Editor’s note: As is well-known, consumer demand exists for active products that provide drug-like effects for cosmetic benefits, such as those described here. Product developers are reminded that the US Food and Drug Administration (FDA) reviews label claims to determine whether a product requires drug registration or may be classified as a cosmetic. In addition, it should be noted that human materials are banned from use in cosmetics in the European Union.
With marketing using superficial terms such as crow’s feet, zits and liver spots, it is easy for consumers to overlook the important fact that human skin is a dynamic, living organ, and since cosmetic appearance is a driving force in consumer perception, skin care studies and research often focus on the effects of moisture-bearing properties to plump dead, keratinized surface cells. Skin care is obviously much more than what is seen on the surface, which is why it is important to understand how cells grow, survive and reproduce in the human body. Understanding these mechanisms provides keys to unlocking diseases that result from abnormal cell development—e.g., physical deformities, senile dementia, slow wound healing and tumors.
In recent years, a growing body of medical research has developed from heightened interest in advancing the processes of wound healing and tissue regeneration with the ultimate goal of identifying a process for scarless wound healing and successfully transplanting tissues engineered from stem cell progenitors. Through this research, human growth factors (HGFs) have emerged as being critical components in cutaneous wound healing with tremendous potential for skin cell rejuvenation. It is important that readers not mistake HGF for human growth hormone (HGH), which is produced by the pituitary gland as a single protein and is associated with stimulating the growth of musculoskeletal tissue.
HGFs: Roles and Results
HGF proteins are produced naturally by ribosomes in many different cell types throughout the body and bind to receptors on the surface of cells primarily to activate cellular proliferation and/or differentiation.1 Growth factors play many key roles (see Figure 1), including:
- acting as chemical messengers between cells;
- turning a variety of cellular activities “on” and “off”;
- increasing the rate at which cells in the body grow;
- and participating in cell division, new cell and blood vessel growth, and collagen and elastin production and distribution.
Many growth factors are quite versatile and stimulate cellular division in numerous different cell types; others are specific to a particular cell type (see Growth Factors and Their Sources). HGF is involved in the growth and regeneration of many different cells in the body, including fibroblast, liver, vascular, thyroid, ovary and pituitary gland cells.
In the skin, aged cells absorb nutrients from HGFs and revert to a more youthful state through angiogenesis and collagen production, among other mechanisms, especially in the facial area (see Figure 2). Similarly, research has indicated that the local application of HGF on areas of the human body damaged by surgery, burns, wounds or accidents increases the rate of healing.2
The FDA allows the use of growth factors in cosmetics because they are found naturally in the body and act locally3 as paracrine and autocrine substances and not endocrine substances4—although, as noted, readers should bear in mind that human materials are banned from use in cosmetics in the European Union.
History of HGF Efficacy
In 1986, scientists Stanley Cohen and Rita Levi-Montalcini were awarded the Nobel Prize in Physiology or Medicine for their work in understanding the role of Epidermal Growth Factor (EGF) and Nerve Growth Factor (NGF) in cell biology. Their research laid the groundwork for current clinical applications of HGF for treating skin conditions and reversing the signs of aging, as well as healing wounds on the cornea of the eye and on the skin.5, 6 Since these 1986 findings, a broader body of research has expanded the knowledge of HGF to include not only EGF, but also other major human growth factors including:
- TGF-b(1-3) (Transforming Growth Factor Beta) to help stimulate collagen, inhibit cellular break down and enable cells to locate nutrients;
- PDFG (Platelet Derived Growth Factor) to help activate wound healing, fostering new skin growth; to reduce scar tissue; and to form stronger blood vessels;
- GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor) to restore the response of blood cells to the breakdown of the skin structure, thus: counteracting infection, e.g., acne; evening out skin discoloration, e.g., hyperpigmentation; reducing inflammation, e.g., rosacea; and brightening a dull appearance; and
- Interleukins (IL3, IL6-8) to help enhance natural cell defenses, balance cell nutrients and improve the anti-inflammatory response.7
In 1994, cosmetic patents of early HGF technology were issued and introduced growth factors into the topical skin care industry. In 2001, two independent double-blind studies were presented to the Society of Investigative Dermatology in Washington, DC that tested topical creams containing natural and bioengineered HGF. Both were found to produce better visual results on the skin surface when used twice daily for 4–6 weeks than procedures involving Botulinum toxina. In addition, each study showed significant increases in the production of collagen, hyaluronic acid, elastin, fibroblasts and epidermal thickness.8
In 2003, further studies were conducted using twice daily applications of a cream containing HGF and cytokine, since growth factors and cytokines are typically released together from fibroblasts and act synergistically.9 Results were obtained through direct measurements of the skin surface topography in vivo at a high resolution. The skin surface roughness was shown to significantly decrease between 10% and 18%, depending on the roughness parameter, after two months. This was compared with a placebo formulation that produced an approximate 10% decrease of two roughness parameters, whereas the remaining parameters remained unchanged.9
A secondary study10 investigated a skin serum containing a proprietary blend of HGFs and cytokines in combination with antioxidant factors. Completed by 79 male and female subjects between ages 30 and 78, the study revealed that wrinkles, lower eyelid bags or sagging, dark circles and skin texture improved by 92% on average after six weeks of twice daily application. These observed improvements were confirmed by the subjects on a questionnaire, where subjects reported feeling the overall look of their skin improved by 78% on average. All subjects tolerated the eye cream well and were pleased by the ease of application and feel of the serum on the skin.
