The breakthrough therapy treats spinal cord injuries

In November 2021, Northwestern University researchers introduced an injectable new treatment that harnessed fast-moving “dancing molecules” to repair tissue and reverse paralysis after severe spinal cord injuries.

Now, the same research team has applied the therapeutic strategy to damaged human cartilage cells. In the new study, the treatment activated gene expression necessary for cartilage regeneration in just four hours. And, after just three days, the human cells produced protein components needed to regenerate the cartilage.

The researchers also found that as molecular movement increased, so did the effectiveness of the treatment. In other words, the “dancing” movements of the molecules were decisive for the activation of the cartilage growth process.

The study was published on July 26, 2024 in Journal of the American Chemical Society.

When we first observed the therapeutic effects of dancing molecules, we saw no reason why it should only apply to the spinal cord. Now, we observe the effects in two cell types that are completely disconnected from each other -? cartilage cells in our joints and neurons in our brain and spinal cord. This makes me more certain that we might have discovered a global phenomenon. It could be applied to many other webs.”

Samuel I. Stupp, Head of Studies and Professor, Northwestern University

An expert in regenerative nanomedicine, Stupp is Professor of Materials Science and Engineering, Chemistry, Medical and Biomedical Engineering, where he is the founding director of the Simpson Querrey Institute for BioNanotechnology and its sister center, the Center for Regenerative Nanomed. Stupp holds appointments in the McCormick School of Engineering, Weinberg College of Arts and Sciences, and Feinberg School of Medicine. Shelby Yuan, a graduate student in the Stupp lab, was the study’s lead author.

Big problem, few solutions

As of 2019, nearly 530 million people worldwide were living with osteoarthritis, according to the World Health Organization. A degenerative disease in which the tissues in the joints are destroyed over time, osteoarthritis is a common health problem and the leading cause of disability.

In patients with severe osteoarthritis, the cartilage can wear down so thin that the joints essentially turn into bone on bone -? no cushion between. Not only is this incredibly painful, but the patients’ joints can no longer function properly. At that point, the only effective treatment is joint replacement surgery, which is expensive and invasive.

“Current treatments aim to slow the progression of the disease or postpone the inevitable joint replacement,” Stupp said. “There are no regenerative options because people have no innate ability to regenerate cartilage in adulthood.”

What are “dancing molecules”?

Stupp and his team hypothesized that the “dancing molecules” might encourage stubborn tissue to regenerate. The dancing molecules invented in Stupp’s lab are assemblies that form synthetic nanofibers that include tens to hundreds of thousands of molecules with powerful cell signals. By coordinating their collective movements through their chemical structure, Stupp discovered that the moving molecules could quickly find and properly engage with cellular receptors, which are also in constant motion and highly crowded in cell membranes.

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

“Cellular receptors are constantly moving,” Stupp said. “By making our molecules move, ‘dance’ or even temporarily pop out of these structures, known as supramolecular polymers, they can bind more effectively to receptors.”

Movement matters

In the new study, Stupp and his team looked at receptors for a specific protein that is critical for the formation and maintenance of cartilage. To target this receptor, the team developed a new cyclic 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 a supramolecular polymer with a special structure that allowed its molecules to move more freely within the large assemblies. The other supramolecular polymer, however, restricted molecular motion.

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

Although both polymers mimicked the signal to activate the TGFb-1 receptor, the polymer with fast moving molecules was much more effective. In some ways, they were even more effective than the TGFb-1 receptor-activating protein in nature.

“After three days, human cells exposed to the long concentrations of more mobile molecules produced greater amounts of protein components necessary for cartilage regeneration,” Stupp said. “For the production of one of the components in 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 has this function in biological systems” .

What’s next?

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 study in human cartilage cells, we predict that cartilage regeneration will be greatly enhanced when used in highly translational preclinical models,” Stupp said. “It should be developed into a new bioactive material for the regeneration of cartilage tissue in joints.”

Stupp’s lab is also testing the dancing molecules’ ability to regenerate bone. and already has promising early results, which will likely be published later this year. At the same time, it tests the molecules in human organoids to accelerate the process of discovering and optimizing therapeutic materials.

Stupp’s team also continues to approach the Food and Drug Administration, with the goal of getting approval for clinical trials to test the therapy to restore the spinal cord.

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

The study, “Supramolecular motion enables chondrogenic bioactivity of a cyclic peptide that mimics transforming growth factor-β1,” was supported by a gift from Mike and Mary Sue Shannon at Northwestern University for research on musculoskeletal regeneration at the Center for Regenerative Nanomedicine of Simp. Querrey Institute for BioNanotechnology.