and Clinics. But the approach has its drawbacks, including the fact that the implants can wear out with time, just as the tires on your car wear out when you drive or your shoes when you walk, Lohmander says.
While prostheses continue to improve--current devices last 20 years or more, and orthopedics manufacturer Zimmer in Warsaw, Ind., recently introduced an artificial knee designed specifically for women--researchers keep searching for more biologically friendly ways to rejuvenate an arthritic joint. Buckwalter and his colleagues have found that as people age, the cells that maintain the knee's articular cartilage begin to fail. The cartilage then weakens, which makes the knee more vulnerable to injury and mechanical malfunction. Treating isolated strips of cartilage in the lab with antioxidants--including purified extracts of green tea--appears to revive those exhausted cells and to prevent or minimize mechanical damage to the joint, Buckwalter says.
Although a whole knee can be replaced, damaged cartilage alone cant be fixed by swapping in something synthetic. The knee goes through two to three million steps per year from normal walking and experiences up to five times the body weight, depending on the height of the step, Stone says. There's no artificial material known to man that you can put in the joint that wont either damage the opposing side or wear down rapidly.
Hence, surgeons have devised a variety of techniques that use some of the patient's own tissue to repair small areas of cartilage damage--nicks, tears or holes that arise from a blow to the knee or some other localized injury. The most common approach involves harvesting a piece of the patient's cartilage and sending it off to a commercial laboratory that multiplies the cartilage cells in a culture dish and ships that expanded material back to the surgeon, who then uses it to patch the knee damage--sort of like filling a pothole, says Farshid Guilak, a bioengineer at Duke University Medical Center.
Guilak is replacing more extensive regions of damaged cartilage by developing stem cells, which have the ability to produce new cells of other types of tissue. The stem cells he uses are a versatile variety harvested from liposuctioned fat. He and his colleagues spread these stem cells over a specially designed woven polyester scaffold. They then bathe this cell-studded material with growth factors that coax the cells to produce cartilage. So far it looks like the cells are up to the job; Guilak and his lab are gearing up to test the scaffold in the hip joints of goats.
In the meantime, Buckwalter and others continue to work on imaging techniques that will allow them to identify molecular changes to the cartilage that could herald impending deterioration. Whether such tools will help surgeons head off osteoarthritis or other potential problems in those who may be at risk, Felson acknowledges, is unknowable right now.
As for Johnny the mandrill, Fu was able to remove some of the scar tissue and inflammation that was causing his patient's discomfort--which is where he intends to leave things for now. I dont think anybody in the world has ever reconstructed an ACL in a monkey, Fu says. I dont pretend I know how to do it. Meanwhile the patient is doing well, enjoying extra helpings of pudding and bananas.