Multi-Center, Double-Blind, Vehicle-Controlled Clinical Trial of an Alpha and Beta Defensin-Containing Anti-Aging Skin Care Regimen With Clinical, Histopathologic, Immunohistochemical, Photographic, and Ultrasound Evaluation
Amy Taub MD,a Vivian Bucay MD,b Gregory Keller MD,c Jay Williams PhD,c and Darius Mehregan MDd
aAdvanced Dermatology/Skinfo, Lincolnshire, IL; Northwestern University Medical School, Department of Dermatology, Chicago, IL bBucay Center for Dermatology and Aesthetics, San Antonio, TX cGregory Keller Plastic Surgery, Santa Barbara, CA dWayne State University, Monroe, MI
LGR6-positive stem cells, there would be differentiation and proliferation of less damaged keratinocytes. Thus, using a dormant resource of our own body, defensins may stimulate the LGR6-positive cells to create a relatively new and “fresh” epidermis. In contrast, topical products that contain a variety of growth factors activate fibroblasts, keratinocytes, endothelial cells, macrophages, and other cellular elements19 that are not “young” cells; they have been present in the skin for an undetermined length of time and subject to mutation and other damaging elements during their lives. Stimulation of these “old” cells by growth factor cosmeceuticals would thus produce more cells potentially damaged by mutation, and/or cells with reduced function due to senescence unlike defensin-activated LGR6-positive stem cells, which produce these newer, non-mutated, and higher functioning skin cells. Topical growth factors emerged as potential agents for skin rejuvenation18,24 about 15 years ago. Drawbacks are that they are unstable when not in their original environment, and that surfactants, oils, and other inactive substances in topical formulations can denature and inactivate them.25 In contrast, defensin-peptides in the full formula are encapsulated in liposomes that prevent their contact with excipients and provide a physiologic microenvironment. With growth factors, penetration through the epidermis is limited by their high molecular weight (20-150 kDa) and hydrophilic nature.18 The target for stimulation (LGR6-positive stem cells) of the defensins (that have molecular weight of just 3-5 kDa) is located in the hair follicle which can be easy reached through the follicular orifice without the need to penetrate through stratum corneum. The liposome solution also contains a high concentration of recombinant albumin, which acts as a carrier protein26 that protects the active molecules from degradation and is commonly used in cell therapies for stabilization of cytokines27,28; albumin also helps to preserve proper structural conformation of the defensins,26 thus ensuring their physiologic functionality. Another concern with growth factors is that in stimulating aging cells, they may also stimulate carcinogenesis, especially if growth factors are up-regulated.18 This concern is supported by the presence of receptors for growth factors on melanoma cells and the expression of specific growth factors by malignant cells.29 Although an FDA investigation showed that the potential for carcinogenesis requires concentrations of growth factors much higher than those found in topical products,18 the possibility still exists that older skin cells may have already mutated to cutaneous malignancy. Growth factors secreted by in vitro cultured human cells are widely used in cosmetic products.25 A variety of sources of human cells is used including human fibroblasts, mesenchymal stem cells, and placental stem cells.25 Over several decades of cancer research, hundreds of peer-review studies unlocked the mechanisms of carcinogenesis, gene expression pathways involved in tumor formation, and specific role of growth factors that may alter and/or stimulate cancer-associated gene-regulatory mechanisms.30 This comprehensive knowledge brings a number of concerns relating to the use of undefined compositions of growth factors for skin care purposes. For example, transforming growth factor- beta (TGF-β), also known as a tumor growth factor, is present in most of the conditioned media.31,32 Multiple cancer research studies show thatTGF-β is a potent trigger of the cancer-related pathways.33,34 TGF-β overproduction, as a driver of the fibrotic process of chronic phases of inflammatory diseases, precedes
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