The efficacy, tolerability and sensory properties of the test formula explain why 98% of subjects reported they would continue the regular use of the product.11 This study corroborates that the topical application of growth factors and cytokines are beneficial in reducing the signs of skin aging on the face, including the area around the eyes.
In 2007, an HGF topical serum study was conducted with 20 patients between the ages of 25–72 who received one of four unlabelled products, including one placebo.12 Results of the study indicated a 94% overall improvement in skin, including: an 85% improvement in skin texture/smoothness; a 79% increase in skin firmness and elasticity; and an 87% reduction in fine lines and wrinkles. The results were based on physician ratings, subjective ratings and objective measures, such as wrinkle count based on clinical photographs taken before and after treatments.
Application of HGFs
Despite the described positive results, there are a few stumbling blocks to making HGF technology widely available, chiefly the cost of bioengineering HGF derived from human sources. Stabilizing the shelf life of naturally sourced HGF and purifying HGF to smell and feel pleasant are others. However, advances in cell sorting, cell culture and protein extraction technology now provide a consistent source and quality process for human fibroblast media collection, shelf life stability and enhanced cosmetic aesthetics.
Specifically, cell sorting techniques now allow only the early stage, healthy fibroblasts to be identified and included in the manufacturing process, excluding other cell types and damaged cells from the culture. Further, advances in cell culture methodologies have given rise to healthier cells with proper phenotypes, where the cells are in a state such that the release of the growth factors and cytokines is optimal. Moreover, extraction technology now provides that proteins are extracted in their full compliment and native state without detrimental conformational changes that would render the protein inactive or less efficacious.
Having followed the described studies and collaborated with immunologists and researchers, the author’s company sought to develop an HGF technologyb for application into a skin care line. Initial consumer response indicates, as anticipated, the products reduce the appearance of wrinkles and repair photodamaged skin without side effects. Currently, a clinical study is under way to examine the cosmetic effects in more depth, with the final results expected in 2011.
Formulating with HGFs
The key to employing HGFs such as the technology described is using them as a system of proteins, which is how they occur naturally in the human body, rather than as separate chemicals taken from a shelf and blended together. To develop the described products, the author’s company used a system of proteins like that produced in young, healthy skin that was carefully reproduced in the laboratory; therefore, working with suppliers skilled in the production of such products is critical to producing efficacious products.
With the doors to stem cell research being opened more broadly, both socially and scientifically,13 the industry can anticipate a significant number of new developments not only in substantiating the role of HGFs in skin cell regeneration, but also in discovering other reparative factors. This will advance the industry’s ability to develop products that impart good cosmetic results and that provide preventative health benefits to allow consumers to lead healthier, longer lives.
- CP Kiritsy and SE Lynch, Role of growth factors in cutaneous wound healing: A review, Crit Rev Oral Biol Med 4 729 (1993)
- TJ Wieman, JM Smiell and Y Su, Efficacy and safety of a topical gel formulation of recombinant human platelet-derived growth factor-BB (becaplermin) in patients with chronic neuropathic diabetic ulcers. A phase III randomized placebo-controlled double-blind study, Diabetes Care 21(5) 822–827 (May 1998)
- MC Robson, Exogenous growth factor application effect on human wound healing. Progress in dermatology, AN Moshell, ed., Dermatology Foundation 30(3) 1–7 (1996)
- E Canalis, TL McCarthy and M Centrella, Growth factors and cytokines in bone cell metabolism, in Annual Review of Medicine 42(17–24) (Feb 1991)
- GK Naughton, PhD, J Mansbridge and G Gentzkow, New developments in growth factors. A metabolically active human dermal replacement for the treatment of diabetic foot ulcers, Artif Organs 21(11) 1203–10 (1997)
- From lab bench to market: Critical issues in tissue engineering, Annals of New York Academy of Science, 961: 372–85 (2002)
- A Gabriel, MD, Wound Healing Growth Factors available at: www.emedicine.medscape.com/ article/1298196-media (May 27, 2009)
- EJ Kim, HY Park, N Puri, M Yaar and BA Gilchrest, The effect of vascular endothelial growth factor on normal human melanocytes, presented at the Society of Investigative Dermatology Meeting, Washington D.C. (2001), Brit J Dermatol online 153(1) 29–36 (June 2005)
- Fitzpatrick and Rostan, Reversal of photodamage with topical growth factors; A pilot study, J Cosm Laser Therapy 5 25-34 (2003)
- Mehta and Fitzpatricj, Endogenous growth factors as cosmeceuticals, J of Drugs in Dermatology 6(10) 1018–23 (Jul 2007)
- G Maguire, PhD; A Ibrahim; J Grosso, MD; M Grosso; and A Al-Qahtani, MD, PhD; Active serum role in skin rejuvenation and in wrinkle diminishment (white paper), A&G Skin Solutions Inc., available at: www.agskinsolutions.com/science.html (2007)
- Mehta and Fitzpatrick, Endogenous growth factors as cosmeceuticals, Dermatologic Therapy 20 350–359 (2007)
- G Maguire, President Obama cuts some restrictions on stem cell research, Chemical and Engineering News (2009)