A new injectable therapy harnesses “dancing molecules” to reverse paralysis and repair tissue after severe spinal cord injuries. When just a single injection was administered to tissues surrounding the spinal cords of paralyzed mice, the animals regained the ability to walk just four weeks later.

The research is published in Science in the article, “Bioactive Scaffolds with Enhanced Supramolecular Motion Promote Recovery from Spinal Cord Injury.”

“Our research aims to find a therapy that can prevent individuals from becoming paralyzed after major trauma or disease,” said Samuel Stupp, PhD, professor of materials science and engineering, chemistry, medicine and biomedical engineering at Northwestern University. “For decades, this has remained a major challenge for scientists because our body’s central nervous system, which includes the brain and spinal cord, does not have any significant capacity to repair itself after injury or after the onset of a degenerative disease. We are going straight to the FDA to start the process of getting this new therapy approved for use in human patients, who currently have very few treatment options.”

The team synthesized “supramolecular peptide fibril scaffolds” bearing two peptide sequences that promote nerve regeneration—one that reduces glial scarring and another that promotes blood vessel formation.

The therapeutic works by tuning the motion of molecules, so they can find and properly engage constantly moving cellular receptors. Injected as a liquid, the therapy immediately gels into a complex network of nanofibers that mimic the extracellular matrix of the spinal cord. By matching the matrix’s structure, mimicking the motion of biological molecules and incorporating signals for receptors, the synthetic materials are able to communicate with cells.

By sending bioactive signals to trigger cells to repair and regenerate, the breakthrough therapy dramatically improved severely injured spinal cords in five key ways: (1) the severed axons regenerated; (2) scar tissue was significantly diminished; (3) myelin reformed around cells; (4) functional blood vessels formed to deliver nutrients to cells at the injury site; and (5) more motor neurons survived.

“Receptors in neurons and other cells constantly move around,” Stupp said. “The key innovation in our research, which has never been done before, is to control the collective motion of more than 100,000 molecules within our nanofibers. By making the molecules move, ‘dance,’ or even leap temporarily out of these structures, known as supramolecular polymers, they are able to connect more effectively with receptors.”

“Given that cells themselves and their receptors are in constant motion, you can imagine that molecules moving more rapidly would encounter these receptors more often,” Stupp said. “If the molecules are sluggish and not as ‘social,’ they may never come into contact with the cells.”

Fine-tuning the molecules’ motion within the nanofiber network to make them more agile resulted in greater therapeutic efficacy in paralyzed mice. The researchers confirmed that formulations of their therapy with enhanced molecular motion performed better during in vitro tests with human cells, indicating increased bioactivity and cellular signaling.

Once connected to the receptors, the moving molecules trigger two cascading signals, both of which are critical to spinal cord repair. One signal prompts the long tails of neurons in the spinal cord, called axons, to regenerate. Similar to electrical cables, axons send signals between the brain and the rest of the body. Severing or damaging axons can result in the loss of feeling in the body or even paralysis. Repairing axons, on the other hand, increases communication between the body and brain.

The second signal helps neurons survive after injury because it causes other cell types to proliferate, promoting the regrowth of lost blood vessels that feed neurons and critical cells for tissue repair. The therapy also induces myelin to rebuild around axons and reduces glial scarring, which acts as a physical barrier that prevents the spinal cord from healing.

After the therapy performs its function, the materials biodegrade into nutrients for the cells within 12 weeks and then completely disappear from the body without noticeable side effects.

“The signals used in the study mimic the natural proteins that are needed to induce the desired biological responses. However, proteins have extremely short half-lives and are expensive to produce,” said Zaida Álvarez, PhD, first author on the study. “Our synthetic signals are short, modified peptides that—when bonded together by the thousands—will survive for weeks to deliver bioactivity. The end result is a therapy that is less expensive to produce and lasts much longer.”

While the new therapy could be used to prevent paralysis after major trauma (automobile accidents, falls, sports accidents, and gunshot wounds) as well as from diseases, Stupp believes the underlying discovery—that “supramolecular motion” is a key factor in bioactivity—can be applied to other therapies and targets.

“The central nervous system tissues we have successfully regenerated in the injured spinal cord are similar to those in the brain affected by stroke and neurodegenerative diseases, such as ALS, Parkinson’s disease, and Alzheimer’s disease,” Stupp said. “Beyond that, our fundamental discovery about controlling the motion of molecular assemblies to enhance cell signaling could be applied universally across biomedical targets.”

“Currently, there are no therapeutics that trigger spinal cord regeneration,” said Stupp, an expert in regenerative medicine. “I wanted to make a difference on the outcomes of spinal cord injury and to tackle this problem, given the tremendous impact it could have on the lives of patients. Also, new science to address spinal cord injury could have impact on strategies for neurodegenerative diseases and stroke.”