Sometimes I wish I could slice open the skin that covers my knees so I could poke around inside a bit. Without pain, of course. Without spilling any blood or other vital juices. And only if I could use magic to close up all the tissue when I was done. If I could do that, I’d love to get a good look at the ends of my thigh and shinbones. These bones meet at the knee. Their complex conjunction — the stuff that joins the two together — is the knee. What I would hope to see in mine would be a glistening white padding over the knobby bone ends, a coating smooth as the finest china, thick as white chocolate covering some sweet harder substrate.
That’s what you see in great knees, those in the best condition, which I suspect mine are not. My knees are 49 years old, and they often crackle and pop. Sometimes they ache when I run. At other times, random painful twinges shoot through them.
I try to be optimistic. An optimist can look at human knees and marvel at their prodigious competencies. The largest, strongest, and heaviest joints in the body, they not only support most of our weight, but they enable us to lope and crawl and stride and skip and tiptoe and otherwise perambulate. Viewed through a darker lens, however, knees also rank among the most vulnerable of body parts. They’re the anatomical site most often treated by bone and joint doctors, according to the American Academy of Orthopaedic Surgeons. Americans visit doctors’ offices close to 11 million times a year because of some kind of knee problem. Over the course of the 1990s, knees overtook hips to become the joint most often replaced by surgeons. First done in 1968, the procedure involves cutting out the ruined knee surfaces and creating a substitute hinge made out of metal and plastic. Total knee replacements more than doubled over the past decade, from 129,000 in 1990 to 267,000 in 1999. Some medical authorities have estimated the number will almost double again over the next 30 years, climbing by 454,000 such operations per year by 2030.
Knees can fail in so many ways. The four fibrous ligaments that lace the shin and thighbones together can be stretched to the point of ripping or snapping. The forwardmost of the two ligaments that crisscross behind the kneecap (the anterior cruciate ligament, or ACL) is particularly prone to injury; more than 95,000 of them in the United States tear every year, according to the orthopedic surgeons’ organization. “People often tear the ACL by changing direction rapidly, slowing down from running, or landing from a jump,” the surgeons’ website informs visitors. “You might hear a popping noise when your ACL tears. Your knee gives out and soon begins to hurt and swell.”
That sounds so decorous, genteel, compared with my experience with ACL destruction. This memory is pinned like a slalom pole to a ski slope in Keystone, Colorado, on the morning of February 8, 1997. It’s a beginner’s slope, and it glitters in the sunshine of a lovely day, but it’s too steep a slope for someone like me who’s spent no more than three hours on downhill skis in the course of her entire lifetime. I start down it, but within a very few seconds realize I’m heading — too fast! — for a grove of trees, so I shift my weight in a clumsy attempt to lurch away from danger. I lose my balance, and as I hit the snow my left leg folds up beneath me at an unnatural angle, a move that detonates a small atomic bomb of pain. Ground zero is my knee, but the pain mushrooms out; the shock wave brutalizes every neuron in my body. Along with the pain, I feel horror. I still feel it today in this memory. It’s the horror of knowing you’ve just made your body do something unspeakable, something that has broken it.
I never did hear the revolting popping sound that’s said to be on the soundtrack of so many ACL disasters; but within moments, the swelling had transformed my trim normal knee into a fat person’s knee, bloated and alien. In the days that followed, along with the pain, waves of nausea washed over me every time an imprudent move reminded me of how loosely my lower left leg had become connected to its upper half. (Orthopedic examination revealed that I had also ripped the collateral ligament that secures the thigh and shinbones along the inside of the leg.) At times it felt as if my shin and foot were connected to the rest of me by nothing more than skin, as if a simple push might break them off.
Little by little, the feeling of vulnerability receded as the side ligament healed. In contrast, anterior cruciate ligaments never heal, my doctor informed me, and many orthopedic surgeons perform surgery to reconstruct torn ACLs. For the repair material, they harvest a strip of tendon from some other site in the body, such as the kneecap or the hamstring. But reconstructive philosophies in the spring of 1997 were in flux, according to my orthopedic surgeon, who recommended waiting a couple of months to see how stable my knee became. “It looks like a third of all patients can resume their normal activities even if they don’t have the surgery. A third are fine if they modify their lifestyle somewhat. And a third wind up having so much instability that they need to have the reconstruction,” he told me.
I wound up in the lucky group. I got some occupational therapy for a few weeks but had no surgery. Six months later, my only reminder of the accident was a dull throbbing after a long day on my feet. Even that disappeared after a few more months. My doctor warned me that I appeared to have injured the edge of the meniscal cartilage in my left knee. It might heal on its own, or it might cause me trouble later on, he said.
Meniscal damage is another common way for good knees to go bad. The menisci are semicircular pads of rubbery cartilage that sit at the junction where the thighbone meets the shinbone; orthopedists like to compare them to shock absorbers. Injuries and wear can cause this tissue to rip and fray in a number of ways, and when that happens, the results can include pain, stiffness, and instability. Doctors have learned that if they trim away the frayed or torn edges of a meniscus, the knee will often feel good as new, though if they take the whole thing out (which of course they tried for a while), bad things happen. Over the past 20 years, it’s become common to effect meniscal repairs arthroscopically, that is, through small incisions using chopstick-sized arthroscopes and special surgical instruments. With more than a million and a half knee arthroscopies performed annually, arthroscopic meniscal repair is the most common operation done today in America, according to Dr. James Tasto, a local past president of the Arthroscopy Association of North America.
