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Bones can mend. Skin can heal. Joints… just get worse.
“Arthritis” is actually an umbrella term for various disease processes, but they all affect the joints—and together they’re the leading cause of disability in America.
At the moment, the best physicians can offer is homespun (physical therapy, gentle exercise, a healthy weight), seriously pharmaceutical, or surgical, swapping out the joint for a titanium surrogate. But something better is in the works.
Photo by Matt Miller/Washington University School of Medicine
Dr. Farshid Guilak, co-director of Washington University’s Center of Regenerative Medicine
Two years ago, Wash. U. lured Dr. Farshid Guilak from Duke and made him co-director of the new Center of Regenerative Medicine. (He also serves as director of research for Shriners Hospitals for Children–St. Louis, where he focuses on juvenile arthritis.)
The center tackles all sorts of regeneration: growing a new retina to replace one that’s deteriorating, making fresh pancreatic cells for someone with diabetes. Guilak grows joints. He uses stem cells from fat (liposuction waste), then gives them the right signal (a cocktail of growth factors, vitamins, and hormones) to grow into cartilage cells.
“They’re burning a lot of energy to do that, so we have to constantly feed them and stir them up to keep them happy,” he says. “We also need to tell them what shape to grow in, because a mass of cartilage in a dish isn’t going to serve as a great joint replacement—so we create a scaffold.”
First the team scans the joint being replaced; then they print a 3-D mold of its exact size and shape. Next, woven polyester is placed in the mold and heated just a bit until it sticks into the right shape while remaining porous. It’s compatible with the body and, over time, will melt away, like resorbable sutures.
“We’re one of the first groups to do this with an entire joint,” Guilak notes. “A lot of people have worked on small pieces of cartilage, like a patch the size of a quarter for a hole in the knee.” The new joints have been tested, with beautiful success, in animals: “The joint integrates into the body and functions like cartilage, and the scaffold slowly disappears.” (The procedure could eventually help animals, too—dogs, for example, that have hip dysplasia or wind up as crippled with arthritis as their aged humans.) Next in the culture dish? “Knees, which are far more complicated. Then shoulders, then the base of the thumb; a lot of women get arthritis there.”
It takes about four weeks to grow a hip. “We’re trying to get it down to two,” Guilak adds. “We keep trying to improve it. These cells make great tissue, but once back in the body, they may be attacked. The lining of the joint is already inflamed. Between the arthritis and your body making all these enzymes and pain mediators…”
The solution to all of that pre-existing inflammation? Smart cells. “We’re working on programming these cells so they release anti-inflammatory drugs, just at the joint site, so they don’t go all over the body and cause side effects.” At the moment, the release can be triggered with a low dose of antibiotic; down the road, Guilak’s goal is for the cells to release the drugs all by themselves whenever they sense increased inflammation.
This would be a great delivery system for the new biologics used for rheumatoid arthritis. (You’ve seen them on TV: Humira and Enbrel and Remicade…). “The biologics are given at such high doses, and they shut off the immune system, so people are prone to infections, bad infections,” Guilak explains. Targeting them and releasing the medicine only when inflammation flares will create “sort of a vaccine for arthritis” with far fewer side effects. The smart cells could live in the joint, or a tiny implant could sit beneath the skin and release the medicine to travel throughout the body. That systemic release would be helpful in rheumatoid arthritis, for example, which can cause depression, fatigue, and other body-wide problems.
Overall, the challenge ahead is figuring out the different pathways arthritis takes, because that’s what determines which drug will be effective. What we call arthritis is a slew of different diseases, all with different pathways and causes.
Photo by Curt Dennison
Dr. Terry Moore, director of adult and pediatric rheumatology at SLU School of Medicine
What causes so many forms of arthritis? That’s what Dr. Terry Moore, director of the adult and pediatric rheumatology divisions at SLU School of Medicine, has been researching for 30 years: “Most inflammatory diseases that affect the joints are caused by immune complex formation in the joint. The body makes an antibody in reaction to some external antigen—a toxin or foreign substance—and this complex produces inflammation. What the antigen is, exactly, is still not known. Viruses are a possibility, and we have looked at the virus that causes mononucleosis and parvovirus, but no studies have been definitive. This normal protective immune response can be overwhelmed and thus produces inflammatory mediators. There’s also the possibility that some kind of environmental challenge stimulates the immune system to react.”
The usual progression of medication for the most inflammatory types of arthritis is from basic anti-inflammatories to more specific medicines, such as methotrexate, leflunomide, and sulfasalazine, that target inflammatory mediators. “Add on hydroxychloroquine, which almost every patient should be on because it helps the body handle immune complexes,” Moore says. Next come the biologics, which tackle tumor necrosis factor, T cells, or interleukin-6.
Someday that progression will be smoothed by smart cells, with pinpointed dosing and far fewer side effects.
FIGHTING ARTHRITIS
This May, researchers at Washington University announced that they’d successfully traced the pathway of the chikungunya virus, which causes joint pain that turns into arthritis. The virus attacks cells that build cartilage, muscle, and bone because they contain a protein called Mxra8 that acts as a molecular “handle” it can grab. The solution? Create a decoy handle, one that opens no doors for the virus. Test results in lab mice are promising.
Burn Away the Pain
If you’re not a candidate for surgery and you’ve tried everything else with no relief, you may want to look into a new procedure called COOLIEF, now being offered at the Pain Management Center at Barnes-Jewish West County Hospital. Dr. Anthony Guarino, an anesthesiologist who’s board certified in pain management, first numbs the nerves that travel to the knee. If that relieves the pain, you’re a candidate for COOLIEF—which is a bit of a misnomer, because it involves the burning, not freezing, of nerve endings. A probe is inserted through a needle, and radiofrequency waves increase the temperature at the tip of the probe to 60 degrees Celsius. It’s an outpatient procedure, with no rehab necessary afterward, and at least half of patients are relieved of that grinding knee or hip pain for the next six to nine months, until the nerve endings grow back.
