New study shows ‘dancing molecules’ can regenerate cartilage in 3 days

In November 2021, researchers at Northwestern University presented a new injectable therapy, which harnesses fast-moving “dancing molecules,” to repair tissue and reverse paralysis after severe spinal cord injuries.

The same research group has now applied this therapeutic strategy to damaged human cartilage cells. In this new study, the treatment activated the gene expression needed for cartilage regeneration in just four hours. And, after just three days, the human cells were producing the protein components needed for cartilage regeneration.

The researchers also found that the effectiveness of the treatment increased as molecular movement increased. In other words, the “dancing” movements of the molecules were essential to trigger the cartilage growth process.

The study was published today in the Journal of the American Chemical Society.

“When we first observed the therapeutic effects of dancing molecules, we saw no reason why this would apply only to the spinal cord,” said Samuel I. Stupp of Northwestern University, who led the study. “Now we’re seeing effects on two types of cells that are completely disconnected from each other: the cartilage cells in our joints and the neurons in our brain and spinal cord. This reinforces to me that we may have discovered a universal phenomenon. It could apply to many other tissues.”

An expert in regenerative nanomedicine, Stupp is a board-appointed professor of materials science and engineering, chemistry, medicine and biomedical engineering at Northwestern, where he is founding director of the Simpson Querrey Institute for BioNanotechnology and its affiliate, the Center for Regenerative Nanomedicine. Stupp holds appointments in the McCormick School of Engineering, the Weinberg College of Arts and Sciences and the Feinberg School of Medicine. Shelby Yuan, a graduate student in Stupp’s lab, is the study’s senior author.

Big problem, few solutions

According to the World Health Organization, nearly 530 million people worldwide suffered from osteoarthritis in 2019. A degenerative disease characterized by the progressive breakdown of joint tissue, osteoarthritis is a common health problem and a leading cause of disability.

In patients with severe osteoarthritis, the cartilage can wear away to the point where the joints become bone on bone, with no cushion between them. Not only is this extremely painful, but the patients’ joints can no longer function properly. In this case, the only effective treatment is joint replacement surgery, which is expensive and invasive.

“Current treatments aim to slow disease progression or delay the inevitable joint replacement,” Stupp said. “There are no regenerative options because humans do not have the inherent ability to regenerate cartilage in adulthood.”

What are “dancing molecules”?

Stupp and his team hypothesized that “dancing molecules” could encourage recalcitrant tissues to regenerate. Previously invented in Stupp’s lab, dancing molecules are synthetic nanofiber assemblies of tens to hundreds of thousands of molecules that transmit powerful signals to cells. By adjusting their collective motions through their chemical structure, Stupp discovered that the moving molecules could quickly find and properly interact with cell receptors, which are also in constant motion and extremely crowded on cell membranes.

Once inside the body, the nanofibers mimic the extracellular matrix of surrounding tissues. By adapting to the structure of the matrix, mimicking the movement of biological molecules, and incorporating bioactive signals for receptors, the synthetic materials are able to communicate with cells.

“Cellular receptors are constantly moving,” Stupp explains. “By making our molecules move, make them ‘dance’ or even temporarily pop out of these structures, called supramolecular polymers, they are able to connect more effectively to the receptors.”

Movement matters

In this new study, Stupp and his team focused on receptors for a specific protein that is critical to cartilage formation and maintenance. To target this receptor, the team developed a new circular peptide that mimics the protein’s bioactive signal, called transforming growth factor beta-1 (TGFb-1).

The researchers then incorporated this peptide into two different molecules that interacted to form supramolecular polymers in water, each with the same ability to mimic TGFb-1. The researchers designed one supramolecular polymer with a special structure that allowed its molecules to move more freely in large assemblies. The other supramolecular polymer, in contrast, restricted molecular movement.

“We wanted to modify the structure in order to compare two systems that differ in the extent of their motion,” Stupp explained. “The intensity of the supramolecular motion in one is much greater than in the other.”

Although both polymers mimic the TGFb-1 receptor’s activation signal, the polymer with the fast-moving molecules proved much more effective. In some ways, they were even more effective than the protein that activates the TGFb-1 receptor in nature.

“After three days, human cells exposed to the long, more mobile molecule assemblies produced greater amounts of protein components needed for cartilage regeneration,” Stupp said. “For the production of one of the components of the cartilage matrix, known as collagen II, the dancing molecules containing the cyclic peptide that activates the TGF-beta1 receptor were even more effective than the natural protein that performs this function in biological systems.”

And after?

Stupp’s team is currently testing these systems in animal studies and adding additional signals to create highly bioactive therapies.

“With the success of the human cartilage cell study, we anticipate that cartilage regeneration will be greatly improved when used in highly translational preclinical models,” Stupp said. “It is expected to develop into a novel bioactive material for cartilage tissue regeneration in joints.”

Stupp’s lab is also testing the dancing molecules’ ability to regenerate bone. Early results are already promising and will likely be published later this year. In parallel, he is testing the molecules in human organoids to speed up the process of discovering and optimizing therapeutic materials.

Stupp’s team is also continuing to build its case with the Food and Drug Administration, with the goal of getting approval for clinical trials to test the therapy for spinal cord repair.

“We are beginning to see the enormous breadth of pathologies to which this fundamental discovery about ‘dancing molecules’ could apply,” Stupp said. “Controlling supramolecular motion through chemical design appears to be a powerful tool for increasing the efficacy of a range of regenerative therapies.”