In November 2021, researchers at Northwestern University introduced a new injectable therapy, which harnesses fast-moving “dancing molecules,” to repair tissue and reverse paralysis after severe spinal cord injuries.
Now, the same research group has applied the therapeutic strategy to damaged human cartilage cells. In the new study, the treatment activated the genetic expression needed to regenerate cartilage in just four hours. And, after just three days, the human cells produced protein components necessary for cartilage regeneration.
The researchers also found that as molecular motion increased, so did the effectiveness of the treatment. In other words, the “dancing” movements of the molecules were crucial to triggering the cartilage growth process.
The study was published today (July 26) in the journal Journal of the American Chemical Society.
“When we first looked at the therapeutic effects of dancing molecules, we saw no reason why it should apply only to the spinal cord,” said Samuel I. Stupp of Northwestern University, who led the study. “Now, we looked at the effects in two types of cells that are completely unconnected to each other: the cartilage cells in our joints and the neurons in our brain and spinal cord. This makes me more confident that we may have uncovered a universal phenomenon. It could apply to many other tissues.”
Stupp is an expert in regenerative nanomedicine and a professor of Materials Science and Engineering, Chemistry, Medicine and Biomedical Engineering at Northwestern University, where he is the founding director of the Simpson Querrey Institute for Bionanotechnology and its affiliated center, 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, was senior author on the paper.
Big problem, few solutions
According to the World Health Organization, nearly 530 million people worldwide suffered from osteoarthritis in 2019. Osteoarthritis, a degenerative disease in which joint tissues deteriorate over time, is a common health problem and the leading cause of disability.
In patients with severe osteoarthritis, the cartilage can wear down so much that the joints basically become bone on bone, with no cushioning between them. Not only is this incredibly painful, but 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 disease progression or postpone inevitable joint replacement,” Stupp said. “There are no regenerative options because humans do not have an inherent ability to regenerate cartilage in adulthood.”
What are ‘dancing molecules’?
Stupp and his team proposed that “dancing molecules” could stimulate regeneration of stubborn tissue. Dancing molecules, previously invented in Stupp’s lab, are synthetic nanofiber-like arrays comprising tens to hundreds of thousands of molecules with potent signals for cells. By fine-tuning their collective motions through their chemical structure, Stupp found that the moving molecules could quickly find and properly connect with cell receptors, which are also constantly moving and extremely crowded in cell membranes.
Once inside the body, nanofibers mimic the extracellular matrix of the surrounding tissue. By adapting to the structure of the matrix, mimicking the movement of biological molecules, and incorporating bioactive signals for receptors, synthetic materials can communicate with cells.
“Cell receptors are constantly moving,” Stupp said. “By making our molecules move, ‘dance,’ or even temporarily jump out of these structures, known as supramolecular polymers, they can more effectively connect with the receptors.”
Movement matters
In the new study, Stupp and his team looked at the receptors for a specific protein that is critical for cartilage formation and maintenance. To target this receptor, the team developed a new circular peptide that mimics the bioactive signal of the protein, called transforming growth factor beta-1 (TGFb-1).
The researchers then incorporated this peptide into two different molecules that interact 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 within the large assemblies. The other supramolecular polymer, however, restricted molecular movement.
“We wanted to modify the structure so that we could compare two systems that differ in the amplitude of their motion,” Stupp explained. “The intensity of the supramolecular motion in one is much greater than in the other.”
Although both polymers mimicked the signal to activate the TGF-b-1 receptor, the polymer with fast-moving molecules was much more effective. In some ways, they were even more effective than the protein that activates the TGF-b-1 receptor in nature.
“After three days, human cells exposed to the longer, more mobile arrays of molecules produced higher amounts of the 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 has this function in biological systems.”
Whats 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 improved when used in highly translational preclinical models,” Stupp said. “It should become a novel bioactive material for cartilage tissue regeneration in joints.”
Stupp’s lab is also testing the dancing molecules’ ability to regenerate bone, with promising preliminary results that are 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 optimizing therapeutic materials.
Stupp’s team is also continuing to build its case with the Food and Drug Administration, with the goal of gaining approval for clinical trials to test the therapy for spinal cord repair.
“We are just beginning to see the enormous range of conditions to which this fundamental discovery about ‘dancing molecules’ could be applied,” Stupp said. “Controlling supramolecular motion through chemical design appears to be a powerful tool for increasing the efficacy of a variety of regenerative therapies.”