A team of researchers has developed a novel brain imaging method that can diagnose mild traumatic brain injuries (mTBIs), even when conventional imaging techniques such as magnetic resonance imaging (MRI) fail to detect any structural abnormalities. This groundbreaking technique involves the use of gadolinium, a standard MRI contrast agent, loaded into hydrogel-based micropatches that are attached to immune cells called macrophages.
mTBIs are known to cause inflammation in the brain, which triggers signals that attract macrophages to migrate to the affected area. By coupling the gadolinium contrast agent to these immune cells, the researchers were able to utilize MRI to detect brain inflammation and improve the accuracy of mTBI diagnosis. The findings of this study are published in Science Translational Medicine.
Mild traumatic brain injuries, categorized as ‘mild,’ account for 70 to 90 percent of reported cases. However, as many as 90 percent of mTBI cases go undiagnosed, even though the effects can persist for years and increase the risk of various neurological disorders such as depression, dementia, and Parkinson’s disease. “Our cell-based imaging approach takes advantage of immune cells’ innate ability to migrate to the brain in response to inflammation, enabling us to identify mTBIs that standard MRI imaging would miss,” said senior author Samir Mitragotri, Ph.D., a Core Faculty member of the Wyss Institute at Harvard University.
Mitragotri and his team aimed to create a more effective diagnostic tool by leveraging their expertise in manipulating immune cells. Their strategy was to attach gadolinium molecules to macrophages, which are known to infiltrate the brain during inflammation. However, they encountered an obstacle as gadolinium requires interaction with water to function as a contrast agent in MRI scans.
To overcome this challenge, the researchers developed a new hydrogel-based backpack that could be manufactured at a large scale. After years of meticulous research, they successfully produced microparticles named M-GLAMs (macrophage-hitchhiking Gd(III)-Loaded Anisotropic Micropatches) capable of generating a strong gadolinium-mediated MRI signal. These microparticles also exhibited stability when attached to both mouse and pig macrophages and retained the gadolinium cargo for a sustained period.
In collaboration with researchers and clinicians at Boston Children’s Hospital, the team tested their M-GLAMs in live animal models. They injected the microparticles into mice and pigs to assess their visibility in vivo and evaluate gadolinium concentration in the brain. The results demonstrated that the M-GLAMs accumulated in the choroid plexus, a known conduit for immune cell entry into the brain, thus highlighting the presence of inflammation. Importantly, the M-GLAMs did not pose any toxicity risk to the animals.
Furthermore, M-GLAMs enabled better imaging with significantly lower gadolinium doses compared to existing contrast agents. This aspect is particularly important for patients who are unable to tolerate current contrast agents due to kidney problems or other complications.
The researchers acknowledge that while the M-GLAMs can indicate the presence of brain inflammation, they are unable to pinpoint the exact location of injuries or inflammatory responses within brain tissue. However, when combined with new treatment methods, such as the one developed in another recent study by the same team, M-GLAMs show potential for rapid and effective identification and reduction of inflammation in mTBI patients, minimizing damage and expediting recovery.
The team has filed a patent application for their innovative technology and aims to collaborate with biotech and pharmaceutical companies to fast-track its progression into clinical trials. The potential of immune cell utilization for various medical functions, including health monitoring, disease diagnosis, treatment, and prevention, is vast. Donald Ingber, M.D., Ph.D., Wyss Founding Director, expressed his admiration for the team’s innovative approach and hopes to see this technology in the hands of clinicians in the near future.