Yet another bad thing that can happen to knees is that the bones that meet there can break. That’s what happened to Meghan McShannic, with whom I talked as she was recovering from knee surgery at UCSD’s Thornton Hospital. McShannic, a youthful 45, worked as the controller for a Bay Area dot-com. She lived in Walnut Creek but had come to San Diego to have her knee surgery, and she shared with me the sad prelude to that decision. Ten or 15 years ago, she and her husband had become avid skiers, she said. They’d traveled throughout the West to indulge their passion and had even bought a house near Tahoe. Toward the end of April 2001, they were out at Alpine Meadows. “It was my 22nd day of skiing that season,” she recalled. “There was two feet of heavy new spring snow, and I caught an edge, and — I don’t know. It was sort of a freak thing. I fall all the time, and there was nothing overly dramatic about this fall. Until I landed.”
McShannic said it was obvious on the slopes that she had broken something, but in the emergency room in Truckee, an X-ray revealed the extent of the bad news. The top of her tibia (the shinbone) had shattered. McShannic had her first surgery in the Bay Area in April of 2001. Her surgeon at that time inserted three large titanium screws to pin the pieces of her bone back together. By August she was walking again, but it was clear that her leg had healed with a deformity. “It basically made me knock-kneed,” she explained. In November of 2001, her Bay Area doctor had examined the interior of the knee with an arthroscope. “That actually improved things quite a bit,” McShannic said. “ ’Cause it cleaned up a bunch of the scar tissue.” But it also revealed more bad news. “All the places where the bone had shattered, I had lost cartilage.”
McShannic wasn’t talking about meniscal cartilage, but rather the other type of cartilage found in knees, so-called articular or surface cartilage. This is the slippery white tissue that covers the ends of the thigh and shinbones. One of its functions is to spread out the loads that are put on those bones as they hold us upright and move us through our activities. Articular cartilage also helps the two bones to glide smoothly over one another. Researchers say the friction in a healthy knee is close to zero. “Cartilage slides against cartilage at least ten times better than ice on ice,” one told me. “And ice on ice is an order of magnitude better than a lot of other materials.”
Another amazing thing about articular cartilage is its wear-resistance. “It’s a remarkable, remarkable material,” exclaimed Dr. William Bugbee, an assistant professor of orthopedics at UCSD’s Medical School. “It can withstand these loads that are upwards of three and four and seven and ten times body weight. Millions and millions of cycles a year for the average person. You think about the loads! No mechanical device on earth can withstand that.” Still, despite its toughness, articular cartilage can be damaged by accidents like the one McShannic suffered. When that happens, yet another remarkable characteristic comes to the fore: its ineptitude at healing.
In this regard, it’s instructive to contrast articular cartilage with skin or bone. Rip into your skin, and within seconds blood starts bringing repair materials to the site. Inflammatory cells and other blood-borne substances trigger a series of reactions that rebuild the damaged tissue; before long the site can look as good as new. Bone is even better at fixing itself, according to Bugbee. When it is injured, it repairs itself with normal bone rather than with some kind of scar tissue.
For centuries people have known that cartilage falls at the other end of the healing spectrum. Writing in 1743, a medical researcher named Hunter noted that “it is universally allowed that ulcerated cartilage is a troublesome thing and that once damaged, it is not repaired.” A couple of factors explain this, Bugbee told me. For one thing, articular knee cartilage has no blood supply. Instead it’s nourished by synovial fluid, a clear, viscous liquid that functions like a sort of futuristic engine oil — one that not only squishes between the moving parts but also absorbs into their surfaces and helps to make them slippery. For all its mechanical elegance, synovial fluid doesn’t contain any of the healing agents carried by blood, such as cells and platelets.
Another reason cartilage heals so poorly may have to do with its structure. “Cartilage is unique,” Bugbee said. Compared to other parts of the human body, the tissue matrix contains a paucity of cells. “It’s sort of like a Jell-O mold,” the surgeon said. “Ever done Jell-Os with fruit inside? Maybe you have a grape every three inches. That’s what cartilage is like. Each grape is a cell, and the Jell-O is the matrix.” That matrix is a complex framework of collagen studded with large, specialized molecules, water, and the cartilage cells. Designed to be smooth and lubricating and withstand huge forces, the matrix is “the white stuff at the end of the chicken bone,” Bugbee said.
If its structure and lack of a blood supply mean that most damaged knee cartilage won’t heal, those same characteristics also make it an excellent candidate for transplantation. “Cartilage doesn’t generate much of an immune response from the host,” Bugbee told me. “We think that’s because there’s no blood supply, so the antibodies in the blood and the cells that identify foreign materials don’t get to it. And number two, the cells that would cause the immune reaction are inside the cartilage matrix.”
