In-Vitro Mechanisms of Cell Proliferation Induction: A Novel Bioactive Treatment for Accelerating Wound Healing

Frank R. George, PhD;1 Ronald J. Lukas, PhD;2 John Moffett, PhD;3 Mary C. Ritz, PhD1


Over the past several years, much has been learned regarding the molecular and physiological bases of wound healing,1 as well as the causes of various chronic wounds, such as pressure ulcers. Recent cellular and molecular studies have substantially increased our understanding of the elegant cascade of signaling events necessary for the wound healing process.1–11 For example, several important biochemical mediators of cell migration and growth have been identified that are involved in tissue reformation.6,12,13 It is understood that, in many instances, these regulatory signals do not appear to be functioning properly in chronic, nonhealing wounds.14 There are distinct phases associated with the process of wound healing, and it is clear that fibroblasts and epithelial cells are two of several cell types critical to establishing and progressing through the wound healing process.1 For example, fibroblasts must proliferate and synthesize collagen to provide a strong matrix for vascularization and epithelial growth.

Growth factors have been considered candidate therapeutics for wound healing because they are synthesized by and stimulate cells required for tissue repair, they are deficient in chronic wounds, and there is evidence that pharmacological application enhances wound repair in a variety of animal models.14 Today, growth factors refer to an expanding class of molecules, sometimes with specificity for certain types of cells, that can have either pro- or antiproliferative effects under differing circumstances. Among the growth factors implicated in tissue repair are insulin-like growth factor (IGF),15 platelet-derived growth factor (PDGF),6 transforming growth factor-beta (TGF-b),16 and epidermal growth factor (EGF).17,18 These molecules and their receptors are the likely molecular substrates for tissue repair. Fibroblasts and endothelial cells and their surface growth factor receptors represent critical cellular targets for growth factors and related molecules associated with wound healing.1–3,8,15

Based on the hypothesis that defects in growth factor signaling contribute to the development and/or persistence of pressure ulcers, reinstitution or normalization of that signaling, whether by introducing new sources of growth factor molecules or by reinstituting appropriate receptor coupling to second messengers, should promote wound healing. However, the complexity and variability of clinical wounds have limited pharmacological approaches to accelerate wound healing, leaving dressings and nonpharmacological ancillary modalities to dominate a market associated with wound management. For example, while numerous studies have cited the in-vitro efficacy of growth factor-derived compounds in promoting cell proliferation,3,4,8,9,13–15 the use of these types of compounds in clinical trials of wound healing typically have not produced encouraging results. One notable exception is the current use of topically applied, platelet-derived growth factor (PDGF) in the treatment of diabetic foot ulcers.19 Although application of this growth factor has demonstrated efficacy in the healing of these and other chronic wounds, it requires a complicated treatment regimen to ensure effectiveness.20

As a result of this work, it has become apparent that focusing on a single growth factor or related compound or receptor site is not the most effective way to initiate and sustain the complex cascade of events needed to progress the wound healing process. Rather, what is required appears to be an appropriate sequential stimulation of multiple growth factor expression and secretion.



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