There may be new hope for diabetics who have lost the use of a limb to vascular disease.

An injectable regenerative gel causes new vessels to grow and restore blood flow in the limbs of diabetic mice with severe vascular disease, and the inventors of the experimental therapy say it could be ready for clinical testing in just a few years.

Peripheral vascular disease is an expensive and often devastating medical condition that affects millions of people and has no long-term treatment options. It is especially prevalent among diabetics, and up to 25 percent of diabetic patients with peripheral vascular disease require amputation. In a recent demonstration using diabetic mice, researchers led by Aaron Baker, a professor of biomedical engineering at the University of Texas at Austin, showed that their regenerative gel restored 85 percent of normal blood flow to limbs with diseased blood vessels.

Today’s clinical options—physical therapy, drugs, surgically placed stents, and bypass surgery—are only temporary fixes, says Baker. Peripheral vascular disease eventually causes them to fail. This has led scientists to experiment with therapies based on proteins called growth factors, which are instrumental in the creation of new blood vessels during wound healing and in the growth of tumors. The idea, Baker explains, is to bypass the diseased vessels with new ones generated by “your own regenerative processes.”

The image at bottom right shows how growth factors combined with a protein called syndecan-4 increase the formation of blood-vessel-like structures in a cell culture model. The upper left panel shows a control that got no drug. The upper right shows the effect of delivering the growth factor alone, and the bottom left shows the effect of delivering the syndecan-4 alone.

But this approach has so far not worked well in humans. Baker says his group’s research suggests this might be because diabetes causes the loss of another protein, without which the growth factors don’t work. In healthy tissue, the protein, called syndecan-4, is embedded in the surface of blood vessel cells, where it’s believed to play an important role in a cellular signaling process that leads to the formation of new branches.

In the recent study, gel containing growth factors as well as syndecan-4 performed substantially better than growth factors alone. Baker and his colleagues think the protein could be the key to an effective regenerative therapy, and the researchers recently received a three-year $2.7 million grant from the U.S. Defense Department to advance the drug through preclinical testing.

The formation of new blood vessels is a complex phenomenon that seems to depend not only on biochemical signals but also on mechanical ones, says Lance Munn, a professor of radiation oncology at Massachusetts General Hospital. Munn, who studies how new vessels form in tumors, says that although scientists have identified many of the key players, it’s still not clear how they work together to form new vessels—and how that depends on the specific context, such as a disease like diabetes or a tumor. So it’s hard to know at this point exactly how and why the new therapy might be working.

Nevertheless, it could be that syndecan-4 is the “missing link” whose absence has made previous experimental therapies based on growth factors ineffective, says Richard Smalling, a cardiologist and director of interventional cardiovascular medicine at the University of Texas Health Science Center at Houston. Smalling is now working with Baker to design and run preclinical trials in larger animals.