Recognizing the opportunity created by those conditions, a couple of UCSD orthopedic surgeons in the early 1980s started performing some of the world’s first transplants of fresh (as opposed to frozen) knee cartilage. Bugbee learned about their work when he did his orthopedics residency at UCSD in the early 1990s. He then went to the Anderson Orthopaedic Research Institute in northern Virginia for additional training in arthritis and joint-replacement surgery. But he returned in the fall of 1997 to become the head of UCSD’s joint-replacement and cartilage-transplant program. Today, in addition to teaching some classes, he specializes in arthritis surgery. He says outfitting patients with artificial (plastic and metal) joints is the mainstay of his surgery business. He probably does 250 of those operations a year (half of them hips and half knees). But he also transplants living knee tissue 40 or 50 times a year. “That’s more than anybody else on earth,” he told me.
I imagine that Bugbee’s med school students enjoy listening to him lecture. He’s good at explaining things. What the surgeon actually transplants, he told me, is a chunk of the end of the dead person’s thigh or shinbone, a chunk that’s covered with healthy articular cartilage. Though most patients only need the healthy cartilage, you can’t transplant it alone because there’s no good way to make it stick to the recipient’s bone and thrive there.
That’s not the case with bone. It does a terrific job of growing into and becoming one with whatever bony cavity it’s placed in. So in the transplant surgeries that Bugbee performs, the bone anchors the cartilage to the new site. A narrow seam exists between the donated cartilage and the patient’s own cartilage, but fibrous scar tissue later fills the gap.
A crucial feature of the knee-transplant surgeries is the fact that tissue cannot be frozen or freeze-dried after removal from the donor. Freezing kills most of the living cells within the tissue. If all you cared about was the bony part of the graft, that wouldn’t be a problem. The second most frequently transplanted tissue (after skin), bone is usually frozen or freeze-dried. In that state, it can be stored for a long time and easily transported, and once placed in a surgical site, it works well as a scaffold into which new living bone cells can grow.
Cartilage, however, is another story. Bugbee explained that the transplant operation requires live cartilage cells because those cells work to keep the matrix healthy. Once in their new home, they can survive for decades. “We’ve done studies and found cartilage cells living 10 and 20 years” after transplantation, the surgeon said. Few tissue banks in the United States have set up systems for collecting and storing fresh human knee tissue. Bugbee says that’s because the logistics of harvesting, screening, and processing the tissue tends to be daunting. San Diego’s tissue bank became an exception to that rule because of the pioneering knee-transplant research done at UCSD 20 years ago. Since then, collecting knees from cadavers has become routine here, which is why Bugbee has been able to do so many of the transplant surgeries.
Open one of the big refrigerators at the Lifesharing tissue bank in Mission Valley, and you’re apt to find a large white plastic tub bearing a red sign marked “Bugbee Knees.” The tub often holds fresh human knee parts double-wrapped in thick blue paper and packaged in clear plastic. Whenever Lifesharing acquires a bigger supply of these parts than Bugbee needs for his upcoming patient lineup, the local tissue bank freezes the excess parts and sells them to a Denver-based company called Allosource. (It in turn sells the frozen knee parts to doctors who need them for other procedures.) Bugbee says the number of orthopedists who have performed the fresh tissue transplants has been growing. “There’s probably a thousand doctors who’ve tried it once. And there might be 50 who’ve done 5 or 10 surgeries and 10 doctors who have done 20 or 30.” (In contrast, Bugbee figures he’s performed close to 200 of the knee transplants.) For most doctors, the shortage of tissue remains a limiting factor, he says.
In the year 2001, 170 San Diego County families gave permission for various parts to be taken from their newly deceased loved ones, according to Sharie Shipley, the senior community development specialist for the San Diego–area tissue bank. Those numbers don’t include the county’s 66 organ donors. When talking about the extraction of tissues or organs from people who’ve died, tissue-bank personnel no longer use the word “harvest,” Shipley instructed me. “We say ‘recover.’ So as not to scare people.” Out of a similar concern, the organization two years ago changed its name from the slightly plunderous-sounding Organ and Tissue Acquisition Center to the gentler Lifesharing.
Better than most people, Shipley knows the joy a single organ donation can bestow. In March of 1995, a donated liver saved her life after she discovered that hepatitis C — undetected in her body for 20 years — was destroying her own liver. “I know firsthand that [organ transplantation] works,” she told me, adding, “that’s why I’m pretty passionate about my job.”
Although the general public tends to be aware of the need for organs (hearts, livers, lungs, kidneys, pancreases, and small intestines), Shipley says people don’t think as much about tissue — material from the body such as kneebone and cartilage. “Mostly, tissue is used to enhance life, rather than save it,” she pointed out. Also, its distribution tends to be diffuse. A single tissue donor might contribute corneas to two different individuals, enough skin to help six burn victims, plus bone, tendons, joints, veins, and heart valves that might benefit an additional 50 or more recipients, according to Shipley. The widespread nature of this benefaction makes it harder to find clear, dramatic stories that can be used to publicize the need for tissue.
