The search continues for skin growth triggers
Complex variables make the hunt difficult
The reason roughly 2,300 topically applied wound treatment agents are on the market is simple: No single one effectively heals all chronic wounds in all situations. But the search is still on. Among the promising contenders are growth factors. What are they, how do they promote wound healing, and can they be harnessed effectively to treat chronic wounds?The term "growth factors" describes a family of short-chain proteins that trigger the healing process by enhancing cellular growth or movement.1 Growth factors also are called cytokines, interleukins, and peptides. Little hard evidence exists to prove that growth factors are definitely involved in the wound healing process, says Vincent Falanga, MD, a dermatologist at the University of Miami School of Medicine.
Role of growth factors remains a mystery
"Most of the evidence rests upon the presence and association of growth peptides during wound repair," he says.2 In vivo testing has shown that growth factors often are associated with the initiation of a cascade of events involving either cellular mitogenesis and proliferation or chemotaxis.
"Some of these molecules, when added to cells in cultures, stimulate growth or stimulate the production of important molecules in the matrix that holds them together," explains Jeffrey M. Davidson, PhD, professor of pathology at the Vanderbilt University School of Medicine and a research scientist at the Department of Veterans Affairs Medical Center in Nashville, TN. "We’ve found that the availability of these molecules might be limited in certain wound healing situations. In diabetic animals, for example, it was very easy to determine that the number of growth factors is reduced in concentration. When we added certain of these molecules back into the system, they had a positive effect."
But it hasn’t turned out to be a matter of putting the right key in the right lock. Many obstacles to understanding have arisen. The process of wound healing is so complex and so little understood that the role of growth factors remains shrouded in questions, and research is hampered by countless variables, such as timing, sequence, amount, availability, and duration of treatment, each of which can have a major impact on healing.
The interplay of these variables makes it extremely difficult to pinpoint which growth factor plays what role in healing and when it is activated by the body’s response mechanisms. In addition, growth factors have highly complex relationships with other cells.
"Growth factors don’t act alone. They have to cooperate with each other and synergize with everything that’s happening around them in a wound to have a beneficial effect," explains Liza Ovington, PhD, program director for wound and continence management at Columbia Healthcare Corp. in Ft. Lauderdale, FL.
Topical use may not be the answer
"The idea is that in the natural process there’s a substance that accelerates wound healing, and if you identify it and make a truckload of it and throw it on a wound, it will make the wound heal faster. That has not turned out to be true," Ovington says. "We’ve found out that certain growth factors applied in a certain amount do one thing, such as increase connective tissue growth, and another amount has a very opposite effect."
A further confounding element is that growth factors are susceptible to the "battleground" conditions of a wound, Davidson explains. "Growth factors start acting most prominently after acute inflammation is under control. Sometimes tissues get locked into that phase, then the [growth factor] molecules have a hard time working." Sometimes they are destroyed.
There’s no question that growth factors are very powerful molecules, Davidson adds. The question is why it takes so much material to get a significant effect, and why have so many clinical trials been unsuccessful? One possibility is that applying growth factors topically is the wrong approach, he says.
Davidson and his colleagues at Vanderbilt are working with a device informally called a "gene gun," which is used to shoot microscopic gold particles covered with recombinant DNA into the epidermis. The DNA has been engineered to express growth factors for a few days and thus is able to introduce the molecules in a potentially more effective manner at the right time and for the right duration during the wound healing process.
So many variables
Davidson describes the wound healing process as an "intricate symphony" during which many different players come and go at specific times. It has thus been extremely difficult to determine the correct combinations and sequences of growth factors to use.
"Even at the laboratory level, setting up these experiments requires complex matrix design," he says. "There are so many variables. It’s going to take quite a while to sort this out."
Researchers such as Falanga remain optimistic: "If one looks at the development of most drugs, it becomes evident that an extended period of time is necessary before the proper use and full range of activities of the drug in treating human disease become apparent. In many cases, initial treatment failures are due to faulty expectations as well as inadequate dosing and delivery systems. It is my opinion that growth factor therapy will follow a similar course but that it ultimately will have a role in the modulation of wound repair."2
References
1. Ovington LG. Innovative therapies for wound management. Podiatry
Today March 1997:46-49.
2. Falanga V. Growth factors and wound healing. Derm Clinics 1993;
11:667-675.
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