‘Dancing Molecules’ Heal Cartilage Damage

According to the World Health Organization, almost 530 million people worldwide were living with osteoarthritis in 2019. It is a degenerative disease in which the tissue in the joints breaks down over time. It is a common health problem and one of the main causes of disability. In patients with severe osteoarthritis, the cartilage can become so thin that the joints essentially become bone on bone – with no cushioning in between. Not only is this extremely painful, but the patient’s joints can no longer function properly. In this case, the only effective treatment is joint replacement surgery, which is expensive and invasive. Current treatments are aimed at slowing the progression of the disease or delaying the inevitable joint replacement. There are no regenerative options as humans are unable to regenerate cartilage in adulthood.

New Therapy Stimulates Cartilage Regeneration

In November 2021, researchers at Northwestern University unveiled a new injectable therapy that harnesses fast-moving “dancing molecules” to repair tissue and reverse paralysis after severe spinal cord injury. Now the same research group has applied the therapeutic strategy to damaged human cartilage cells. In the new study, the treatment activated the gene expression required for cartilage regeneration within just four hours. And after just three days, the human cells produced the protein components required for cartilage regeneration. The new therapy uses synthetic nanofibers to mimic the natural signaling of a protein that is crucial for the formation and maintenance of cartilage. The researchers found that intensifying the movement of molecules within the nanofibers resulted in more components being needed for regeneration. After just four hours, the treatment activated the gene expression required for cartilage formation. The therapy could be successfully used to treat osteoarthritis. The researchers also found that the effectiveness of the treatment increased with increasing molecular movement. In other words, the “dancing” movements of the molecules were crucial for triggering the cartilage growth process.

The researchers led by Samuel I. Stupp of Northwestern University, who led the study, observed the effects in two cell types that are completely independent of each other – cartilage cells in our joints and neurons in our brain and spinal cord. Stupp is an expert in regenerative nanomedicine and Board of Trustees Professor of Materials Science and Engineering, Chemistry, Medicine and Biomedical Engineering at Northwestern University, where he directs the Simpson Querrey Institute for BioNanotechnology and its affiliated Center for Regenerative Nanomedicine.

The Effect of the “Dancing Molecules”

Stupp and his team suspected that “dancing molecules” could stimulate the stubborn tissue to regenerate. The dancing molecules invented in Stupp’s lab are assemblies that form synthetic nanofibers of tens to hundreds of thousands of molecules with strong signals for cells. By tuning their collective movements through their chemical structure, Stupp discovered that the moving molecules can quickly find and contact cellular receptors, which are also in constant motion and extremely crowded on cell membranes. Once inside the body, the 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 the receptors, the synthetic materials can communicate with the cells.

In the new study, Stupp and his team investigated the receptors for a specific protein that is crucial for the formation and maintenance of cartilage. To target this receptor, the team developed a new circular peptide that mimics the protein’s bioactive signal, transforming growth factor beta-1 (TGFb-1). The researchers then incorporated this peptide into two different molecules that interact with each other in water to form supramolecular polymers, both of which have the same ability to mimic TGFb-1. The researchers designed one supramolecular polymer with a special structure that allowed the molecules to move more freely within the large assemblies. The other supramolecular polymer, on the other hand, restricted molecular movement.

Although both polymers mimicked the signal to activate the TGFb-1 receptor, the polymer with the fast-moving molecules was much more effective. In some respects, they were even more effective than the protein that activates the TGFb-1 receptor in nature. After three days, the human cells exposed to the long arrays of the more mobile molecules produced larger amounts of the protein components required for cartilage regeneration. For the production of one of the components of the cartilage matrix, called collagen II, the dancing molecules with the cyclic peptide that activates the TGF-beta1 receptor were even more effective than the natural protein that has this function in biological systems.”

In view of the success of the study on human cartilage cells, the experts assume that cartilage regeneration will be significantly improved in highly translational preclinical models. The aim is to develop a new type of bioactive material for the regeneration of cartilage tissue in joints. Stupp’s lab is also testing the ability of the dancing molecules to regenerate bone – and already has promising initial results that are expected to be published later this year. At the same time, he is testing the molecules in human organoids to accelerate the process of discovering and optimizing therapeutic materials. Stupp’s team also continues to seek Food and Drug Administration approval for clinical trials testing the spinal cord repair therapy. The researchers believe the fundamental discovery about “dancing molecules” could have applications in a variety of diseases. Controlling supramolecular movements through chemical design appears to be a powerful tool to increase the effectiveness of a range of regenerative therapies.