One factor does make it harder to secure organs as opposed to tissue: the only people who can donate organs are individuals who’ve been declared brain dead by at least two doctors (unconnected to the transplant team). Before their brains die, such patients are placed on ventilators to help them breathe. As a result, when their brains die, their organs are never deprived of oxygen, and thus they suffer no irreversible damage. Shipley says people don’t understand this requirement. “They say, ‘There are car accidents every day. Why are there so many people on the waiting list for organs?’ ”
With tissue, you have a bit more leeway. The donor doesn’t have to die in a hospital while on a ventilator. Shipley says when a corpse is quickly refrigerated, Lifesharing can recover tissue from it for up to 24 hours after the death. (Without refrigeration, Lifesharing’s outer limit drops to 12 to 13 hours postmortem in most cases.) But other factors restrict the number of tissue donors. The dead person can’t have had any sort of infectious disease; Lifesharing personnel interview the family members and medical personnel run tests to screen for this. And when the tissue in question is knee cartilage, age also shrinks the potential pool. Bugbee won’t use the joints of anyone over the age of 40. And he says, “A lot of the 30s to 40s don’t have healthy tissue.” Among younger people, car accidents and suicides tend to be a common cause of death. But those events often mangle otherwise impeccable knee joints.
I got a taste of the unpredictability of Bugbee’s work when he invited me to observe one of his transplant operations. As things turned out, we had to wait two weeks before the demands of his travel schedule and the supply of available knee parts came together in a way that enabled Meghan McShannic to have her surgery. McShannic’s knee pain had increased a lot in January. “I don’t know if it was the weather or what. But most of January, I was limping pretty badly.” In February, she had flown down to consult with Bugbee (whom she’d heard about from her brother-in-law, a pediatric orthopedic surgeon in San Diego). Bugbee had answered all her questions. “He told me that a tibial plateau fracture was one of his favorite reasons to perform [a transplant] and that they typically had good outcomes.” If she didn’t attempt to have the cartilage repaired, “I was looking at a total knee replacement in three to five years,” McShannic said. She felt too young for that.
McShannic had thus flown to San Diego again on the evening of March 13. At 6:30 the following morning, a cluster of medical personal fluttered around her in a cubicle near the Thornton Hospital’s operating rooms. She signed consent forms and talked with the anaesthesiologist, while Bugbee stood nearby, filling out statistical forms that he would later draw upon for his ongoing research. I asked how long McShannic’s operation would take. “Probably two hours,” he guessed. “There’s a bit more fiddling around because we have to take the old hardware out, and that can be a little tricky.”
Conservative though it was, Bugbee’s guess was bit short because of what he discovered once he opened up McShannic’s knee. Before the surgeon made his first incision, the anaesthesiologist had rendered the woman unconscious, put a tube down her throat to deliver air to her lungs, then wrapped her upper body in what he described as “every warming device known to man.” While he did that, Bugbee and his assistant, the hospital’s chief orthopedics resident, moved McShannic’s troubled knee around, flexing it and testing the range of motion. “Under normal conditions, if somebody had a lot of pain in the knee, you couldn’t do that to them. They’d be screaming,” the anaesthesiologist told me. But asleep and paralyzed, McShannic couldn’t feel the doctors’ manipulations.
A nurse had scrubbed every inch of McShannic’s leg with a mixture of iodine and alcohol, then slipped a tight white support stocking over it, followed by surgical dressings over all the parts that wouldn’t be operated on. Finally, the surgeons had wrapped McShannic’s leg in an adhesive plastic sheet impregnated with iodine. This stuck to every inch of the woman’s exposed skin. When Bugbee pierced the plastic with his scalpel, pressing down to cut through the skin below, I couldn’t imagine what else anyone could do to keep germs out.
It took Bugbee only a few minutes to bring the four-inch-long incision through all the layers of underlying tissue, exposing the bones that meet at the knee. The top of the outer half of the shinbone was the mess he had expected it to be, but amidst the whiteness of the end of the thighbone, he spotted something else that McShannic’s X-rays and other tests had failed to reveal. This bone too was missing a fingernail-sized chunk of its protective cartilage. Bugbee made an on-the-spot decision to repair it. He asked one of the nurses to call the tissue bank and have the top half of the donated knee sent over; he would transplant part of it into the upper defect.
He then turned his attention to the tasks of removing the three long titanium screws embedded in McShannic’s tibia and extracting the wrecked pieces of bone around them. The latter challenge required the kind of tools I associate with the woodshop rather than the operating room: various saws, a mallet, a hammer, rasps of several sizes. “Not much left there,” Bugbee grunted as he yanked out the largest piece. It reminded me of a beef bone that had been gnawed for a while by a dog.
Using calipers, the two doctors measured the void in McShannic’s knee, then they moved to another nearby table. On it the nurses had placed a basin containing a shiny white object: one half of the top end of the donor’s shinbone. “Here’s the tendon that attaches to your quad muscle, and that’s the patellar tendon right under this fat,” Bugbee said. The fat looked like the yellow sludge you find when cutting up raw chicken. With his scalpel, the surgeon lifted up and snipped off two kidney-shaped pads I recognized as being the menisci. He pointed out the satiny smoothness and milk-white purity of the cartilage underneath the areas the menisci had covered. Next to the protected areas, the adjacent cartilage had a breath of yellow, a hint of roughness. “That shows you why the menisci are so important,” Bugbee said.
