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Cartilage Grafts for Damaged Knees

Nanofiber scaffolds seeded with patient-derived stem cells could repair ravaged joints.

Our joints are one of the first body parts to suffer the inevitable ravages of aging: cartilage may be torn in overzealous basketball games or slowly worn away over years of use. Scientists are now experimenting with a combination of stem cells and novel scaffold materials designed to mimic real tissue, in hopes of permanently vanquishing the pain that accompanies this damage and perhaps preventing the onset of arthritis. In animal models, these transplants appear to spur regeneration of cartilage that better resembles native tissue.

Culturing cartilage: Mesenchymal stem cells (labeled green) are grown on a scaffold of nanofibers (labeled red). The approach might one day help repair damaged cartilage.

Cartilage damage accrues from both trauma and normal wear and tear, often culminating in osteoarthritis, a degenerative joint disease that affects about half of the population by age 65. Existing treatment for small cartilage defects typically involves inflicting additional damage on the injured joint, to encourage cell-rich blood and bone marrow to clot in the area. Or treatment involves transplants of cartilage cells, called chondrocytes, collected from a healthy joint, then grown in culture and injected into the damaged area. Both procedures trigger growth of new tissue, a scarlike version of cartilage that is more fibrous than regular cartilage and doesn’t seem to have the same durability.

“It’s like a pothole filler,” says Rocky Tuan, chief of the Cartilage Biology and Orthopedics Branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, in Baltimore. “It’s not the same as resurfacing, but if the stuff hangs in there, it will last a couple of winters and it’s fine.”

In an effort to truly regenerate cartilage rather than simply patch it, Tuan and his colleagues have developed a nanofiber scaffold that’s structurally similar to the extracellular matrix, a fibrous material that provides support to connective tissue in the body.The scaffold is generated via electrospinning, a process adopted from the textiles industry. The researchers apply a strong electric field to a liquid polymer, which forms into long fibers in an attempt to dissipate the charge. The fibers are collected in a tangled ball, much like cotton candy.

The nanoscale structure of the material is key: experiments have shown that cells grow better on a nanoscale fiber scaffold than on a millimeter-scale one made of the same material. “These scaffolds are more on the scale of what a cell would normally see,” says Farshid Guilak, director of the Orthopaedic Bioengineering Laboratory, at Duke University, in Durham, NC, who was not involved in the research.

The scaffolds are seeded with mesenchymal stem cells–adult stem cells derived from bone marrow, fatty tissue, and other sources, and which can be differentiated into muscle, bone, fat, and cartilage. “The advantage is that you don’t have to damage other tissue to get the cells,” says Tuan.

In a recent pilot experiment in pigs, researchers sutured the cell-laden scaffolds over damaged cartilage in the animals’ knees. Six months later, new tissue had formed, with a smooth surface and mechanical properties similar to those of native cartilage. The tissue also expressed molecular markers characteristic of normal cartilage. “Ultimately, it’s important for this new tissue to have an extracellular matrix made of native cartilage molecules so that, in the long term, the properties of new tissue will emulate that of real cartilage,” says Alan Grodzinsky, director of the Center for Biomedical Engineering, at MIT, who was not involved in the work.

The stem-cell-seeded scaffolds repaired the damage better than scaffolds with no cells or those seeded with ordinary cartilage cells, although scientists don’t yet know why. It may be because the stem cells proliferate better than cartilage cells, or because they are more receptive to molecular signals coming from the wounded tissues.

A number of other tissue-engineering approaches using cell transplants, scaffold materials, or a combination of the two are currently under way, including some in clinical trials. (The most advanced of them use one or the other, largely because it is easier to gain approval from the Food and Drug Administration this way.) Tuan says that he aims to begin human tests in the next two years. First, his team must do additional studies in large animals, such as goats or sheep, over a longer period of time, to make sure that the treatment is safe and effective. The polymer that Tuan uses is already approved for medical use, and the cells would come from the patients themselves, eliminating risk of immune rejection.

Tuan’s group is also working on making the scaffolds bioactive, tagging them with biological molecules that encourage growth of the appropriate cells. Ultimately, he would like to design a system in which stem cells can be collected from the patient and immediately delivered to the scaffold without culturing, which would then be transplanted into the patient.

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