Surgery: light – thermal – and electrical application – Light – thermal – and electrical application – Electrical therapeutic systems
Reexamination Certificate
1999-01-15
2001-12-25
Jastrzab, Jeffrey R. (Department: 3762)
Surgery: light, thermal, and electrical application
Light, thermal, and electrical application
Electrical therapeutic systems
C607S050000, C607S155000
Reexamination Certificate
active
06334069
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
This invention relates to electromechanical devices and methods for therapeutically treating human body tissue, and more particularly to a device for and a method of stimulating cell proliferation and related molecular events using high frequency pulsed electromagnetic energy.
BACKGROUND OF THE INVENTION
The present invention is an important advancement in the fields of endogenous pharmacotherapeutics, electromagnetic medicine, wound physiology and treatment, and regulation of the cell cycle, and has specific application in the area of wound healing, and in particular, the healing of chronic wounds, such as pressure ulcers, diabetic ulcers and venous stasis ulcers. Prior to discussing the present invention in detail, it is helpful to understand the specific mechanisms of wound healing, the immediate need for wound healing therapies, and the current state of the art.
While the specific mechanisms of action have not been fully determined, research over the past several years has substantially increased understanding of the nature of wound healing and the elegant cascade of signaling events necessary for the initiation of cell growth and migration and tissue regeneration, which collectively constitute the wound healing process. Importantly, numerous biochemical mediators of cell migration patterns and cell-cell/cell-extracellular matrix interactions involved in the reformation of tissue/organ systems have been identified.
There are distinct phases associated with the process of wound healing. In the inflammatory phase, platelets aggregate to deposit granules, which promote fibrin deposition, and stimulate the release of growth factors. Leukocytes migrate to the wound site and begin to digest and transport debris away from the wound. It is also during the inflammatory phase that monocytes are converted to macrophages, which release growth factors for stimulating angiogenesis and the production of fibroblasts. Next, in the proliferative phase, granulation tissue forms and epithelialization begins. Fibroblasts, key cell types in this phase, proliferate and synthesize collagen to fill the wound and provide a strong matrix on which epithelial cells grow. As collagen is produced by fibroblasts, vascularization extends from nearby vessels to supply nutrients to the regenerating tissue. The red loops of blood vessels give the wound a granular appearance, thus the term granulating. Epithelialization involves the migration of epithelial cells from the wound surfaces to seal the wound. Epithelial cells are driven by the need to contact cells of like type and are guided by a network of fibrin strands which function as a grid over which these cells migrate. Contractile cells called myofibroblasts appear in wounds and aid in wound closure. These cells exhibit collagen synthesis and contractility, and are common in granulating wounds. In the final phase of wound healing, the differentiation or tissue remodeling phase, collagen in the scar undergoes repeated degradation and resynthesis. It is during this phase that the tensile strength of the newly formed skin increases.
Clearly, growth factors are important messengers in coordinating this complex orchestration of cellular events. Today, growth factors refer to an expanding class of molecules, sometimes with specificity for certain types of cells, that can have either pro-proliferative or antiproliferative/differentiation effects, depending upon the specific circumstances. Their immediate molecular targets are specific members in the superfamily of receptor tyrosine kinases. Relatively little is known about the regulation of growth factor activity, but spatial and temporal gradients of growth factor and receptor expression are evident, and expression of a given growth factor or its receptors can be induced by other growth factors, suggesting that sequences of growth factor-mediated messages networked across cell types and integrated with other signaling cascades are central to tissue/organ development, maintenance and healing processes.
Thus, the recent realization that growth factors can serve as paracrine, autocrine, juxtacrine and intracrine (which refers to actions of growth factors within a cell) signals to regulate proliferation, migration, and interaction of cells critical to wound healing is important to understanding and developing wound treatments. For example, central to tissue/organ repair and remodeling is the critical revascularization of damaged tissue. Vascular endothelial growth factor (VEGF) is a recently discovered agent that promotes proliferation and migration of endothelial cells. Stimulating the expression of VEGF receptors in endothelial cell precursors allows those cells to respond to VEGF secreted from other cells or to VEGF acting via autocrine/intracrine mechanisms. Stimulating the release of VEGF from fibroblasts and/or other cell types (or stimulating VEGF production in endothelial cells) promotes mitotic and/or migratory activity of endothelial cells. Also critical to tissue repair is establishment of the extracellular scaffold to support cell migration and/or proliferation. Stimulating the release of agents such as fibroblast growth factors (FGF) from any of a number of cell types promotes proliferation and migration of fibroblasts, which are involved in production of extracellular matrix materials such as collagen. Moreover, stimulating FGF receptor production in fibroblasts capable of recognizing paracrine, autocrine, or intracrine FGF also plays a role in stimulating fibroblast activity and the production of extracellular matrix. Other agents implicated in tissue repair include insulin-like, platelet, transforming, and epidermal growth factors. Those molecules and their receptors are the likely molecular substrates for tissue repair. Endothelial cells, fibroblasts and keratinocytes, among others, are the cell types whose activity is critical to tissue repair and represent the likely cellular targets for these growth factors and related molecules associated with the healing of pressure sores.
It is also well known that regulatory signals normally found in the repair of acute wounds are not present in chronic wounds such as pressure ulcers and venous stasis ulcers. For example, chronic wounds frequently have poorly vascularized, thick fibrotic scar tissue surrounding the wound bed, are characterized by keratinocytes incapable of proliferation and migration, and have few active fibroblasts. These occurrences are clearly indicative of defects in growth factor signaling.
With the understanding that defects in growth factor signaling contribute to the development and/or persistence of chronic wounds, it is logical to conclude that reinstitution or normalization of that signaling would promote wound healing. 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 some evidence that pharmacological application enhances wound repair in a variety of animal models of dermal incisional and excisional repair.
However, clinical studies have been disappointing and some experts have suggested that an alternative to single growth factors as therapeutic agents is the utilization of growth factors in combination to elicit synergistic clinical efficacy. This lack of therapeutic efficacy may be in part because wound healing is a complex programmed sequence of cellular and molecular events, including macrophage activation during inflammation, cell migration, angiogenesis, provisional matrix synthesis, synthesis of collagen by fibroblasts, and reepithelialization. Current pharmaceutical approaches do not fully mimic the necessary spatial and temporal patterns of growth factor activity needed to promote wound healing. Overall, the complexity and variability of clinical wounds have limited pharmacological approaches to accelerate wound healing, leaving dressings and nonpharmacological ancillary modalities to dominate the market associated with wound man
Bryant Robert T.
George Frank R.
Loya Arthur A.
Ritz Mary C.
Jastrzab Jeffrey R.
Morrison & Foerster / LLP
Regenesis Biomedical, Inc.
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