p38 MAPK inhibition reduces diabetes-induced impairment of wound healing.

In healthy tissue, a wound initiates an inflammatory response characterized by the presence of a hematoma, infiltration of inflammatory cells into the wound and, eventually, wound healing. In pathological conditions like diabetes mellitus, wound healing is impaired by the presence of chronic nonresolving inflammation. p38 mitogen-activated protein kinase (MAPK) inhibitors have demonstrated anti-inflammatory effects, primarily by inhibiting the expression of inflammatory cytokines and regulating cellular traffic into wounds. The db/db mouse model of type 2 diabetes was used to characterize the time course of expression of activated p38 during impaired wound healing. The p38α-selective inhibitor, SCIO-469, was applied topically and effects on p38 activation and on wound healing were evaluated. A topical dressing used clinically, Promogran™, was used as a comparator. In this study, we established that p38 is phosphorylated on Days 1 to 7 post-wounding in db/db mice. Further, we demonstrated that SCIO-469, at a dose of 10 µg/wound, had a positive effect on wound contraction, granulation tissue formation, and re-epithelialization, and also increased wound maturity during healing. These effects were similar to or greater than those observed with Promogran™. These results suggest a novel approach to prophylactic and therapeutic management of chronic wounds associated with diabetes or other conditions in which healing is impaired.

The role of oxidised regenerated cellulose/collagen in chronic wound repair and its potential mechanism of action.

Normal wound healing is a carefully controlled balance of destructive processes necessary to remove damaged tissue and repair processes which lead to new tissue formation. Proteases and growth factors play a pivotal role in regulating this balance, and if disrupted in favour of degradation then delayed healing ensues; a trait of chronic wounds. Whilst there are many types of chronic wounds, biochemically they are thought to be similar in that they are characterised by a prolonged inflammatory phase, which results in elevated levels of proteases and diminished growth factor activity. This increase in proteolytic activity and subsequent degradation of growth factors is thought to contribute to the net tissue loss associated with these chronic wounds. In this study, we describe a new wound treatment, comprising oxidised regenerated cellulose and collagen (ORC/collagen), which can redress this imbalance and modify the chronic wound environment. We demonstrate that ORC/collagen can inactivate potentially harmful factors such as proteases, oxygen free radicals and excess metal ions present in chronic wound fluid, whilst simultaneously protecting positive factors such as growth factors and delivering them back to the wound. These characteristics suggest a beneficial role for this material in helping to re-balance the chronic wound environment and therefore promote healing.

The role of oxidised regenerated cellulose/collagen in wound repair: effects in vitro on fibroblast biology and in vivo in a model of compromised healing.

Irrespective of underlying chronic wound pathology, delayed wound healing is normally characterised by impaired new tissue formation at the site of injury. It is thought that this impairment reflects both a reduced capacity to synthesize new tissue and the antagonistic activities of high levels of proteinases within the chronic wound environment. Historically, wound dressings have largely been passive devices that offer the wound interim barrier function and establish a moist healing environment. A new generation of devices, designed to interact with the wound and promote new tissue formation, is currently being developed and tested. This study considers one such device, oxidised regenerated cellulose (ORC) /collagen, in terms of its ability to promote fibroblast migration and proliferation in vitro and to accelerate wound repair in the diabetic mouse, a model of delayed wound healing. ORC/collagen was found to promote both human dermal fibroblasts proliferation and cell migration. In vivo studies considered the closure and histological characteristics of diabetic wounds treated with ORC/collagen compared to those of wounds given standard treatment on both diabetic and non-diabetic mice. ORC/collagen was found to significantly accelerate diabetic wound closure and result in a measurable improvement in the histological appearance of wound tissues. As the diabetic mouse is a recognised model of impaired healing, which may share some characteristics of human chronic wounds, the results of this in vivo study, taken together with those relating the positive effects of ORC/collagen in vitro, may predict the beneficial use of this device in the clinical setting.

Mechanism of action of PROMOGRAN, a protease modulating matrix, for the treatment of diabetic foot ulcers.

Proteases play a critical role in many of the physiologic processes of wound repair. However, if their activity becomes uncontrolled proteases can mediate devastating tissue damage and consequently they have been implicated in chronic wound pathophysiology. Previous studies have shown that chronic wound fluid contains elevated protease levels that have deleterious effects, degrading de novo granulation tissue and endogenous biologically active proteins such as growth factors and cytokines. Therefore, we have proposed that an effective therapeutic approach for chronic wounds would be to modify this hostile environment and redress this proteolytic imbalance. Using an ex vivo wound fluid model, we show the ability of a proprietary new wound treatment to bind and inactivate proteases. We have shown that the addition of this test material to human chronic wound fluid obtained from diabetic foot ulcer patients resulted in a significant reduction in the activities of neutrophil-derived elastase, plasmin, and matrix metalloproteinase when compared to wet gauze. This study provides mechanistic evidence to support the hypothesis that this novel treatment modality for chronic wounds physically modifies the wound microenvironment, and thereby promotes granulation tissue formation and stimulates wound repair.