Researchers are developing new techniques to protect, repair and regenerate articular cartilage, the layer of connective tissue that covers the ends of bones and enables joints to move smoothly, slowing the progression of osteoarthritis. To prevent and prevent the need for joint replacement surgery.
Cartilage does not have a blood supply or nerves and has limited ability to repair itself. The loss of its shock-absorbing layer and the resulting grinding of bone on bone is at the root of many cases of joint pain and arthritis. According to recent federal statistics, osteoarthritis, the most common form, affects more than 32.5 million people in the U.S. In 2017, there were more than 754,000 knee replacements and more than 448,000 hip replacements, and that number will continue to grow over the next decade. are supposed to.
The surgery is less risky than before but still comes with the potential for complications. The prosthetic components used to replace joints can loosen or wear out after 15 to 20 years, making them a bad choice for younger patients.
“We shouldn’t wait for osteoarthritis to develop, but instead stop the entire degeneration process so patients never have a joint replacement,” says Michael Longker, professor of surgery at Stanford University School of Medicine and co-director of its institute. Have to do it.” for stem cell biology and regenerative medicine.
Researchers are working on several fronts to prevent cartilage injuries in young athletes from turning into osteoarthritis a decade or two later, and to regrow cartilage once more in older patients. They are programming stem cells to become cartilage cells, developing drugs to reverse the course of osteoarthritis, experimenting with ways to deliver new cells and compounds more effectively, and Materials are designed to help new cells integrate with existing tissue.
The challenges are many. Surgeons continue to refine procedures to harvest patients’ own cells to repair damaged cartilage. But no approach has successfully regenerated the quality of the cartilage with which the body begins. Many clinics offer untested, uncontrolled stem cell treatments for joint issues, which the Food and Drug Administration warns patients to avoid. Meanwhile, no disease-modifying drugs have been FDA approved for osteoarthritis. The agency’s guidelines state that such a drug must demonstrate that not only does it avoid or significantly delay the complications of joint failure and the need for joint replacement, but that it also prevents deterioration in joint function and Minimizes the worsening of pain.
Mark C. Hochberg, a professor, says, “If we can find a compound that we can inject into the knee or hip to reduce cartilage degradation and restore normal cartilage, or both, as well as reduce pain.” If you can, this is the holy grail.” at the University of Maryland School of Medicine and chief of its divisions of rheumatology and clinical immunology.
development of better drugs
Dr. Hochberg led a study of spirifermin, a new experimental growth factor that works by stimulating cartilage cells called chondrocytes. His team gave 549 patients with knee osteoarthritis either one of four different dosing regimens or a placebo. According to a 2019 study published in the Journal of the American Medical Association, people who received the highest dose once or twice a year gained articular cartilage thickening over a two-year period, compared to a placebo group in which There was slight cartilage loss. According to a report published earlier this year, those who received the highest dose had no total knee replacement in five years in their injected knee, compared with 15 patients in the other groups who did have a replacement. .
Still, sprifermin didn’t significantly reduce the pain. German drugmaker Merck KGA is looking for a partner to advance the development of Sprifermin.
Another injectable drug, loricivin, works by inhibiting proteins that contribute to the progression of inflammation, cartilage degeneration and osteoarthritis, while also stimulating the growth of cartilage-forming cells. According to a study published in July in Rheumatology & Therapy, patients with moderate to severe knee osteoarthritis who received a single injection of the drug saw improvements in their pain, function, and less impact of their symptoms in 24 weeks. Two large new trials, further evaluating the drug’s effect on pain, inflammation, function and cartilage protective effects, are expected to be completed at the end of the year, says Dr. Yusuf Yazisi, a rheumatologist at NYU Langone Health and BioSplice. Therapeutics’ chief medical officer, who is conducting the trial.
Still, some drugs that showed promise in animal studies did not perform well in human clinical trials because the body cleared the drug from the joint before reaching the deeper layer of cartilage containing target cells. Paula Hammond, Head. Department of Chemical Engineering at the Massachusetts Institute of Technology.
