Lab-Grown Spinal Cord Model Replicates Injury and Tests "Dancing Molecules" Therapy

Scientists at Northwestern University have developed an innovative lab-grown model utilizing human spinal cord organoids that accurately replicates injury responses and could accelerate regenerative therapies. For the first time, the model successfully replicated cell death, inflammation, and glial scarring, a dense barrier that blocks nerve regrowth.

Organoids are mini versions of organs grown from stem cells that mimic real tissue structure and function. Using injured human spinal cord organoids, researchers tested "dancing molecules," a therapy previously shown in animals to reverse paralysis and repair tissue. Treated organoids showed significant neurite outgrowth, the long projections that connect nerve cells, and the scar-like tissue diminished.

The therapy, introduced in 2021, uses molecular motion to repair traumatic spinal cord injury. Injected as a liquid, it gels into a network of nanofibres that imitates the extracellular matrix, the natural scaffold around spinal cord cells. Fine-tuning the molecules' collective motion improves their engagement with cell receptors. In mice, a single injection given 24 hours after severe injury helped the animals walk again within four weeks.

Samuel I. Stupp, the study's senior author and inventor of the therapy, stated that one of the most exciting aspects of organoids is that they can be used to test new therapies in human tissue. Short of a clinical trial, it's the only way to achieve this objective. After applying the therapy, the glial scar faded significantly to become barely detectable, with neurites growing, resembling the axon regeneration seen in animals. This is validation that the therapy has a good chance of working in humans.

To model spinal cord injury, the team created two common injuries: a laceration with a scalpel and a compressive contusion, similar to damage from a serious crash or fall. Both caused cell death and glial scar formation, as seen in real injuries. The team also added microglia, the brain's immune cells, to simulate inflammatory responses. Researchers were the first to introduce microglia into a human spinal cord organoid, meaning the organoid has all the chemicals that the resident immune system produces in response to an injury, making it a more realistic, accurate model of spinal cord injury.

Applied to injured organoids, the liquid therapy gelled to form a scaffold, calmed inflammation, reduced scarring, extended neurites, and encouraged orderly nerve growth. In spinal cord injury, axons, a type of neurite, are often severed, disrupting nerve communication and causing paralysis; regenerating these projections could help restore function.

Before developing the injury model, researchers tested the therapy on a healthy organoid. The dancing molecules spun out long neurites on the surface of the organoid, but when molecules that had less or no motion were used, nothing was observed. This difference was very vivid. The remarkable efficacy of this therapeutic approach is attributed to the supramolecular motion of the molecules, allowing for frequent interactions with cellular receptors.

The therapy has received Orphan Drug Designation from the U.S. Food and Drug Administration. Next, the team plans more advanced organoids, including models of chronic injury with tougher scar tissue, and ultimately personalized implants grown from a patient's own stem cells to avoid immune rejection.

This work, published in Nature Biomedical Engineering, emphasizes not just the potential for advances in therapy but also the transformative role of organoids in nurturing a deeper understanding of human physiology and pathology. Organoids allow researchers to expedite their investigations and reduce costs relative to both animal experiments and human clinical trials.