by Charles Q. Choi

When the body gets wounded, it naturally generates molecules known as growth factors that are critical to helping it heal. Now researchers have engineered new versions of these growth factors that can help repair wounds and bone defects in mice faster and more effectively than their own natural versions.

Scientists have long sought to use growth factors to help the body regenerate. These chemicals have led to therapies that help promote new blood vessel and bone formation.

However, low healthy doses of growth factors are often not as useful as one might like, while larger doses “have the potential to be harmful, by generating tissue like bone where you don’t want bone or by inducing cancer,” says Jeffrey Hubbell, a bioengineer at the Swiss Federal Polytechnic School of Lausanne. “Growth factors have gotten, as a class, a bit of a black eye.”

Hubbell and his colleagues reasoned some of the problems associated with the potentially therapeutic use of growth factors were related to how researchers did not bind these molecules properly with the extracellular matrix, the structure that surrounds and supports cells and tissues.

“We have been studying the basic biology of the interactions between growth factors and the extracellular matrix for several years, and we have through that research become convinced that a major limitation in the use of growth factors in medicine was that they were not being used in their physiological context,” he says. “The context can make or break many topics — I love a good hamburger, but in the shower it does not taste so good.”

Finding the right home for growth factors

The scientists determined that growth factors naturally work closely with the extracellular matrix, mostly by being bound to it. They reasoned they could improve healing by enhancing the way these molecules bind to the extracellular matrix.

They tested 25 well-known growth factors against six key proteins that make up the extracellular matrix. They found one growth factor, a protein known as placenta growth factor-2 (PIGF-2), was the best at binding to all six extracellular matrix proteins.

Hubbell and his colleagues then borrowed the little snippet of PIGF-2 that made it bind powerfully to the extracellular matrix and grafted it onto three other growth factors. Each of those had experienced problems being adapted for clinical use, “and we wanted to show that we could improve all three,” he says.

The molecules they augmented were vascular endothelial growth factor (VEGF), which triggers blood vessel formation crucial for the repair of most tissues; bone morphogenetic protein–2 (BMP-2), which triggers the formation of new bone; and platelet-derived growth factor–BB (PDGF-BB), which recruits stem cells that help wounds regenerate.

The scientists discovered their changes increased the affinity at which this trio of growth factors bound to the extracellular matrix by two- to 100-fold. “We developed a rather simple protein-engineering method—indeed, in the end, the most powerful methods are the simplest methods,” Hubbell says.

When the researchers tested these modified proteins on injured mice, they found the new growth factors greatly enhanced their recovery. For instance, the mice experienced much faster wound closing, greater formation of new blood vessels and substantially more bone growth. In fact, the team found that the engineered molecules sped wound closure by about 50 percent compared with the same amount of regular growth factors.

“What surprised me most was how well it worked in each of the three examples we tested,” Hubbell says. “The improvements when using the protein-engineering approach were not subtle, but rather very obvious even without statistical analysis.”

Initial results good, clinical trials still far off

The investigators noted that with these changes, they could reduce the dose of therapeutic growth factors by 10- to 100-fold in mice. “If we can do that in the human clinic, we think that that is a tremendous benefit in terms of reducing unwanted side effects,” he says.

They are now fusing the PIGF-2 sequence to other growth factors. “We are hotly pursuing other areas, such as cartilage repair in osteoarthritis, regeneration in hearing loss and spinal cord repair,” Hubbell says.

They now plan to extend their studies to larger animals and eventually begin preliminary human trials. “To move from the rodent to man is a huge step and should not be underestimated,” Hubbell says. “We have a lot of work left to do."

The researchers caution that sometimes much is made about the ability of some animals like newts to regenerate entire limbs. "We are a long, long, long way from that,” Hubbell says. “And other tissues are very difficult, such as the heart muscle — we are also a long way from that.”

The scientists detailed their findings in the Feb. 21 issue of the journal Science.

Top Image: via Shutterstock.