In-Vitro Mechanisms of Cell Proliferation Induction
In-Vitro Mechanisms of Cell Proliferation Induction
These studies tested the effects of a novel biophysical stimulus, cell proliferation induction (CPI), a low-level, confined, radiofrequency signal, on the rate of cell proliferation in vitro. A series of experiments were conducted to establish the dose and time course parameters of the CPI signal effects on fibroblast and epithelial cell proliferation. Subsequent studies examined the potential requirement for specific biochemical signaling pathways in the CPI signal's pro-proliferative effect. The results showed that CPI treatment significantly increased the proliferation of both fibroblasts and epithelial cells as a function of dose and time. In addition, CPI treatment caused an immediate release of a diffusable growth factor via a Ca+2 dependent pathway. The nature of these findings suggests that CPI serves as a cellular mitogen, which signals rapid induction into the cell cycle. Therefore, this novel bioactive treatment that uses a specific form of radiofrequency signal may have the potential to effectively accelerate wound closure via stimulation of endogenous growth factor pathways with subsequent proliferation of cell types critical to the wound reconstruction process.
Over the past several years, much has been learned regarding the molecular and physiological bases of wound healing, 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. For example, several important biochemical mediators of cell migration and growth have been identified that are involved in tissue reformation. It is understood that, in many instances, these regulatory signals do not appear to be functioning properly in chronic, nonhealing wounds. 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. 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. 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), platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-beta), and epidermal growth factor (EGF). 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.
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, 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. 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.
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. In light of this realization, a novel bioactive technology has recently been developed based upon the concept of endogenously stimulating the cellular processes that initiate proliferation of fibro-blasts with subsequent introduction of granulation and epithelialization leading to wound closure.
This novel biotechnological approach to the treatment of wounds is based upon the mitogenic (i.e., cell-cycle stimulating) properties of a specific spatial-temporal conformation of a low-level, confined, high-frequency, electromagnetic field. This cell proliferation induction (CPI) technology* has combined an understanding of wound physiology, cellular proliferation mechanisms, and market needs to produce an effective treatment within a low-cost, user friendly, and scientifically based product. Preliminary findings have shown that presenting this field as a train of rapid pulses at or near the cycle time for Ca+2 channels promotes the release of endogenous growth factors and increases the number of cells entering and progressing through the cell cycle. This, in turn, triggers the cascade of second messenger events necessary for cell growth and proliferation. The net effect of this "energy to molecule" transduction is observed as a significant increase in the rate of cell replication.
The purpose of this report is to present findings from a series of in-vitro studies evaluating the cellular mechanisms involved in CPI. Specifically, this report shows dose-response, time-course effects of CPI on fibroblast and epithelial cell proliferation. In addition, data are presented suggesting that the proliferative effects of CPI treatment result from the rapid stimulation of growth factor secretion via Ca+2-mediated signaling pathways.
These studies tested the effects of a novel biophysical stimulus, cell proliferation induction (CPI), a low-level, confined, radiofrequency signal, on the rate of cell proliferation in vitro. A series of experiments were conducted to establish the dose and time course parameters of the CPI signal effects on fibroblast and epithelial cell proliferation. Subsequent studies examined the potential requirement for specific biochemical signaling pathways in the CPI signal's pro-proliferative effect. The results showed that CPI treatment significantly increased the proliferation of both fibroblasts and epithelial cells as a function of dose and time. In addition, CPI treatment caused an immediate release of a diffusable growth factor via a Ca+2 dependent pathway. The nature of these findings suggests that CPI serves as a cellular mitogen, which signals rapid induction into the cell cycle. Therefore, this novel bioactive treatment that uses a specific form of radiofrequency signal may have the potential to effectively accelerate wound closure via stimulation of endogenous growth factor pathways with subsequent proliferation of cell types critical to the wound reconstruction process.
Over the past several years, much has been learned regarding the molecular and physiological bases of wound healing, 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. For example, several important biochemical mediators of cell migration and growth have been identified that are involved in tissue reformation. It is understood that, in many instances, these regulatory signals do not appear to be functioning properly in chronic, nonhealing wounds. 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. 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. 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), platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-beta), and epidermal growth factor (EGF). 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.
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, 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. 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.
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. In light of this realization, a novel bioactive technology has recently been developed based upon the concept of endogenously stimulating the cellular processes that initiate proliferation of fibro-blasts with subsequent introduction of granulation and epithelialization leading to wound closure.
This novel biotechnological approach to the treatment of wounds is based upon the mitogenic (i.e., cell-cycle stimulating) properties of a specific spatial-temporal conformation of a low-level, confined, high-frequency, electromagnetic field. This cell proliferation induction (CPI) technology* has combined an understanding of wound physiology, cellular proliferation mechanisms, and market needs to produce an effective treatment within a low-cost, user friendly, and scientifically based product. Preliminary findings have shown that presenting this field as a train of rapid pulses at or near the cycle time for Ca+2 channels promotes the release of endogenous growth factors and increases the number of cells entering and progressing through the cell cycle. This, in turn, triggers the cascade of second messenger events necessary for cell growth and proliferation. The net effect of this "energy to molecule" transduction is observed as a significant increase in the rate of cell replication.
The purpose of this report is to present findings from a series of in-vitro studies evaluating the cellular mechanisms involved in CPI. Specifically, this report shows dose-response, time-course effects of CPI on fibroblast and epithelial cell proliferation. In addition, data are presented suggesting that the proliferative effects of CPI treatment result from the rapid stimulation of growth factor secretion via Ca+2-mediated signaling pathways.
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