McShannic’s meniscal tissue was “not great,” he declared. But it wasn’t bad enough, in Bugbee’s judgment, to warrant cutting it out and trying to replace it with donated menisci. Picking up a blue marker, he sketched on the donated piece of bone the form he wanted to extract from it. “You know what they say about orthopedists?” he asked me. “We measure with a micrometer. We mark with chalk. And we cut with a chainsaw.”
It took Bugbee a while to carve the donor bone into the dimensions he needed: about an inch and a half long, an inch wide, and a half-inch thick. Then he used something that looked like a wire clipper to tear the fringe of soft tissue off all the edges of the block, a step he said would help minimize any immune response to the transplant. When he filed the end of the block to remove a bit more bone and smooth the surface, his actions again recalled those of a skilled woodworker. “Okay, folks. Here it is,” he finally declared. “The crux of the operation!” Back at McShannic’s side, he slipped the piece into the void at the top of her tibia. Her intact meniscus on that side slid into place, and when a technician turned on a fluoroscope that brought X-ray images of McShannic’s knee onto a nearby screen, Bugbee crowed, “Yeah, baby!”
“That looks really nice,” his assistant murmured.
The repair of the smaller defect in the surface of McShannic’s thigh bone was uneventful. Bugbee used a circular drill to bore into both McShannic’s and the donor’s bone, removing a round plug of the same diameter from each. To get the thickness of the donor plug just right, he worked on it with various saws and files, then he tapped it with a mallet into the receptor hole in the woman’s leg and secured it there by using small bioabsorbable pins that would later dissolve within the bone. (He’d needed three-millimeter titanium screws to affix the larger piece to the tibial end.) By 10:30 a.m., the surgeons were sewing up the gaping hole in McShannic’s leg. “Basically, we resurfaced a good portion of half the knee,” Bugbee said. He sounded satisfied.
I thought it ironic when, that evening, a national news story reported a warning issued that day by the U.S. Centers for Disease Control and Prevention about the dangers of infection from transplanted knee tissue. Such an infection last November had killed a healthy 23-year-old Minnesota man less than a week after he’d undergone a knee surgery just like the one I watched Bugbee do on McShannic. The subsequent CDC investigation into the death had turned up 25 similar cases (though none fatal) over the past 16 years. Bugbee knew all about the report, I found when I later asked him about it.
“The bottom line is that this tissue can transmit disease,” he agreed. “The fresh tissue we use poses unique problems, because it can’t be sterilized.” So the way it’s processed and screened for disease is critical. As more doctors were beginning to do the knee transplants, “More tissue banks want to get in the business of procuring fresh grafts, like the one you saw, and selling them, because they can get 5 to 10 to $12,000 for one.” In the case of the transplant that killed the Minnesota man, the knee tissue had come from a donor whose body had been unrefrigerated for 19 hours after his death. “That’s totally unacceptable,” Bugbee stated. Furthermore, the knee parts, once extracted, probably sat in a refrigerator for 30 days before being transplanted. “My analogy to people is, it’s like a carton of milk. Milk’s pasteurized, so it shouldn’t have a lot of pathogens in it. But would anyone drink a gallon of milk if it had sat in the fridge for a month? You’ve really got to wonder,” he said.
The UCSD doctors’ original limit on the acceptable interval between harvest of the knee tissue and transplantation was three to five days, Bugbee said. But additional research had made him feel confident “that the tissue is healthy and very good quality up to about a week or so.” He thought it was possible that still more work might push his comfort zone to a 14-day limit. The other quality controls employed by the Lifesharing team also contributed to his confidence that the knee tissue he was using was safe, he told me. Over the past 20 years, the UCSD knee doctors had not documented one case of infection or disease transmission related to the graft. “But [nationwide] this is becoming a big industry,” he remarked. “And it’s really kind of scary, because most doctors don’t know much about tissue. They just have their hospital or their office call the tissue bank or the agency and say, ‘Send me a distal femur.’ That’s about all they know. And that’s not okay.”
The possibility of infection and the scarcity of tissue donors are among the biggest reasons why researchers are now trying to find other ways to repair knee cartilage. “San Diego and in particular UCSD is one of the premier places in the field for cartilage research,” Bugbee said. To learn more about this, he encouraged me to talk to one of his colleagues named Robert Sah.
I found Sah in his fifth-floor office in the Jacobs School of Engineering building on the UCSD campus. He wore thick square lenses, a pinstriped shirt, no tie, dark pants, white Nikes. His hair was black and glossy, except for one quarter-size patch of gray near his right temple.
