Osteoarthritis: stem cell treatment could regenerate cartilage without requiring surgery

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What does a Mesozoic dinosaur discovered in Kansas have in common with John the Baptist and hundreds of millions of people around the world? Osteoarthritis. Not to be confused with its sister diseases, rheumatoid arthritis (inflammation caused by an autoimmune reaction in the joints) and osteoporosis (progressive weakening of bones) Osteoarthritis (OA) is the progressive thinning of joint cartilage – the smooth, lubricating connective tissue that covers the ends of bones at a joint. Articular cartilage allows for painless movement in the joints, at least when it is healthy.

When the cartilage becomes damaged and thin, the bond rubs against the bone. In some patients, you may actually hear a crackling sound as the bones rub against each other. Over time, the friction wears down the bone until the nerve ends are exposed, and everyday movements – walking, sitting, even writing – lead to excruciating pain.

In the later stages of osteoarthritis, after all other pain relief options have failed, the last resort is joint replacement. This poses three major problems: First, joint replacement does not significantly reduce pain for 10% of patients. Second, 10% of joint replacements fail within 15 years and need to be replaced. And third, about 1% of patients develop an infection due to the surgery. While these percentages may seem relatively small, there are over a million joint replacement surgeries in the United States alone. every year. This means that hundreds of thousands of people suffer from complications associated with joint replacement or do not experience pain relief.

The medical community has worked for over a century to develop strategies to repair damaged cartilage before surgery is necessary. However, these strategies have significant flaws, including short-term repairs and long paybacks. According to a recent study in npj Regenerative medicine, researchers have developed a strategy without these pitfalls – a stem cell-based bioimplant.

We can repair cartilage by drilling holes in bones, but should we be doing it?

The traditional explanation for joint cartilage damage associated with osteoarthritis has been “mechanical trauma” – the inevitable “wear and tear” of aging and overuse. However, over the past few decades our understanding has changed; we now know that osteoarthritis is of multifactorial origin. Mechanical trauma plays a role, but so do genetics, nutrition, diabetes, immunity, limb alignment and even joint shape. Regardless of the underlying mechanism, one aspect remains the same: Osteoarthritis involves damage to the articular cartilage.

The body is not good at repairing joint cartilage. Before the 1950s, there was no established medical technique that provided much help. The patients either endured the pain or underwent risky joint replacement (with questionable results). However, that changed in 1959, when a seven-sentence article appeared in the Proceedings of the Congress of the British Orthopedic Association. In the surprisingly concise article, Dr Kenneth H. Pridie, a British clinician who treated patients with osteoarthritis, noted that “Yes [ends of bones] were drilled and the holes were not too far apart, smooth [cartilage] would spread to the surface.

The seven-sentence article by Dr. Kenneth H. Pridie describing a technique that would become the most common strategy for regenerating cartilage. (Credit: Martin & Jakob., ISAKOS Journal. 2021)

Shortly after the publication of this revolutionary procedure, Pridie passed away, leaving scientists to wonder where he got this idea and who would allow him to perform this operation, as well as more practical questions, such as “what size drill bit ? “And” how far apart is it too far from each other? “

Six decades later, scientists are still trying to answer these questions. However, in the 1980s, researchers discovered the basic mechanism underlying the Pridie technique: by piercing the ends of the bone, bone marrow cells could access the damaged joint and generate a new one. cartilage. Currently, this technique – called microfracture – is the most common treatment to regenerate joint cartilage. It is a quick procedure (usually lasting between 30 and 90 minutes), minimally invasive, and the recovery time is relatively short (four to seven months).

But there is a downside: this new cartilage is biomechanically inferior to the original articular cartilage. As a result, it can wear out after just a few years and the procedure has to be repeated, increasing the likelihood of a complication (such as infection). Denis Evseenko – professor of orthopedic surgery, stem cell research, and regenerative medicine at USC’s Keck School of Medicine – wanted his bioimplant to create strong joint cartilage that could last for decades. To do this, he had to find a way to harness the power of the isolated cell that can create joint cartilage.

Only one cell knows the recipe for articular cartilage

Cartilage is one of the simplest connective tissues in the body. Or, at least, it’s simple in terms of the ingredients: water and a handful of different proteins (several of which you probably have in your pantry). But there is only one chef that can whip up the right articular cartilage: chondrocytes.

Chondrocytes live a life of loneliness. Embedded in the cartilage, each cell governs its own microenvironment where it is solely responsible for maintaining the cartilage in this region. We are still learning about these cells, but we know that when they can no longer fulfill their role, there is rarely a replacement. While some scientists struggled to understand how cells in the bone marrow could be used to regenerate cartilage, others were investigating how to harness chondrocytes for the same purpose.

A new technique appeared in the 1980s: a surgeon removes a small segment of bone from a patient, extracts a few chondrocytes and replicates them in a Petri dish. Once a sufficient number of chondrocytes are generated, the surgeon replants them into the patient. The cartilage that results from this procedure is just as strong as the original. However, this technique has failed to gain traction as it requires multiple surgeries and it can take up to two years for the implanted chondrocytes to repair the cartilage.

One of the reasons for the long recovery time is the use of “old” chondrocytes. As a person ages, chondrocytes slow down the production of cartilage. When an old chondrocyte replicates, it creates another chondrocyte which acts like an old chondrocyte (in that the production of cartilage is slow). Researchers had long suspected that chondrocytes created from stem cells would act like young chondrocytes (with rapid cartilage production), but no one knew how to create chondrocytes derived from stem cells until 2010.

If the body wants stem cells to create chondrocytes, it sends carefully synchronized signals to the stem cell. Give the wrong signal at the wrong time, and you could have a totally different cell type. Determining the right signals and the right timing is a difficult problem to solve. But in 2010, a group of researchers at the University of Manchester did just that: They created chondrocytes from stem cells.

Armed with this new knowledge, Evseenko and his group of researchers set out to design a therapeutic bioimplant that captures the best of two current cartilage regeneration strategies: a fast, minimally invasive procedure with a short recovery time that produces strong articular cartilage. A tall order, but equipped with chondrocytes derived from stem cells, they succeeded in 2018.

Their bioimplant consisted of a cartilage-like matrix encrusted with chondrocytes derived from stem cells. Four weeks after being applied to a mouse knee joint, the chondrocytes had replaced their cartilage-like environment with strong articular cartilage. These results were promising, but the joints of small animals are structurally different from those of large animals, including humans. In particular, small animals have very thin articular cartilage. So before moving on to clinical trials in humans, researchers needed to switch to something bigger than a mouse: the Yucatan mini pig.

The thick articular cartilage of the Yucatan minipig makes it an excellent model for studying osteoarthritis treatments. (Credit: Davis et al., PLOS ONE, 2014)

A “mini pig” may not seem like a good example of a large animal, measuring only about 16 inches high and 36 inches long. However, they weigh around 160 pounds. To cushion all this weight on their small joints, their joint cartilage is very thick, similar to that of humans.

To mimic the damage to the articular cartilage associated with osteoarthritis, the researchers cut out segments of articular cartilage at the knee joint. They applied their bioimplant to the area. The pigs recovered for six months, and when the researchers examined the joints again, it was immediately clear that the joint cartilage had regenerated in the pigs treated with the implant. More importantly, the cartilage was thick and shock absorbing, far superior to the cartilage produced by the microfracture technique.

Work will now progress in humans with the support of a $ 6 million grant from the California Institute of Regenerative Medicine.

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