New products containing cellular growth factors, used alone or in combination with existing products such as alpha-hydroxy-acids, are beginning to find a place in the treatment of damaged skin. Proponents believe that topical application of growth factors helps restore skin damaged by the elements and the years to a younger, healthier condition.

The past 15 years have seen an increasing array of options become available for cosmetic skin repair – most notably tretinoin, collagen and the hydroxy-acids. While each of these have proven their utility in reducing wrinkles and/or repairing photodamaged skin, each also carriers a side-effect profile requiring careful management. The early clinical studies with growth factor products suggest that the novel compounds may offer efficacious treatment of select conditions, without some of the potential side effects seen with previous approaches.

What are They?
Growth factors are a remarkable group of proteins that perform a vast array of functions in human growth and development. Endogenous growth factors perform a variety of complex roles including immunomodulation, regulation of cell division, wound healing and tissue generation.

Each member of the growth factor family binds to a unique receptor. The bound growth factor initiates or, in some cases, blocks cell division. Growth factors work alone and in concert to regulate specific types of cells and tissues. See chart.

VEGF (Vascular endothelial growth factor) for example encourages production of new blood vessels. Biotech companies developing both pro-VEGF and anti-VEGF compounds to respectively encourage or discourage new vessel growth depending on the disease being targeted. Cancer researchers are interested in inhibiting new vessel growth to starve tumors. Similarly ophthalmologists are evaluating this approach to new vessel growth in eye diseases such as age-related macular degeneration and diabetic retinopathy. At the opposite end of the spectrum cardiologists and vascular surgeons are now evaluating gene therapy with VEGF related products to encourage new vessel growth in the heart and major blood vessels, effecting a natural kind of bypass operation.

While the earliest products in this category were derived from bovine sources, growth factor enriched solutions now entering the market are derived from human sources. The growth factors are contained in liquid compounds derived from the nutrient solutions utilized in the process of creating bioengineered skin tissue. Biotech production of human skin tissue is a complex process in which fibroblasts derived from neonatal foreskins are bathed in a rich nutrient solution. Fibroblast growth factor is part of the culture medium used to produce bioengineered tissue now used for the treatment of burns, deep wounds and skin ulcers.

Researchers at a company that grows skin tissue in a unique three dimensional matrix were surprised to find that cells grown in the solution themselves produced a rich array of additional growth factors (including VEGF, keratinocyte growth factor and TGF-beta), soluble matrix proteins and anti-oxidants. Since all of these ingredients are associated with normal skin growth and healing in humans, the next obvious step was to develop and test a product for human use. Utilizing their existing aseptic facilities, the researchers developed a process for collecting and concentrating the rich solution.

Preliminary work confirmed that the nutrient solution increases the growth of new skin cells after as little as three days in vitro. Increases were noted in the growth of both fibroblasts and keratinocytes. Increased collagen deposition was also observed in treated cells grown in three-dimensional matrices.

Early clinical work indicated direct application of nutrient solution to volunteers produced no more irritation than a control solution. No adverse events or histologic abnormalities were observed. Continued testing of a solution designed to optimize skin penetration over four weeks in volunteers with sun damaged skin also produced no untoward effects.

Investigators then proceed to conduct two double-blind clinical studies, both of which were presented at the Society of Investigative Dermatology meeting in Washington, DC (May 12, 2001). In those two trials, volunteers applied the solution twice daily for 30 days and 60 days respectively. In each study statistically significant increases were seen in production of collagen, hyaluronic acid and in elastin. The researchers also reported increases in fibroblasts and in epidermal thickness.

Safety Concerns
The new product was well tolerated by patients, with no significant adverse reactions noted. In particular, the product did not produce allergic or photosensitivity reactions. However, researchers were mindful of the possibility that untested topical growth factors expresses cytokines that might stimulate the wrong kind of skin growth, e.g. precancerous and cancerous skin lesions. Extensive evaluations of both TGF-beta and VEGF have failed to demonstrate this. Indeed, keratinocytes do not have VEGF receptors. Squamous cell carcinomas appear to have their growth inhibited by VEGF. Melanomas do have receptors for VEGF, but VEGF does not appear to induce these cancers to proliferate.

The leading product now on the market undergoes exhaustive safety screening including but not limited to karyology, in vitro tumorogenicity and USP sterility testing. Microbiological screening includes assays for mycoplasma, pyrogens and endotoxin.

Place in the Clinic
The role of solutions containing growth factors in the clinic is evolving. They may have a place as stand alone products in some cases. In other cases, these products might be applied as part of a multi-step approach. For example, a patient might undergo a peel with alpha hydroxy acids followed by the application of one of these solutions to increase penetration of growth factors, reduce inflammation and speed healing.

Products containing growth factor are also more than likely to find their way into the over the counter cosmetic market. One might expect to see them appear relatively soon in everything from hand creams and hair conditioners to lip balms and make-up.