November 14, 2001 (29)

Tissue engineering could become new coronary bypass

ANN ARBOR---A spongy plastic material impregnated with two kinds of growth factor has been shown to encourage the formation of healthy new blood vessels in living rats, according to a tissue engineering research team at the University of Michigan.

The ability to grow new blood vessels in a controlled fashion could lead to better treatments for coronary artery disease, to speed wound healing, or to help diabetic patients who are suffering from peripheral vascular disease.

"This new approach allows us to deliver a controlled dose of growth factors to a specific tissue," said David J. Mooney, a professor of biologic and materials science in U-M's College of Engineering and School of Dentistry. "To grow a replacement tissue cell by cell, you need a combination of growth factors delivered in the right sequence at the proper time and in the right place. Just injecting a large amount of it with a needle doesn't work."

Coronary artery disease occurs when blocked vessels fail to deliver enough blood and oxygen to the heart muscle itself. The coronary bypass operation, which is performed nearly 3 million times per year in the United States, involves removing an artery or vein from one part of the body and then stitching it onto the threatened area of the heart. The ribcage must be cut open, and the heart's beating is stopped during the procedure.

However, this polymer may be able to grow new vessels on site with much less invasive surgery.

Two naturally-occurring growth factor chemicals are key to the formation of proper blood vessels, VEGF, the Vascular Endothelial Growth Factor, and PDGF, the Platelet-Derived Growth Factor. But simply basting an area of tissue with both chemicals does not result in satisfactory angiogenesis, or vessel development. The vessels may form, but they end up falling apart because they are not constructed properly. And if VEGF levels fall too low, vessels are even subject to "pruning and remodeling," the researchers report.

The new polymer formulation combines proper doses of VEGF and PDGF in a way that encourages the proper structure of vessels and guides their growth for weeks. It was developed in Mooney's labs at the School of Dentistry and the College of Engineering with graduate students Thomas P. Richardson, Martin C. Peters and Alessandra B. Ennett, and was reported in the November 2001 edition of Nature Biotechnology.

In the polymer, VEGF starts the process of angiogenesis and recruits the endothelial cells which line blood vessels. PDGF then recruits smooth muscle cells to form the resilient outer layer of the artery or vein. Only with the two chemicals working together in appropriate doses do robust vessels develop. The U-M team hit on a way to release VEGF from the polymer immediately in the first few days after implantation, and then to slowly release measured doses of PDGF by using microcapsules that dissolve over time. The polymer itself will also melt away over time.

"The polymer might be used as a heart patch," Mooney said. "You'd lay a sheet of it on the muscle and it could encourage the formation of a lot of vessels through it and around it."

To test the polymer, the researchers implanted four different versions of the material under the skin on the backs of laboratory rats. One polymer held just VEGF, one just PDGF, one had both with the PDGF in time-release microcapsules, and one was just the semi-porous polymer without any added growth factors.

The VEGF by itself led to a dramatic increase in vessel formation, but the vessels were smaller than normal and were missing some of the cell types they needed to function well. PDGF by itself did not lead to any appreciable difference in the formation of blood vessels, though the existing vessels around the polymer did appear to grow larger in the presence of the growth factor.

Together, however, the growth factors created new blood vessels that were large and well-formed.

Though polymer "scaffolds" have been used in a variety of tissue engineering experiments, this is the first time multiple growth factors have been incorporated for release in a controlled-dose fashion. Mooney is confident his team will be able to impregnate a polymer with several growth factors and to release them in a timed fashion.

This new ability to deliver multiple growth factors in a controlled way has applications to many other kinds of tissue engineering beyond angiogenesis, Mooney said, since tissue formation probably rarely relies on just a single chemical signal.

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