Regrown blood vessels have staying power

U. PITTSBURGH (US) — A minimally invasive method that delivers growth factor to regenerate blood vessels could be used to effectively treat heart disease.

When growth factor compound was injected under the skin of mice, scientists were surprised to see that substantial blood vessels grew.

“We had structures that resembled arterioles—small arteries that lead to a network of capillaries,” says Yadong Wang, professor bioengineering at the University of Pittsburgh.


Furthermore, the structures stuck around. At least a month later, after only one injection of the growth factor complex, the new blood vessels were still there.

The research is published in the journal, Proceedings of the National Academy of Sciences.

In the human body, growth factors control a variety of functions, including cell proliferation, migration, and differentiation. There are even growth factors that inhibit growth of certain cell types or cause cell suicide. “They are very potent molecules,” says Wang.

Because they are so powerful, the body keeps a tight rein on growth factor, quickly destroying free-floating growth factor. The half-life for most growth factor injected under the skin is short-lived—only 30 minutes or less.

With this limitation in mind, the researchers investigated ways to use growth factor efficiently and hit on heparin, one of the molecules that bonds growth factor to its receptor on the cell’s surface. When it binds to the receptor and the growth factor, heparin actually increases the activity of growth factor and stabilizes it.

“Our idea was, ‘et’s use heparin as is, without any modification, to stabilize the growth factor and also to present it to the receptor, ” says Wang.

But there was a catch: When heparin is bonded to growth factor, the resulting substance is water-soluble.

Because the human body is mostly water, when the complex is injected into the body, it dissolves within seconds, so the researchers had to figure out a way to keep the complex from dissolving long enough for it to do its work of regenerating blood vessels.

The trick, they discovered, was to use a polycation—a molecule with multiple positive charges. Heparin has several negative charges. If it’s neutralized with a polycation, it can be brought out of solution into what is called a coacervate—an aggregate of tiny oil droplets.

In this first-ever report of using coacervate for the controlled delivery of growth factor, the team delivered fibroblast growth factor-2. This led to extensive and persistent new blood vessel formation. The team used only one growth factor to induce the formation of mature blood vessels. These vessels were stabilized by special cells called mural cells.

Wang has gone on to use the delivery platform to study the controlled release of other growth factors that bind heparin: nerve growth factor, vascular endothelial growth factor, epidermal growth factor, bone morphogenetic proteins, and many others. “In all cases, the controlled delivery using coacervate was much more effective,” he says.

The complex is highly efficient: Since the heparin and growth factor are both active ingredients, and polycation is added only to bring it out of the water, as much growth factor as necessary can be delivered.

“High loading efficiency is important because it allows us to reduce the frequency of injections,” Wang adds.

Healing a broken heart

Because the coacervate is not very viscous, “you can use a needle as thin as a hair” to inject it, says Wang. “So if you inject that through tissue, the damage you create is very small.” It could be done through a catheter, a long tube with a needle through it. This means the chest wouldn’t have to be opened up—a huge advantage over open-heart surgery.

“After a heart attack, the muscle is dead, and what’s replacing it is scar tissue—a lot of collagen, but not many cardiac muscle cells. No muscle, no contraction,” says Wang.

Once a heart attack has happened, the patient generally has two choices: Get a stent to open the blockage, or have surgery to bypass it. The heart tries to heal itself, but its self-remodeling efforts can have deleterious effects, like dilating ventricles until they’re too big.

“If we can use growth factors to reverse that kind of adverse remodeling process, then we can probably rescue the heart function, which is the most important thing,” notes Wang.

The growth factor complex would be injected right after the heart attack, or a few days later, to change how the heart repairs itself.

“Our hope would be to reduce scarring, keep as much of the muscle alive as possible, and induce quick blood vessel formation to bring as many nutrients as possible in order to reestablish an environment for muscle growth,” Wang says.

Eventual human clinical trials and using a disease model to investigate the efficiency of the treatment in heart attacks are part of future research plans, Wang says. ‘This treatment is very promising in bench-to-bedside translation.”

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