When I asked about the origins of his interest in knee cartilage, Sah traced it back to a class he took toward the end of his undergraduate career at the Massachusetts Institute of Technology. He’d been studying bioelectrical engineering, but he didn’t know what he wanted to do with his life. Then he took a class that examined the ways in which physical forces interacted with the human body. When his professor discussed knee cartilage, Sah was spellbound. “Cartilage is very interesting electrically, because when you squeeze it, it actually generates voltages and currents.” It also responds to mechanical force in complex ways. “If you squeeze it the right way, it maintains itself and gets stimulated. On the other hand, if you squeeze it too hard, too fast, it starts to look like it’s breaking down.” Intrigued, Sah entered a joint Harvard/MIT program that let him get a doctorate in engineering as well as a medical degree. In 1992 he joined the bioengineering group within UCSD’s applied mechanics and engineering sciences department.
Bioengineering since has become a full-fledged UCSD department, one with a national reputation as a tissue-engineering research center. That means it’s one of two dozen or so places around the United States where scientists are striving to create replacement human body parts made out of live tissue. Targets of various efforts nationwide include the pancreas, bladder, tendons, kidney, nerves, and even the heart. Some success has already been achieved; burn centers can now buy engineered skin. From his UCSD quarters, Sah has similar aspirations for the knee. “What we’re trying to do is give Bill Bugbee what he wants to implant, off the shelf,” Sah said. “Maybe he’ll take a little bit of tissue from the patient, give it to us, and then we’ll grow it up and make a joint fragment or a joint, then give it back to him so he can put it in a defect.”
Sah recalls that tissue engineering “was just coming into vogue” about the time he joined the faculty on the local campus. He says cartilage repair in particular got a lot of attention in 1994, when a group of Swedish researchers published a lead article in the New England Journal of Medicine. In it they described how they had taken little pieces of cartilage out of various human subjects, isolated the cells in a laboratory, grown many more of those cells, then placed each patient’s cells in a site in his or her knees. “Some of the patients felt pretty good after that,” Sah says. Although the study later received a lot of criticism because the Swedes hadn’t compared their cell-manipulation and reimplantation therapy to other forms of care, “Their work gained a lot of notoriety in the popular press, and people wanted to do it everywhere.”
Today a Cambridge, Massachusetts-based company called Genzyme Biosurgery processes and cultures articular cartilage tissue using a variation of the Swedish technique, and a couple of European companies have come into existence with similar processes. Other approaches to cartilage repair have also been devised, Sah said. He told me about one in which the doctor “goes in and does a microfracture — actually sort of digging into the bone and causing a little bit of bleeding at that spot.” No graft material is added, but the procedure “in many cases makes the patient feel much better also.” Another approach, called mosaicplasty, requires the surgeon to drill out little cores of bone and cartilage from a non-weight-bearing part of the knee and implant the plugs in the damaged weight-bearing section. All the approaches to engineered cartilage share a common drawback, however. Although in many cases, they cause a cartilage-like material to grow into the defect being repaired, the filled-in material lacks the structure of normal, healthy cartilage.
Normal cartilage is “very, very organized,” Sah explained. “At the surface, cartilage cells are sort of pancake-like. Then deeper down, they’re spherical. And then they become sort of oblong in the very deep regions.” Sah said the tissue matrix that’s associated with the cells at the various levels also changes as you go from top to bottom. “In the surface region, the collagen’s oriented parallel to the surface, then it sort of becomes mixed, and then the fibers are oriented vertically.”
One of the major ways Sah and his associates at UCSD have contributed to the world’s understanding of cartilage is by studying how the mechanical properties of articular cartilage vary from the surface to the deep regions. Quantifying that isn’t so easy to do; cartilage is only a few millimeters thick. But Sah’s group came up with a way to make the cartilage cells take up a dye that interacts with their DNA. “So then you can compress the tissue via mechanical manipulation and see how these intrinsic markers move relative to one another.” What they found, Sah says, is that “basically when you squeeze cartilage from the surface to the deep regions, the surface compresses a lot, but the deep region compresses very little.” Those deeper regions can be up to 25 times stiffer than the surface zone, Sah’s group found.
The tissue formed by most cartilage-engineering efforts to date hasn’t developed that sort of organization, and it’s been found to be “a lot softer than cartilage in compression,” Sah says. “Especially if you indent it or sheer it or put it in tension, it’s very, very weak.” Sah thinks it’s likely that the organization of normal cartilage explains its amazing strength. The complex organization also seems to have other consequences. “Cells in the surface region make a variety of molecules that are different from those made by the deeper cells,” according to Sah. One dubbed superficial zone protein, produced near the surface, seems to play a key role in lubricating the joint. But most engineered tissue, in contrast, doesn’t manufacture that protein.
Sah sounds these days like a man with a lot of balls in the air. “We really don’t understand why knees become arthritic and exactly what happens as they do.” So his group is part of a large National Institutes of Health study of how cartilage changes with age. The UCSD researchers also are trying to use what they’ve learned about the stiffness of normal cartilage to help develop clinical tests that will help identify knee problems early. One of their biggest projects, however, is to grow cartilage in the lab that has the stratification of natural cartilage. Achieving the same structure as natural cartilage should give the engineered cartilage similar strength and lubricating capacity, the researchers hope.
