In 2019, an estimated 530 million people worldwide were living with osteoarthritis, according to the World Health Organization. Osteoarthritis is a degenerative disease that causes tissues in the joints to wear down over time, and is a common health problem and a leading cause of disability.
In patients with severe osteoarthritis, the cartilage can wear down to the point that the joints become bone-on-bone with no cushion between them. Not only is this incredibly painful, but the joints can no longer function properly. At this point, the only effective treatment is joint replacement surgery, which is expensive and painful.
In November 2021, Northwestern University researchers introduced a new injectable treatment that uses fast-moving “dancing molecules” to repair tissue and reverse paralysis after severe spinal cord injuries.
Now, in a new study, the same research team has applied the treatment strategy to damaged human cartilage cells, and the treatment activated the expression of genes necessary for cartilage regeneration in just four hours. Three days later, the human cells were producing the protein components needed for cartilage regeneration.
The researchers also found that as the movement of the molecules increased, the effectiveness of the treatment increased. In other words, the movements of the molecules were crucial in stimulating the cartilage growth process, as shown by the results of the study published on July 26 in the Journal of the American Chemical Society.
“Current treatments aim to slow disease progression or delay inevitable replacement, and there are no regenerative options because humans do not have the innate ability to regenerate cartilage in adulthood,” said study leader Samuel I. Stubb, a professor at Northwestern University who specializes in regenerative nanomedicine and is founding director of the Simpson Quarry Institute for Nanobiotechnology and its affiliated Center for Regenerative Nanomedicine, according to EurekAlert.
“When we first observed the therapeutic effects of dancing molecules, we couldn’t find any reason why they would only apply to the spinal cord,” he adds. “Now we’re seeing effects in two completely unrelated cell types: cartilage cells in our joints, and neurons in the brain and spinal cord. This makes me more confident that we’ve discovered a universal phenomenon that may apply to many other tissues.”
dancing particles
Stubb and his team hypothesized that “dancing molecules” might encourage stubborn tissues to regenerate. The dancing molecules are structures made up of synthetic nanofibers containing tens to hundreds of thousands of molecules that carry powerful signals to cells. By tuning their collective movements through their chemical structure, Stubb discovered that the moving molecules could quickly find and correctly interact with cellular receptors, which are also in constant, densely packed motion on cell membranes.
Once inside the body, the nanofibers mimic the extracellular matrix and surrounding tissues. By matching the structure of the matrix, mimicking the movement of biological molecules, and incorporating biosignals from receptors, the synthetic materials can communicate with cells.
“Cellular receptors are constantly moving by making our molecules move, ‘dance,’ or even temporarily jump out of these structures known as supermolecular polymers, and can more effectively communicate with the receptors,” says Stubb.
Movement is important.
In the new study, Staub and his team looked for receptors for a specific protein important for the formation and maintenance of cartilage. To target this receptor, the team developed a new circular peptide that mimics the protein’s biological signal, called transforming growth factor beta 1 (TGFb1).
The researchers then combined this peptide into two different molecules that interact to form polymers, each of which has the ability to mimic TGF-β1. The researchers designed one of the superpolymers with a special structure that allows its molecules to move more freely within larger aggregates. The other superpolymer restricted the molecules’ movement.
“We wanted to modify the structure in order to compare two systems that differed in their range of motion, and the motion of the supermolecular particles in one was much greater than the motion in the other,” says Stubb.
Although both polymers mimicked the signal to activate TGF-β1, the polymer with the faster-moving molecules was more effective. In some ways, they were more effective than the protein that activates TGF-β1 in nature.
“After three days, human cells exposed to prolonged assemblies of the more mobile molecules produced greater amounts of the protein components needed for cartilage regeneration and for the production of a component of the cartilage matrix known as collagen II,” Staub notes. “The dancing molecules containing a cyclic peptide that activates the transforming growth factor receptor beta 1 were even more effective than the natural protein that has this function in biological systems.”
next step
The Stop team is currently testing these systems in animal studies, adding additional signals to create highly active biotherapeutics.
“With the success of the study in human cartilage cells, we expect cartilage regeneration to be greatly enhanced when used in highly translatable preclinical models, and should develop into a novel bioactive material for cartilage tissue regeneration in joints,” Stubb says.
Stubbe’s lab is also testing the dancing molecules’ ability to regenerate bone, and already has promising preliminary results, likely to be published later this year. At the same time, it is testing the molecules in human organoids to speed up the process of discovering and improving therapeutics.
The Stop team also aims to get approval to conduct clinical trials to test the treatment for spinal cord repair.
“We are beginning to see the enormous breadth of diseases to which this fundamental discovery of dancing molecules could apply,” says Stubb. “Controlling ultra-molecular motion through chemical design appears to be a powerful tool for increasing the efficacy of a range of regenerative therapies.”