When Sir Martin John Evans published evidence of the first embryonic stem cell cultures in 1981, the research offered a glimmer of hope in the medical field. Many thought that these unspecialized cells could be a panacea.
The idea is tantalizing: With a little coaxing, these cells have the potential to turn into anything from skin to cartilage. They could even grow into complete organs or body parts. And in recent years, researchers have learned that these cells have another special property: they can spur growth in nearby tissues.
Thirteen years ago, it was this latter property that enticed Anthony Hollander, the head of the Institute of Integrative Biology at the University of Liverpool, to figure out new ways to repair meniscus tears in knees. Now, Hollander and his team have finally completed the first in-human trial of the so-called “living bandage.” And today, he was officially granted a patent (US Pat. No. 9,539,364) for the invention.
The bandage consists of a thin scaffold of collagen—a protein found in connective tissue that can form a porous but tough material. The researchers infuse this layer with a type of stem cells, known as mesenchymal cells, cultured from the bone marrow of each patient. During the repair, the doctor places the bandage between the two sides of the meniscus and then sutures the meniscal-collagen sandwich together. The idea is that the stem cells emit growth factors that promote the healing of the meniscus tissue, helping the two sides knit back together.
The new study, published recently in Stem Cells Translational Medicine, documented the first test of this bandage in five human subjects ages 18 to 45 with meniscus tears. After two years, three of the patients remained symptom free.
Meniscus tears are a common injury, but they are notoriously difficult to repair. This pair of c-shaped cartilage rings in each knee act like shock absorbers, cushioning the knee from impact while walking, running, jumping and lunging. They protect the caps of cartilage that cover the ends of bones that come together in the knee. As we age, however, continued stress causes the menisci to wear, which means tears.
The problem, Hollander explains, is that the meniscus doesn’t heal like a cut on your arm. Tears in the outer edges of the disc heal relatively well. This region, known as the red-red zone, has relatively good blood supply. But that decreases towards the inner edges of the disc, known as the white-white zone. Tears in this region don’t easily repair themselves. The injuries addressed in this study all occur in the region of intermediate vascularity (red-white zone) as well as the white-white zone, meaning these tears are the most difficult to fix.
Until the last several decades, the repair for meniscus tears was the removal of part or all of the meniscus containing the break. But researchers now believe this leaves the joints more susceptible to osteoarthritis—a degenerative condition in the joints. Without the cushion of the meniscus the joint is thought to suffer greater wear and tear as the cartilage of the knee is stressed during basic daily activities like walking and stair climbing. Even so, this procedure remains the most common treatment for meniscus tears.
So are stem cells the solution?
“I'm not jumping out of my chair saying I have to grab this technology and have to employ this in my practice,” says Howard Luks, chief of sports medicine at New York Medical College. Not only did the test have a relatively small test group (five people), it had a modest success rate (three out of five).
Luks, however, acknowledges that the results do show some promise. “The tear in their paper here is a very complex tear, and your average orthopedist can't do that,” he says. “They can repair certain tears, but it would be more challenging to fix the one that they fixed.”
There are, however, more factors at play in the development of osteoarthritis, he notes. “For too long we’ve thought from a mechanistic process,” he says. Though removal of the meniscus can trigger osteoarthritis, it is one of many factors that can spur the onset of the disease.
Biochemistry is likely also involved, says Luks. Injury or excessive impact in the joint may set off what he calls a “chemical cascade” in the knees. “The chemicals and compounds within the knee become hostile to the viability of the remaining cartilage,” he says. And once the process starts, doctors haven’t yet figured out how to stop it. So whether the patients in this trial will develop osteoarthritis is still unknown.
Other methods of physical repair have been shown to be equally effective for fixing such tears, Luks notes, including a method known as abrasion therapy. In this procedure, the surgeon shaves the lining of the knee joint (synovium) to induce some bleeding and assist with meniscus regrowth.
“For decades we avoided repairing menisci in the white-white zone with the thought that it just wasn't going to work,” he says. “But then a bunch of us started to repair them, and we found that it did work.”
Scott Rodeo, tissue researcher and clinician at the Hospital for Special Surgery in New York City, had another issue with the study: “There's no control group,” he says. “There's no tracking of the implant itself.”
This first test in humans, however, was intended to test the safety of the living bandage, says Hollander. Because failure rates are high for surgery in the white zone of the meniscus, he says, “we feel confident in concluding that there was some direct benefit of the treatment.” Though he hopes to have a control group in future studies, he notes that there are ethical concerns with such a group. “As there is plenty of evidence that surgery alone fails,” he says, having patients undergo such a procedure could be considered unethical.
The living bandage is, however, one of the more promising methods of stem cell use in meniscus repair. When Hollander started research in this arena, most other groups were attempting to use stem-cell-infused collagen structures as a foundation for stem cells to grow tissue that fills in broken sections of the meniscus. “When you’re doing tissue engineering you’re doing space filling, you’re making a big chunk of tissue,” Hollander explains.
Hollander, however, had an inkling these methods weren’t going to work. Stem cells are extremely difficult to control when inserted into joints. “The knee is a very hostile environment,” says Luks. “[So] these cells typically don't live long in the knee and they don't behave the same way that we thought that they would.”
To top it off, Hollander wanted to try something different. “I don't like to do the same thing as other people,” he says with a laugh. So he decided to try to exploit other properties of the stem cells, eventually developing the living bandage. Since then he’s developed a spin-off company, Azelon, to market the product.
These days, many doctors are already claiming successful use of stem cells in meniscus repair: from application of stem cells suspended in gel to collagen structures. But the technology is far from wide use, says Rodeo, particularly in the United States, where culturing of stem cells is strictly regulated. At this point, “the commercial application is well ahead of the science,” he says. There is much more to learn about all of these applications before they can safely be used commercially.
Hollander thinks stem cell bandages are extremely promising not just for knees, but also a range of soft tissue repairs, from rotator cuffs to mothers’ anal sphincters torn in labor. For now, however, he’s focusing on menisci. “Just to do this one application has taken us years,” he says. “We can’t do everything.”
Hollander has already procured funding for a larger trial. He also plans to streamline the process, cutting some of its expense—an issue that concerned both Rodeo and Luks. To do this, Hollander hopes to switch to the use of donor stem cells, so that patients don’t need to undergo two procedures, to first aspirate the stem cells and then implant the bandage.
“We're trying to freeze the [living bandage] so that it can be stored for some months in the hospital and then just pulled out of the freezer, warmed up and implanted,” he says. “That makes it a much more simple process—much more cost effective for health care providers.”
Though much more testing needs to be done to confirm the efficacy of the living bandage, the team seems to be on the right track.
“Bottom line is, it pays to save a meniscus,” says Luks. “If a meniscus is repairable, it should be repaired.”