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Potential arthritis treatment prevents cartilage decay

Six days after IGF-1 treatment with the dendrimer nanoparticles (blue), the particles penetrated through the knee cartilage. Credit: Brett Geiger and Jeff Wyckoff

Osteoarthritis, a disease that causes severe joint pain, affects more than 20 million people in the United States. Some medications can help alleviate pain, but there are no treatments that could reverse or slow the breakdown of cartilage associated with the disease.

In progress that could improve treatment options available for osteoarthritis, MIT engineers have designed new material that can deliver drugs directly to cartilage. The material can penetrate deep into the cartilage and deliver drugs that could potentially treat damaged tissue.

"This is a way to get right into the cells that are experiencing harm and to introduce different kinds of drugs that could change their behavior," says Paula Hammond, head of the MIT Chemical Engineering Department, Koch Institute for Integrative Cancer Research and principal author of the study.

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

Brett Geiger, graduate of MIT, is the lead author of the paper, appearing in issue 28 Scientific translation medicine. Other authors include Sheryl Wang, MIT graduate, Robert Padera, professor of pathology at Brigham Hospital and Women's Hospital, and Alan Grodzinsky, professor of biological engineering at MIT.

Better delivery

Osteoarthritis is a progressive disease that can be caused by traumatic damage such as ligament rupture; it can also result from the gradual destruction of cartilage as people age. A smooth connective tissue that protects joints, the cartilage is produced by cells called chondrocytes but can not easily be replaced after damage.

Previous studies have shown that IGF-1 can help with cartilage regeneration in animals. However, many anti-osteoarthritis drugs that have shown promise in animal studies have not been proven in clinical trials.

The MIT team suspected that it was because the drugs were removed from the joints before getting into the deep layer of chondrocytes they were supposed to target. To overcome this, they decided to design material that could penetrate the entire cartilage.

Nanocarteria treatment reduced cartilage degeneration in rat knuckle with joint injuries (bottom right) compared to untreated rodents (top left, degeneration outlined in red). Credit: B.C. Geiger et al., Science Translational Medicine (2018)

The ball-shaped molecule that has come up contains many branched structures called dendrimers that separate from the central nucleus. The molecule has a positive charge at the tip of each of its branches, helping to bind to the negatively charged cartilage. Some of these cartridges can be replaced by a short, flexible, water-loving polymer, known as PEG, which can be rotated to the surface and partially cover a positive charge. The IGF-1 molecules are also attached to the surface.

When these particles are injected into the joint, they cover the cartilage surface and then disperse. This is easier for them than free IGF-1 because positive ball balls allow them to bind the cartilage and prevent it from being washed. However, charged molecules are not continuously accepted. Thanks to flexible PEG chains on the surface that cover and expose the charge while moving, the molecules can be briefly detached from the cartilage and allowing them to move deeper into the tissue.

"We have found the optimal range of charging so that the material can bind the tissue, release more diffusion and not be so strong that it just gets stuck on the surface," says Geiger.

Once the particles reach the chondrocytes, the IGF-1 molecules bind to cell surface receptors and stimulate the cells to start producing proteoglycans, cartilage building blocks and other connective tissues. IGF-1 also promotes cell growth and prevents cell death.

Joint repair

When scientists injected the particles into the knee joints of rats, they found that the material had a half-life of about four days, ten times longer than IGF-1 injected alone. The drug concentration in the joints remained high enough to have a therapeutic effect of approximately 30 days. If this applies to humans, patients could benefit greatly from joint injections – which can be given only monthly or twice weekly – researchers say.

In animal studies, researchers found that cartilage in damaged joints treated with nanoparticle-drug combination was much less damaged than cartilage in untreated joints or joints treated with IGF-1 alone. Joints have also shown reduced joint inflammation and bone formation.

The cartilage in rat joints is about 100 microns thick, but scientists have also shown that their particles can penetrate up to 1 millimeter of cartilage – the cartilage thickness in the human joint.

"This is very difficult, and medications are usually cleansed before they can move a large part of the cartilage," says Geiger. "When you start thinking about translating this technology from studies in rats to larger animals and humans for one day, the ability of this technology to succeed depends on its ability to work in thicker cartilage."

Scientists have begun to develop this material as a way to treat osteoarthritis that arises after a traumatic injury, but believes it could also be adjusted to treat osteoarthritis associated with age. They are now looking to explore the availability of different types of drugs, such as other growth factors, drugs that block inflammatory cytokines and nucleic acids such as DNA and RNA.

Explore the following:
Scientists will discover why knee injury leads to osteoarthritis

More information:
BC. Geiger et al., & Quot; Carcinoid Nanocarteria Improve the Administration and Efficacy of Osteoarthritis Growth Factor & quot; Scientific translation medicine (2018). … scitranslmed.aat8800

Magazine links:
Scientific translation medicine

Massachusetts Institute of Technology

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