It’s a complex challenge. Sah says researchers have known for years that you can’t just grow the cartilage cells in typical ways. If you culture them on a standard flat surface, “They stop making cartilage-type molecules and start making other molecules that are not typical of cartilage,” he explains. To prevent such abnormalities from developing, a research group at Rush–Presbyterian–St. Luke’s Medical Center in Chicago figured out how to use a “three-dimensional gelatinous material in which the cells seem to be very happy,” Sah says. In this gel material, the cartilage cells create a little halo of collagen-rich matrix around themselves. Sah says it’s possible to take the cells and their halos out of the gel material “and pile them up in a dish…very close together but separated by this little bit of matrix.” When you do that, “They fuse together and form a tissue-like material very quickly.”
Sah says the UCSD and Chicago groups have been cooperating for four years to refine the cartilage-culturing techniques, but in 2001 the UCSD group took a step further. Working on the assumption that how you put the cells together affects the structure of what you can make, Sah’s group has started taking chunks of cow cartilage and from it isolating cells from the surface region and cells from the deeper zones. They’ve cultured both, dissolved away the culture material, and put the haloed cells into dishes in two distinct layers. Sah says after a week or two, “We get this little chunk of material that’s pretty white and opaque. You can pick it up. It feels not quite like Jell-O. Not that stiff. But it’s definitely stronger than a wet tissue paper. It’s sort of spongy.”
Most important: when the UCSD researchers have tested their engineered material in the laboratory, they’ve found that the cells at its surface were secreting the critical superficial zone protein. Furthermore, the surface cells appeared to be making tissue that was softer and had a less dense matrix, while the cells in the deeper regions were spaced further apart and had a denser, stiffer matrix.
Sah says what his group has produced is still much weaker than normal articular cartilage. He says one of the big questions now is how strong the (engineered) cartilage has to be before it can be used to resurface a large defect. “Certainly if you have cartilage with normal properties, that’s probably going to work.” Bugbee’s transplant surgeries demonstrate that, Sah says. “But the question is: how close to functional adult cartilage do you need to get?” Sah’s hunch is if you can produce engineered cartilage that compares to newborn tissue, it will have a reasonable chance of surviving transplantation. He thinks the key to getting his layered cartilage to mature to a newborn state in a matter of weeks rather than months is to use an appropriate bioreactor — a sort of incubator that accelerates the tissue growth. He says his group has been working for several years with a La Jolla tissue-engineering company called Advanced Tissue Sciences. Their work on bioreactors for engineered cartilage has indicated that compressing and recirculating the medium that the tissue is growing in can speed up its maturation.
Once it’s strong enough, the engineered cartilage will have to be tested first in animals, then in humans. Someone also will have to figure out how to mass produce it. Growing cartilage is “not quite like bringing up a baby,” says Sah. “But you sort of have to feed it every day, change the culture medium. Ultimately there needs to be some automation and development of bioreactors that makes the whole process very reliable and robust.” For all the work that remains, Sah sounds as if he has no doubt that within 20 years — possibly as soon as 10 — doctors will be able to reupholster ravaged, aching knees with lab-grown cartilage that functions as well as the natural kind.
“That’s the holy grail,” Bugbee concurs. The UCSD surgeon also sounds confident that someday he’ll be using bioengineered knee parts in his operations. In the meantime, he thinks the human body is still the best laboratory for manufacturing human articular cartilage, so he’s happy to use the material from cadavers. As enthusiastic as he is about that procedure, however, Bugbee stresses that it’s not the best choice for everyone. He says no single therapy is.
He says the 20-year-old who gets a small divot in his articular cartilage would be a terrible candidate for a total knee replacement. Total knee replacements typically require a six- to ten-inch incision. “The entire joint surface is removed, sort of like peeling the tread off a tire,” Bugbee explained. Furthermore, the artificial knee joints wear out over time. Parts connected to the bone can loosen. Plastic components deteriorate, and the more active someone is, the faster they do so. “Generally in the population over 50 or 60 years old, a joint replacement has a 90 percent chance of lasting at least 10 years or longer and an 80 percent chance of lasting 20 years,” Bugbee says. “That’s pretty good odds. But it’s not what you want in a 20-year-old guy.”
For the 20-year-old with a limited problem, Bugbee says all the newer cartilage-repair techniques probably would be reasonable choices. They work less well when you start applying the same techniques to 40-year-olds. Bugbee sees men like this all the time. “They had a football injury at age 20 and their knee’s starting to go bad. They’re looking for something that’ll turn their knee into a 20-year-old knee, and that’s just not going to happen. But there are ways we can help them that aren’t [total knee replacements].” He says for such people, the knee-tissue-transplant operation solves their problems about 75 percent of the time.
Bugbee also hears from 75-year-olds with end-stage arthritis, people in so much pain that they can barely walk, as their bones grind on bone. Sometimes these folks will have heard about how scientists can take their knee tissue and culture it and put it back in and restore their ravaged joint surfaces. The surgeon says he has to disabuse them. At least for now, “A knee replacement is a much better operation for those people!” That surgery is “very predictable at improving their function and relieving pain, with a low complication rate.”
