In osteoarthritis of the knee, cartilage that should cushion the bones erodes, leaving people in pain. Anti-inflammatory drugs can offer some relief, but they can’t cure the disease or bring back cartilage that’s already lost. Joint replacement gets people moving again, but their implants must eventually be replaced.
A possible solution might be found in a person’s nose. Ivan Martin, head of biomedicine at the University of Basel and the University Hospital Basel, and colleagues led a study published Wednesday in Science Translational Medicine that reports on bioengineering nasal chondrocytes — cells that form cartilage — and implanting them in the knee to grow new cartilage and resist inflammation better than the original knee cartilage. He’s been studying three-dimensional culture systems for cells to understand how tissues develop, how to control tissue formation, and how to turn tissues generated in the lab into possible grafts for tissue repair.
Martin chatted with STAT about his team’s work, which has moved from lab dishes to mice, sheep, and ultimately two patients. This interview has been edited and condensed for clarity.
When did you set your sights on osteoarthritis of the knee?
It took us, let’s say, 15 years to learn all the possible tweaks to be able to generate human, engineered cartilage tissue in a three-dimensional size and shape with some functional properties. Once we learned how to generate these grafts, then we started implementing them into clinical studies for different indications.
What steps did you need to take to get there?
We had to investigate how these engineered cartilage tissues would behave in an environment which is different from their native origin. And so for the knee joint, we had to run different studies, in vitro and in animal models, to understand whether these cartilage would also be compatible with implantation in a joint.
What’s the take-home message from your paper?
Our research indicates that this engineered cartilage not only is capable of regenerating cartilage tissue, but it also is resistant to inflammation signals, which are typically very high and strong in a degenerated joint like the ones in patients suffering from osteoarthritis. So this cartilage is actually able to counteract it, to reduce inflammation in the joint.
Did you expect the bioengineered nasal tissue to behave the way it did? And why does it work better than knee tissue?
That was quite surprising. But then we identified that the nasal cartilage cells have a certain gene signature typical of cells from the neural crest, where our hierarchically superior organs, like the eyes or the brain, derive. Stemming from this compartment enables these cartilage cells from the nose to have a higher regenerative capacity than the cartilage cells from a joint — and also a higher plasticity, so the capacity to adapt to a different environment.
Have people tried this before?
In the past, especially for cartilage regeneration, what the field has done and is still doing is taking cells from the same joint, so articular cartilage cells, and expanding them and injecting them in the same joint. We use a different source of cells, and we organize these cells into a functional tissue prior to implantation. So we are not injecting a suspension of cells, but we are injecting an effective cartilage tissue.
What is the procedure like?
First, we take a small biopsy of the nasal septum, which is a few millimeters in diameter, under local anesthesia. Out of this little tissue we isolate the cells and we grow them in the lab. And once we have enough — this takes about two weeks — then we load them into a carrier. It’s a sponge made of collagen and we let them colonize the sponge and mature and develop new tissue, which takes another two weeks. So after a total of four weeks, then we have this mature cartilage tissue which we implant into the patient.
How long do you think this new cartilage might last?
We have to be realistic. In these two patients, the implanted cartilage is preventing them from having to undergo total knee replacement. But we don’t know long-term what will happen. What we envision is the possibility of a combination therapy. So where this engineered cartilage is implanted in the knee and is resistant and reducing inflammation, at the same time, we want to take care of a primary cause for the generation of the cartilage, by surgically correcting it in some patients. We may need to introduce a simultaneous pharmacological treatment or we may just need to be very careful with targeted physiotherapy, which we know is very important.
How long since their implants?
It’s now over two years that they are being followed up.
You are focusing on osteoarthritis, not rheumatoid arthritis?
We are targeting osteoarthritis where inflammation is not the cause of osteoarthritis, but there is another cause that leads to inflammation, like, for example, the abnormal loading in the joint. It’s also not general osteoarthritis. Those two patients are suffering from so-called medial osteoarthritis [affecting the middle of the knee]. The next target is patellofemoral osteoarthritis [affecting the kneecap and part of the femur].
What else is next?
There are several gradual steps. The first one is to continue with further clinical studies in a larger cohort. We need to extend it to a suitably powered clinical trial with a control arm to demonstrate the effectiveness.
Was it challenging to create this bioengineered tissue implant?
Yes. That is why it took us 15 years of preclinical work.
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