To keep injured cartilage from getting worse, MIT researchers are focusing on ways to get drugs into cartilage tissue and keep them there. They are using microscopic particles called nanocarriers to deliver IGF-1, an insulin-like growth factor, into the tight mesh that holds cartilage in joints. The researchers designed the carriers to be simply “sticky” to drive them deep into the cartilage without getting stuck on the outer surfaces. This may allow the IGF-1 compound to be delivered “until complete regeneration occurs” in one or a few injections. Dr. Hammond says.
In animal studies, his team found that cartilage in injured joints treated with the nanocarrier-drug combination was much less damaged than cartilage in untreated joints or joints with the drug alone. MIT is now planning studies in larger animals.
The system could be used to deliver a variety of treatments, says Alan Grodzinski, a professor of biological, mechanical and electrical engineering at MIT involved in the research. They say there probably won’t be a magic bullet for all patients, and combination therapy may be necessary.
Cartilage growing with stem cells
Instead of slowing cartilage loss or treating symptoms, some researchers are turning to so-called regenerative medicine, which is guiding stem cells to effectively regrow cartilage.
Surgeons currently use a technique called microfracture to treat damaged cartilage by drilling tiny holes in the surface of a joint, prompting the body to make new tissue. But there is a type of tissue called fibrocartilage, which is more like scar tissue than natural cartilage.
“It’s still better than rubbing bone against bone, but it doesn’t give rise to the correct cartilage, and over time it wears out,” says Charles KF Chan, MD, an assistant professor of surgery at Stanford.
Dr. Chan discovered in 2018 that skeletal stem cells located at the ends of bones can give rise to cartilage, bone marrow or bone. Before turning into bone, the cells go through the cartilage stage. In experiments with the microfracture technique in rats, Dr. Chan and his team discovered a way to reverse the growth of cells toward cartilage and away from fibrocartilage. They used a powerful molecule called bone morphogenetic protein 2 to stimulate skeletal stem cells to initiate bone formation. They then stopped the process at the cartilage stage with a molecule called VEGF that blocks another molecule important for bone formation.
Result, Dr. There’s a cartilage made of cells similar to natural cartilage, Chan says, with comparable strength and function—which also restored mobility to mice with osteoarthritis and significantly reduced their pain. To prove that it could work in humans, the researchers performed the same procedure on human skeletal stem cells transferred to mice. Stanford’s Dr. Longkar says doctors could have used the technology to boost cartilage before patients had any problems. The team is now trying the approach in larger animals.
Researchers at the University of Southern California are testing a different approach.
They embedded cartilage-forming cells — derived from pluripotent stem cells that can become any type of cell in the body — in a collagen membrane. Using surgical glue, they applied it like a patch to a cartilage injury in a small pig. The cells integrated into the host tissue and remained there for six months, repairing the damage and becoming indistinguishable from the host cartilage with a cocktail of growth factors.
Denis Avsenko, associate professor of orthopedic surgery at USC’s Keck School of Medicine, whose lab led the research, says the aim is to prevent cartilage injury in a relatively healthy joint from developing into osteoarthritis and eventually requiring joint replacement. Is. Dr. Avsenko says his team is building 64 implants called Plurocort for the first human trials starting in 2024.
improving existing methods
Until new stem cell therapies and disease-modifying drugs are shown to be safe and effective in humans, surgeons continue to refine existing techniques for cartilage repair.
Surgeons are also working to make joint replacement more effective, as many patients report pain, stiffness, and mobility issues after the operation. Approved drugs for rheumatoid arthritis and new stem-cell treatments may help relieve stiffness and swelling after joint surgery.
Scott Rodeo, an orthopedic surgeon and co-director of a soft tissue research program at New York’s Hospital for Special Surgery, is testing whether cells derived from human umbilical cord nerves stem from injecting them into the muscle and tendon of an injured rotator cuff. Stimulate cell activity and promote better repair after surgery. It aims to conduct a similar test with stem cells to repair cartilage.
“If we can modify that basic immune and inflammatory response, it could have a profound effect on tissue repair and tissue healing,” Dr. Rodeo says.
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