Most unfortunate of all are the men and women in their 30s and 40s and 50s with end-stage arthritis. Bugbee says he’s amazed by how many of them there are, people whose joints are in ruins many decades before the rest of their bodies will die. The surgeon says he’s doing more and more total joint replacements for such people. He has a couple of theories about why the numbers have climbed.
“I think one is that people have higher expectations for their quality of life and functioning. Two generations ago, there were probably people in their 40s who had an injury and developed arthritis.” But no one could do anything for them. “So they just lived with it,” Bugbee said. “Now, people won’t accept living with pain. We can put a man on the moon, and people watch CNN and they see these bombs going through chimneys, and they come to the doctor and say, ‘Doc, why can’t you make my joint work normally and take this pain away?’ The expectation is different.”
Beyond that, Bugbee says, “We’re a more active society. So we’re at greater risk. There’s a lot more trauma, sports injuries, and things like that that lead to early arthritis. All these 40- and 50-year-old men who were playing football when they were teenagers and tore their meniscus or their ligament and had it taken out. Twenty years later, inevitably, they’re going to have arthritis in the knee.”
When it gets bad enough, the younger sufferers get total knee replacements, and when those fail, they can be replaced. Bugbee estimates that 20 to 30 percent of his practice involves redoing artificial joints that have worn out or become loose or infected or dislocated. He’s got patients who are on the fourth and fifth ones, he says. But replacing an artificial joint is never as easy as installing the first one. You can’t just pop out a failing component and replace it with a new one. “They’re cemented in, or bone grows into them, and when they fail, they can fail in a number of ways that can damage the bone or the tissue or the muscles. Every time you do it, the outcome is generally worse, because the tissue’s more damaged.”
It all sounded pretty depressing. I wondered if there was another end of the spectrum, one populated by dancing, skiing octogenarians whose knees had somehow reached advanced age unblemished. Bugbee acknowledged this was so.
“But here’s what I tell people,” he said. “Diseased cartilage is like any other disease. We’re all genetically programmed to get something. You’re chosen to either get cancer or heart disease or cardiovascular disease or arthritis or osteoporosis. What’s different about those people you read about who are running marathons in their 70s, while you and I in our 40s are starting to have aches and pains, is probably in the genes. Probably they have some genetic makeup that makes their cartilage better, healthier, or what have you.” They’ve also been lucky. They didn’t have that big football injury at age 22. They avoided that automotive smash-up; dodged all the ruinous pitfalls on all the ski slopes. Bugbee thinks it’s amazing most people do survive a lifetime with their joints working. He says he tells people who wind up with arthritis, “Well, look at it this way. I could be your oncologist and not your arthritis doctor.”
I thought about his words on the afternoon when I watched a Lifesharing technician carve up a donor knee. I’d had to stand several feet away from the operating table during Meghan McShannic’s transplant operation, well outside the sterile surgical field. I still longed to see the inner workings of someone’s knee up close. Early one Sunday night, I got a call from the tissue bank, informing me that a 33-year-old man had died from a heart attack over the weekend, and his family had donated his tissue to Lifesharing.
I didn’t watch the tissue-bank representative detach the man’s knees from the body. This step normally takes place in a Lifesharing operating room next to the county medical examiner’s office on Overland Drive. A technician saws off each lower leg about two inches below the tibial tuberosity. The knee is sawed from the thigh at a similar distance above the kneecap, then the whole block goes into a plastic bag along with some preservative solution. (For corpses whose families want a public viewing, dowels and other shaping materials are used to disguise the fact that anything is missing.)
The following day at the tissue bank in Mission Valley, I donned a set of sterile surgical garments. By the time I entered the facility’s clean room, a tissue coordinator named James Kratz was working on one of the knees. The sight shocked me at first. The white skin of the dead man reminded me of chicken flesh, but the muscle within it was the dark maroon of a beefsteak. The contrast between the two resembled no meat I’d ever seen, yet Kratz’s grave, practiced movements recalled the artistry of the kitchen. He removed the kneecap, then pointed out the various ligaments to me as he sliced through them, disconnecting the top part of the knee from its bottom half. As he scraped away globs of fat, I asked if the amount was normal.
“This is a pretty big guy,” Kratz replied. “Two hundred and twenty pounds. There’s a lot of muscle. I wouldn’t say he was a lean person, but he wasn’t obese either.”
When Kratz had extracted the end of the thighbone from most of the soft tissue that encased it, he noticed some yellow splotches marring the whiteness. He peered at them. They weren’t fat deposits, he felt confident. A few minutes later, Kratz also pointed out a rough, spongy area underneath where one of the man’s menisci had sat. The technician expressed skepticism that this tissue would pass Dr. Bugbee’s inspection. It probably couldn’t be transplanted.
I wondered if the dead man had been a runner, but no one seemed to know. I wondered if he’d suspected there was anything wrong with his knees. At 33, had they ached? Had he worried they might make his life miserable when he grew old? If so, he need not have fretted, I reflected. Whatever might have troubled his knees later, it didn’t matter anymore.