An ulcer is described as a localized shedding of an epithelium. It is critical to treat these ulcers, because as soon as the epidermal cells die, a major barrier to bacteria is breached, and it can cause further necrosis to the surrounding tissues (Martini, 2001). An ulcer that is considered chronic, or nonhealing, is one that does not heal in a timely fashion.

There are many types of chronic ulcers, but the most common types that affect the skin are diabetic ulcers, venous leg ulcers, and pressure ulcers. These wounds can affect just the epidermis (partial-thickness), or they can reach into the dermis as well (full thickness). Pressure ulcers in the U.S. are estimated to occur in up to 2 million people (Kirsner et.al., 1998), about 9.2% of all hospitalized patients. Pressure ulcers alone cost the health care system $1.3 billion annually (Boyce, 2002). These sores often occur when blood flow to an area of skin is cut off by continual pressure against superficial blood vessels. Diabetic foot ulcers affect 600-800 thousand people a year in the U.S., in about 6-20% of all diabetics hospitalized (Loots et.al., 1999), costing over $1billion annually. Venous ulcers, mostly of the leg, affect 1 million people a year (Kirsner et.al., 1998). These are mainly triggered by venous hypertension, corresponding to the failure of internal valves of the veins in the lower extremities. This situation may lead to neutrophil accumulation and activation in the tissue, causing the release of enzyme granules and free oxygen radicals that cause cell death and disruption of extracellular matrix (Smith et.al., 2000 ). The leukocytes may also prevent the free flow of oxygen, nutrients, and cytokines by occluding the capillaries.

A theory on the failure of ulcers to heal is the absence of the glycoprotein FN within the wound space. FN interacts with cellular integrins through interactions with three of its functional domains, signaling and providing traction support for migration. In a healing wound, the FN that is found within the fibrin clot allows for fibroblasts in the surrounding tissues to infiltrate and to construct the granulation tissue and provisional matrix for wound repair. In fact, the lag period of three days before fibroblasts begin to infiltrate the fibrin clot has been ascribed to the time needed for fibroblasts in the surrounding collagen matrix to switch cell surface receptors in order to bind FN specifically, as well as for FN to appear in the periwound space (Clark, 2001; Clark et.al., 1996b; Gailit et.al., 1996). Additionally, it has been shown that in vitro, fibroblasts required FN to migrate from a collagenous matrix into a fibrin matrix, simulating the in vivo wound environment (Greiling and Clark, 1997).

Thus fibroblasts appear to require FN to be present in the wound to begin the healing process. However, it has been found that FN is absent in the matrix of nonhealing ulcers (Herrick et.al., 1992). Additional observations revealed that chronic wound fluid was lacking any high-molecular weight (intact) FN, but contained FN fragments (Wysocki and Grinnell, 1990). This observation has been confirmed in other studies as well. The cause of this FN degradation appears to be the highly proteolytic environment of the chronic wound. In addition to the FN molecule becoming degraded by enzymes such as serine proteases (neutrophil elastase or chymotrypin-like enzyme), the proteins that normally protect FN in the acute wound environment (alpha 1-trypsin, serine-protease inhibitor) become degraded as well (Wysocki et.al. 1990; Wysocki et.al. 1993; Rao et.al., 1995; Grinnell et.al., 1996; Grinnell et.al. 1994;, Grinnell et.al. 1992 ). The cause of these degradations appear to be more complicated than just these couple of enzymes and there have been many other factors and enzymes that were identified to be potentially responsible for FN degradation and wound closure prevention (Rao et.al., 1995; Ginnell, Ho et.al., 1996; Bonnefoy et.al., 2000).