Paralyzing damage in spinal cord injury (SCI) is often caused by the zealous immune response to the injury. NIBIB-funded engineers have developed nanoparticles that lure immune cells away from the spinal cord, allowing regeneration that restored spinal cord function in mice.
Just as in the brain, the spinal cord has a blood brain barrier that protects the delicate nerves from potential damage from various insults, including blocking immune cells from moving in to clean up debris from the injury.
When the spinal cord suffers a traumatic injury, the blood brain barrier is damaged, and the rapid influx of immune cells creates an environment that aims to quickly shore-up the injury, yet also inhibits regenerative processes that can successfully rebuild and reconnect delicate damaged nerves.
Now NIBIB-grantee Lonnie Shea, Ph.D., the Steven A Goldstein Collegiate Professor, Biomedical engineering, and his colleagues at the University of Michigan in Ann Arbor have developed a strategy that redirects many immune cells away from the injury while also inducing those that do reach the SCI to switch to an anti-inflammatory profile, producing factors that foster a regenerative healing process, which can preserve function. The unique strategy is reported in the July edition of the Proceedings of the National Academy of Sciences.
Although the immune response is attempting to do its job, rushing to the site of a SCI. The rapid removal of injured cells and repair of the damaged area by immune cells often results in a buildup of fibrotic tissue that essentially fills the wound with structural cells that are not functional neurons. Recognizing this, the Michigan engineers have designed an approach that reduces immune cells at the site of the spinal injury, while also promoting greater regeneration."
David Rampulla, Ph.D., director of the NIBIB program in Delivery Systems and Devices for Drugs and Biologics
The Michigan team designed nanoparticles that can be injected into the bloodstream directly after an injury to the spinal cord. The nanoparticles employ several simple mechanisms that allow them to reprogram the immune cells: the nanoparticles mimic the small size of cell debris and so the immune cells go to work engulfing the nanoparticles. The nanoparticles are also negatively charged, which facilitates binding to the positively charged immune cells. Immune cells that are redirected from the spinal cord are ultimately sequestered in the spleen, which acts to filter-out debris and recycle components of both red and white blood cells.
Some cells do escape the diversion by nanoparticles, but overall there is a dramatic reduction in the number of immune cells that enter the wound area. The smaller number of immune cells results in the cells switching from an inflammatory to a regenerative function that supports the delicate regenerative healing process allowing growth and reconnection of the damaged neural networks.
The team tested the nanoparticles in a mouse SCI model, where they observed reduced fibrosis and increased regenerative processes. In addition, in functional studies, mice that received the nanoparticle therapy showed enhanced locomotor function.
"We hope these encouraging results could lead to a novel treatment for many of the 12,000 new spinal injury patients in the US each year," says Shea. "In addition, this nanoparticle technology may have applications in treating the significant number of diseases that are caused by an immune response ranging from arthritis to sepsis."
Park, J. et al. (2019) Intravascular innate immune cells reprogrammed via intravenous nanoparticles to promote functional recovery after spinal cord injury. PNAS. doi.org/10.1073/pnas.1820276116.