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Potential arthritis treatment prevents cartilage breakdown

Six days after treatment with IGF-1, carried by dendrimeric nanoparticles (blue), the particles penetrated through the cartilage of the knee joint. Credit: Brett Geiger and Jeff Wykoff

Osteoarthritis, a disease that causes severe joint pain, affects more than 20 million people in the United States. Some medications can help relieve pain, but there are no treatments that can alter or slow down the cartilage disorder associated with this disease.

In a move that could improve the treatment options available for osteoarthritis, MIT engineers developed a new material that can inject drugs directly into cartilage. The material can penetrate deep into the cartilage, delivering medicines that can potentially heal damaged tissue.

“This is a way to directly get into cells that are harmed, and introduce various types of therapies that can change their behavior,” says Paula Hammond, head of chemical engineering at MIT, a member of the Institute of Massachusetts Institute of Technology. Cancer Research, and senior author of the study.

In a rat study, researchers showed that providing an experimental drug called insulin-like growth factor 1 (IGF-1) with this new material prevented the destruction of cartilage much more effectively than injecting the drug into the joint itself.

Brett Geiger, a graduate student at the Massachusetts Institute of Technology, is the lead author of the article, which appears in the November 28 issue The science of translational medicine, Other authors are Cheryl Wang, a graduate student at the Massachusetts Institute of Technology, Robert Pader, associate professor of pathology at Brigham and Women's Hospital, and Alan Grodzinsky, professor of biological engineering at the Massachusetts Institute of Technology.

Best delivery

Osteoarthritis is a progressive disease that can be caused by a traumatic injury, such as tearing a ligament; it can also be the result of a gradual deterioration of cartilage as people age. Smooth connective tissue that protects the joints, cartilage is produced by cells called chondrocytes, but cannot be replaced after damage.

Previous studies have shown that IGF-1 can help regenerate cartilage in animals. However, many osteoarthritis drugs, which showed their results in animal studies, did not show success in clinical trials.

The team at the Massachusetts Institute of Technology suspected that this was due to the fact that the drugs were cleared of the joint before they could reach the deep layer of chondrocytes they were aimed at. To overcome this, they began to develop material that could penetrate the cartilage.

Nanorubka treatment reduced the degradation of cartilage in the knees of rats with injuries of the joint (lower right) compared to untreated rodents (upper left, degeneration, indicated by red). Credit: B.C. Geiger et al., Science Translational Medicine (2018)

The sphere of the shape of the molecule, which they invented, contains many branched structures, called dendrimers, which are separated from the central core. The molecule has a positive charge at the tip of each of its branches, which helps it to bind with negatively charged cartilage. Some of these charges can be replaced by a short flexible, water-absorbing polymer, known as PEG, which can swing on the surface and partially cover a positive charge. IGF-1 molecules are also attached to the surface.

When these particles are injected into a joint, they cover the surface of the cartilage, and then begin to dissipate through it. This is easier to do than for free IGF-1, because the positive charges of the spheres allow them to bind to the cartilage and do not allow them to drain. However, charged molecules do not stick permanently. Due to the flexible PEG chains on the surface, which cover and detect charge as they move, molecules can detach from cartilage for a short time, which allows them to move deeper into the tissue.

“We found the optimal range of charge so that the material could bind the fabric and detach for further diffusion, and not be so strong that it just gets stuck on the surface,” says Geiger.

When particles reach chondrocytes, IGF-1 molecules bind to receptors on cell surfaces and stimulate cells to begin producing proteoglycans, the building blocks of cartilage and other connective tissues. IGF-1 also promotes cell growth and prevents cell death.

Joint repair

When the researchers injected particles into the knee joints of rats, they found that the material had a half-life of about four days, which is 10 times longer than IGF-1, injected by itself. The concentration of the drug in the joints remained high enough to have a therapeutic effect for about 30 days. If this is true for people, patients can benefit greatly from joint injections, which can only be given monthly or fortnightly, the researchers say.

In animal studies, researchers found that the cartilage in damaged joints treated with a combination of nanoparticles and drugs was much less damaged than the cartilage in untreated joints or joints treated only with IGF-1. The joints also showed a reduction in joint inflammation and the formation of bone spurs.

The cartilage in the joints of rats is about 100 microns, but the researchers also showed that their particles can penetrate into pieces of cartilage up to 1 mm – the thickness of cartilage in a human joint.

“It is very difficult to do. Drugs are usually cleaned before they can move through most of the cartilage, ”says Geiger. "When you start thinking about transferring this technology from research into rats to larger animals and someday people, the ability of this technology to succeed depends on its ability to work in thicker cartilage."

Researchers have begun to develop this material as a way to treat osteoarthritis, which occurs after a traumatic injury, but they believe that it can also be adapted for the treatment of age-related osteoarthritis. Now they plan to explore the possibility of delivering various types of drugs, such as other growth factors, drugs that block inflammatory cytokines, and nucleic acids, such as DNA and RNA.

Explore further:
Scientists find out why a knee injury leads to osteoarthritis

Additional Information:
BC. Geiger El-al, "Nanorubes penetrating through the cartilage improve the delivery and effectiveness of the treatment of growth factor in osteoarthritis", The science of translational medicine (2018). stm.sciencemag.org/lookup/doi/ … scitranslmed.aat8800

Journal Handbook:
The science of translational medicine

Provided by:
Massachusetts Institute of Technology

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