A novel fusion protein that includes growth factor and self-assembles into nanoparticles holds promise as a platform for wound healing, researchers say. In a study conducted in mice, a construct of keratinocyte growth factor (KGF) and an elastin-like peptide (ELP) - a major structural component of skin and connective tissue promoted greater healing than either component administered separately or together.
In a study conducted in mice, a construct of keratinocyte growth factor (KGF) and an elastin-like peptide (ELP) - a major structural component of skin and connective tissue promoted greater healing than either component administered separately or together.
Clinical use of growth factors has been disappointing because they are readily absorbed into the bloodstream, meaning that repeated reapplication is needed to achieve even modest benefit. Growth factors also are expensive to manufacture.
They genetically fused an elastin polypeptide and keratinocyte growth factor.
"Because of the physical properties of the elastin polypeptide, when the fusion protein is exposed to physiological temperatures, it immediately comes out of solution and forms the center of a small ball, with the growth factor displayed on the outside of the ball," Dr. Yarmush says.
"It is a very elegant approach for making nanoparticles; it is very easy to purify and make in large quantities," he says. "The longevity of the particles within the skin will allow it to heal better and faster, and hopefully get better results for patients.
"The nanoparticles will remain in the skin longer than if you just add the KGF itself. (This) provides you with a mechanism for improved local drug delivery that is better than just smearing the KGF on the skin," he adds.
Boost in regrowth
In this study, KGF and ELP administered together resulted in re-epithelialization coverage of 31 percent. That increased to 36 percent when the fusion protein version of the two components was used. The nanoparticles also induced significant granulation in the animals.
Researchers found that administering ELP alone had no effect on keratinocyte proliferation, nor did it affect the enhancement of proliferation by KGF.
Administering free elastin had the biological effect of creating a very thick dermis, which is not necessarily a good thing, as this can result in a less-pliable skin, Dr. Yarmush says. But fusing the KGF to the elastin seemed to modulate that effect, "In which case you do not obtain a thicker dermis," he says.
Dr. Yarmush sees the work as an initial proof of concept in an animal model. He believes the elastin polypeptides can be used as a platform with other growth factors fused to it.
"KGF induces keratinocyte growth, but we may want to stimulate the ingrowth of blood capillaries, or nerves, or bring in stem cells with a stem cell-derived growth factor," he says.
Eventually, it might be possible to customize a blend of different growth factors to the type of wound to be healed. Deeper or more expansive wounds might benefit from a different mix than a smaller surface wound.
The size of the nanoparticle also might modify the therapeutic benefit and impact how rapidly the body clears the fusion protein. One of the characteristics of the elastin used in the study is that it is composed of repeat sequence blocks that can be stacked or combined to create different sizes of nanoparticles.
But further development of this new delivery platform into useful clinical products is not in Dr. Yarmush's immediate future. He sees himself more as an engineer who develops tools and believes that companies need to license the technology and carry out the development into clinical products.
Eliot N. Mostow, M.D., M.P.H., chairman of dermatology at the Northeastern Ohio Universities Colleges of Medicine and Pharmacy (NEOUCOM) at Rootstown, calls the study "very exciting and promising because it resulted in more granulation and quicker healing. It would be a shame if what they have shown here doesn't get further development."
Wounds tend to become either too dry or very moist, with the result that whatever is applied quickly gets drained, washed away or absorbed. Changing the dressing can also pull away and disrupt the healing wound, he says.
Dr. Mostow's major concerns are whether the process can be scalable to commercial levels and at a reasonable cost. The initial answer appears to be yes to both.
For more information:
Self-assembling elastin-like peptides growth factor chimeric nanoparticles for the treatment of chronic wounds. Koria P, Yagi H, Kitagawa Y, Megeed Z, Nahmias Y, Sheridan R, Yarmush ML. Proc Natl Acad Sci U S A. 2011 Jan 18;108(3):1034-1039. Epub 2010 Dec 30.PMID: 21193639.