"Stents have been known to induce severe trauma," says Robert Levy, chair of pediatric cardiology at the Children's Hospital of Philadelphia. "Repairing blood vessels with cell therapy is a very important concept that can be realized with magnetic targeting."
Levy and his colleagues engineered nanoparticles, or tiny spheres, of polylactic acid, a biodegradable polymer used in sutures and other medical applications. The team then loaded each nanoparticle with a small dose of magnetically responsive iron oxide and inserted it into a bovine endothelial cell--a cell found in a blood vessel's inner lining. The bovine cells were genetically altered to express a fluorescent marker, making them easily detectable.
Next, the researchers surgically implanted small metal stents in the carotid arteries of live rats. They injected the rats with a solution of treated endothelial cells and created a steady magnetic field around each rat using two large, external electromagnetic coils. Levy says that the magnetic field he and his colleagues applied was less than a tenth of the strength of the fields generated by conventional MRI machines. After 48 hours, the team created images of the rat using bioluminescence imaging.
The researchers found that the magnetic field caused the cells to migrate to the metal stents under two scenarios: when cells were injected directly into the carotid artery, near the stent location, and when they were injected farther away, in the aortic arch, whence they could have branched out to all areas of the body. In tests that didn't use a magnetic field, the cells migrated throughout the body with little direction.
Magnetically directing cells, particularly endothelial cells, to the sites of metal stents may have a significant therapeutic effect, says Levy. During surgical implantation, stents tend to scrape off endothelial cells, whose normal functions include helping prevent blood clotting. Endothelial cells are also barriers to inflammatory cells. While inflammatory cells normally flock to an injury to help repair it, in the absence of endothelial cells, they build up excessively, creating arterial blockage. In recent years, stents have been engineered to release anticlotting drugs to prevent arteries from reclosing. But such drug-releasing stents have problems of their own, including preventing endothelial cells from regenerating.
"Two years ago, clinicians noticed that patients in significant numbers were having problems with these stents, probably because the endothelium wasn't properly healed," says Levy. "Clotting, myocardial infarctions, and sudden deaths occurred, and this has caused a big uproar over stent usage."
Levy hopes that magnetically directing new endothelial cells to blood vessels may solve many of the problems that stents currently face. His team plans to continue experimenting on rats, using endothelial cells derived from rats instead of cows, to minimize risk of rejection. Now that he has found a way to direct cells to metal stents, Levy is also looking at other potential therapies, including nitric oxide, which is known to relax and dilate blood vessels. He is currently engineering cells to genetically express enzymes that produce nitric oxide, and he will eventually load them with iron-oxide nanoparticles that will drive them to the sites of stents, further opening arteries.
Levy adds that the magnetic-based technique has applications outside of cardiovascular therapy. For example, in treating lung cancer, clinicians often use metal stents to keep airways open. However, a patient's tumor may continue to grow, eventually obstructing the passage despite the stenting. Magnetically targeted therapies could help deliver specific drugs to stent sites to treat tumors, in addition to keeping airways open.
"Metallic implants are also widely used in other areas, like orthopedics, for complex fractures, and correcting spinal curvature, where cell therapies could also be helpful," says Levy. "Steel implants are widely used in medicine, and there are all sorts of situations where applications could be used."
What's more, Levy envisions that such therapies can be applied using conventional MRI machines. The magnetic field generated by MRI cores is an order of magnitude more powerful than the ones Levy used in his experiments, so fewer iron-oxide nanoparticles could produce the same effect.
Robert Langer, Institute Professor at MIT, believes that Levy's technique is a promising step toward directed cell therapies. "They were able to localize more drugs into the targeted areas," he says. "I think it's a neat idea that has a lot of potential."
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