Six days after treatment with IGF-1 , carried by dendrimer nanoparticles (blue), the particles have penetrated the cartilage cartilage. Credit:…
Six days after treatment with IGF-1
, carried by dendrimer nanoparticles (blue), the particles have penetrated the cartilage 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 drug treatments may help alleviate the pain, but there are no treatments that can reverse or slow the cartilage distribution associated with the disease.
In an advance to improve the treatment options available for osteoarthritis, MIT engineers have designed a new material that can administer drugs directly to the cartilage. The material can penetrate deep into the cartilage and deliver drugs that can potentially heal damaged tissues.
“This is a way to get directly to the cells that experience the damage and introduce different types of therapeutic agents that can change their behavior,” said Paula Hammond, Head of MIT’s Chemical Engineering Department, a member of MIT’s Koch Institute for Integrated Cancer Research, and the leading author of the study.
In a study in rats, researchers showed that delivering an experimental drug called insulin-like growth factor 1 (IGF-1) with this new material prevented cartilage loss much more effectively than injecting the drug into the joint itself.
Brett Geiger, an MIT doctoral student, is the main responsibility for the paper, as shown in the November 28 issue of Science Translational Medicine . Other writers are Sheryl Wang, an MIT student, Robert Padera, professor of pathology at Brigham and Women’s Hospital, and Alan Grodzinsky, a professor of biotechnology.
Osteoarthritis is a progressive disease that can be caused by a traumatic injury that tears of a ligament; It may also be due to the gradual wear of cartilage as people age. A flexible connective tissue that protects the joints, cartilage is produced by cells called chondrocytes, but is not easily replaced when damaged.
Previous studies have shown that IGF-1 can help regenerate cartilage in animals. However, many arthropod medicines that showed promise in animal studies have not worked well in clinical trials.
The MIT team suspected that this was because the drugs were cleared from the joint before they could reach the deep layer of chondrocytes they were destined to target. To overcome it, they decided to design a material that could penetrate the entire cartilage.
Nanocarrier reduces cartilage degeneration in the knee of jointed joint rats) compared to untreated rodents (upper left, degeneration outlined in red). Credit: B.C. Geiger et al., Science Translational Medicine (2018)
The spherical molecule that they emerged contains many branched structures called dendrimeres that branch from a central nucleus. The molecule has a positive charge at the tip of each of its branches, which helps bind to the negatively charged cartilage. Some of these charges can be replaced by a short, flexible, water-loving polymer, known as PEG, which can turn around on the surface and partially cover the positive charge. Molecules of IGF-1 are also attached to the surface.
When these particles are injected into a joint, they coat the cartilage surface and then begin to diffuse through it. This is easier for them to do than it’s free IGF-1 because the spikes’ positive charges allow them to tie to cartilage and prevent them from being washed away. However, the charged molecules do not permanently adhere. Thanks to the flexible PEG chains on the surface that cover and uncover the charge as they move, the molecules can be loosely released from cartilage so they can move deeper into the tissue.
“We found an optimal charging range so that the material can both bind the tissue and bind for further diffusion and not be so strong that it just sticks to the surface,” says Geiger.
When the particles reach the chondrocytes bind the IGF-1 molecules to receptors on the cell surface and stimulate the cells to start producing proteoglycans, the cartilage building blocks and other connective tissues. IGF-1 also promotes cell growth and prevents cell death.
When the researchers injected the particles into the joint of rats they found that the material had a half life of approximately four days, which is 10 times longer than IGF-1 is injected on its own. The drug concentration in the joints remained high enough to have a therapeutic effect for about 30 days. If this applies to humans, patients would be able to benefit from joint injections – which can only be given monthly or twice a week – f The orphans say.
In animal studies, researchers found that cartilage in injured joints treated with the nanoparticle drug combination was much less injured than cartilage in untreated joints or joints treated with IGF-1 alone. The wires also showed reductions in led bone inflammation and bone inflammation.
Rat in cartilage is about 100 microns thick, but the researchers also showed that their particles could penetrate into pieces of cartilage up to 1 millimeter cartilage thickness in a human joints.
“It’s a very hard thing to do. Drugs will usually be cleaned before they can move much of the cartilage,” says Geiger. “When you start thinking about translating this technique from studies into rats to larger animals and today people, this technique depends on its success due to its ability to work in thicker cartilage.”
The researchers began to develop this material as a way to treat osteoarthritis that occurs after traumatic injury, but they think it can also be adapted to treat age-related osteoarthritis. They are now planning to investigate the possibility of delivering different types of drugs, such as other growth factors, drugs that block inflammatory cytokines and nucleic acids such as DNA and RNA.
Researchers discover why knee injury leads to osteoarthritis
BC. Geiger et al., “Cartilage penetrating nanocarrier improves delivery and efficacy of growth factor treatment of osteoarthritis”, Science Translational Medicine (2018). stm.sciencemag.org/lookup/doi/ … scitranslmed.aat8800