Reopening blocked blood vessels can mean the difference between life and death for many patients, including children with pulmonary hypertension and adults with coronary artery disease. But the procedure used for restoring blood flow can cause extensive vascular injury, wiping away an essential protective layer of cells lining the walls of arteries and veins: the endothelium.
It may take the body weeks or months to heal that damage. Some long stretches of damaged vessels may never fully regrow the endothelium, which naturally propagates inward from the healthy edge toward the center of the wiped-out area.
“Our idea is that if we could put some seeds of endothelium regrowth within the boundaries of this denuded arterial segment, so that the endothelium can grow from those foci, we could speed up the process dramatically,” said Michael Chorny, PhD, a researcher at The Children’s Hospital of Philadelphia and research assistant professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania, who specializes in developing delivery systems for therapies. “By changing the pattern of endothelium recovery, we may in practice restore it on scale of days.”
Speeding up this recovery process could prevent the clinical effects of endothelium loss by stopping them in their earliest stages. Endothelial cells perform many important functions. They protect the arterial walls from coming into direct contact with blood, maintain vascular homeostasis, and produce important molecules for blood vessel functioning.
When the endothelium is damaged, significant clinical problems can occur days, weeks, or even months later, including the rare problem of delayed formation of clots (late thrombosis) and the relatively more common re-hardening and re-narrowing of blood vessels (neoatherosclerosis) that is more aggressive than the original disease. These post-procedure effects are often worse in patients treated with a stent that releases antiproliferative drugs, because these drugs can interfere with endothelial regrowth.
To achieve the faster regrowth of endothelial cells and prevent these complications, the tricky part is getting the replacement endothelial cells into the right position in the damaged blood vessel. Dr. Chorny and a team of collaborators at CHOP are working on ways to pull them into place with the help of the magnetic force.
They have developed techniques to get cells, including endothelial cells, to take up biodegradable magnetic nanoparticles, and have shown that these nanoparticles do not impede cells’ biological functioning.
Magnetic nanoparticles have been in clinical use for years as an imaging agent. Simple methods also exist for deriving patient’s own endothelial cells in sufficient numbers, meaning that two steps underlying the approach are already clinically viable.
The researchers reported their latest progress in magnetically guiding these endothelial cells into damaged blood vessels in a living animal in the Journal of Controlled Release in January. The study was led by a team at CHOP including Dr. Chorny, cardiologists Ilia Fishbein, MD, PhD and Robert Levy, MD, and organic chemist Ivan Alferiev, PhD.
As part of this approach, the body is exposed to a strong, uniform magnetic field, which in future clinical applications could be generated by available equipment including magnetic resonance imaging (MRI) and magnetic navigation systems.
In the presence of this magnetic field, the nanoparticles inside cells become strongly responsive to the magnetic force. To focus this force in the diseased area, the researchers took advantage of magnetizable stents placed in the arteries — a structural support commonly implanted during the blood vessel reopening procedure that causes endothelial damage in the first place.
They showed that the magnetically guided endothelial cells were localized as intended in the region of stent placement, and that the number of cells increased over time in the week after delivery. In a comparison group where endothelial cells were not magnetically guided, the cells were not positioned effectively in the damaged stretch of the blood vessels. The next steps in research on this technique will be to work with larger animal models with human-sized blood vessels, Dr. Chorny said.
“We hope we can someday use this combination of magnetic field and a permanent or temporary stent to localize a patient’s own reintroduced endothelial cells, hopefully to achieve full restoration of the endothelium, not on the scale of months to maybe never, but in only hours or days,” Dr. Chorny said. “This way we may prevent the potential adverse effects associated with this fairly frequently used procedure.”
In other studies, Dr. Chorny has used magnetic guidance strategies to deliver different types of therapeutic agents, including small-molecule drugs, gene delivery vectors, and therapeutic enzymes. In the team’s ongoing studies focusing on restoring endothelium, they are also investigating combination techniques, such as using magnetic nanoparticles not only as a delivery method to position cells in the damaged parts of blood vessels, but also as a gene vector to make endothelial cells produce molecules that support regrowth — effectively re-seeding the scorched ground of blood vessels with cells that are their own fertilizer factories as well.