PUMPING IRONY: A Joint Reconstruction Project

My Lovely Wife will turn 70 this fall, which means that she’ll have been dealing with a bum right knee for slightly more than a half-century. When I met her in 1976, she told me how she’d injured her knee while dancing the Highland fling in an English pub. The surgical procedure upon her return home was less than successful — she emerged from the operation with no meniscus — but she grew to understand her knee’s tendencies and learned how to cope with its occasional betrayal.

Osteoarthritis gradually set in over the years, limiting her mobility while somehow raising her pain threshold. At various points, she explored the pros and cons of knee replacement before discarding the idea as premature or reckless. As long as she can get around without a wheelchair, she recently told her doctor, she’ll continue dealing with her troublesome joint as best she can.

There’s good reason to approach such a decision with caution. Despite its popularity — U.S. surgeons replace more than 700,000 knees each year — the procedure carries some risks. Blood clots can form in the leg and travel to the lungs, nerves at the site of the implant can be damaged, and infection at the incision site or in the deeper tissue can require additional surgery. The metal and plastic inserted into the joint can wear out over time as well, requiring a second joint replacement.

There’s no cure for osteoarthritis, but an obscure federal agency three years ago challenged researchers to search for antidotes — and provided generous funding to create some incentive. The subsequent research, as Gina Kolata reports in The New York Times, has shown some promise.

Powered by grants ranging as high as $42 million, three separate research teams have demonstrated enough potential in animal trials to advance to a second phase of funding from the Advanced Research Projects Agency for Health (ARPA-H). Their approaches range from cartilage-regeneration techniques to a “living knee” implant.

One team, led by Stephanie Bryant, PhD, a professor of chemical and biological engineering at the University of Colorado Boulder, has focused on a pair of treatment options: For patients with minor cartilage damage, they repurposed a drug already approved by the Food and Drug Administration and developed a delivery system that pumps intermittent doses into the cartilage for months following a single injection. For those coping with more serious cartilage and bone damage, they’ve tested a mix of engineered proteins that, once injected into the knee, recruit progenitor cells to mend the lesions.

Tested on animals with arthritic joints, both approaches showed regenerative results in a matter of weeks, Bryant notes, adding that similar results were achieved when treating human cells from patients undergoing joint replacements.

“In two years, we were able to go from a moonshot idea to developing these therapies to demonstrating that they reverse osteoarthritis in animals,” she says. “Our goal is not just to treat pain and halt progression, but to end this disease.”

“Our goal is not just to treat pain and halt progression, but to end this disease.”

Duke University orthopedic surgeon Benjamin Alman, MD, and his team are taking a similar approach, testing a variety of drugs for their ability to regrow existing cartilage and bone cells. “The idea would be, if a patient’s problem is mostly in cartilage, we would target cartilage,” Alman tells the Times. “If it is mostly bone, we would target bone.”

Researchers were able to regenerate damaged cartilage and bone in trials involving rats and mice. In the next phase, they’ll try it on humans. “I tend to be very skeptical,” he says, “but this surprised me.”

Columbia University biomedical engineering professor Clark Hung, PhD, and his team are focusing their attention on creating a longer-lasting replacement knee for people who are too young to gamble on the current models, which may need to be replaced in 15 to 20 years.

“The people we speak with are in tremendous pain, with limited mobility, and are suffering. They don’t want to wait years and years to be eligible for a replacement,” says Hung. “They want to play with their kids now, pain-free, not when the kids have grown up and left the house.”

Their solution, the NOVAKnee, is surgically implanted by the same process as metal and plastic knees, but it’s made from a combo of biomaterials encased in a biodegradable scaffolding infused with stem cells that are designed to regenerate the cartilage and bone tissues as the scaffolding degrades.

“The material needs to have load-bearing properties when first implanted, but also needs to biodegrade over time,” explains Nadeen Chahine, PhD, a professor of biomedical engineering at Columbia. “We selected polymers that are new to the medical implant field. The new materials allow us to balance strength, ductility, and manufacturability using 3D printing. We had to optimize the implant to achieve a design that wouldn’t fail mechanically, is safe for implantation in the body, and can seamlessly integrate into the clinical workflow.”

After testing the load-bearing and flexibility properties of the implanted joint in robotics-assisted cadavers, researchers are ready to try them in large animals. As with the other projects qualifying for ARPA-H’s second phase of trials, the Columbia team must show their treatment options pass human preclinical and clinical trials. Then they must bring them to the commercial market — at no more than 25 percent of the price of the current standard of care, according to Kolata’s piece in the Times.

When I mentioned these treatment options to MLW the other day, she said any sort of injectable treatment would be preferable to the surgical complexities of a joint replacement. But those procedures would have to present a well-proven track record before she’d consider such a move. Besides, even after coping with her bum knee for 50 years, she’s in no particular hurry. “When it comes to medical science, procrastination is the best strategy,” she said. “They’re always finding better ways to do things.”

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