Our central hypothesis is that the inflammatory response to thermal injury results in an imbalance of endogenous proteases and their inhibitors resulting in impaired healing. In this collaborative effort, we propose that burn wound healing can be improved through the use of topical wound dressings with the capacity to affect key mediators involved in the inflammatory response. The therapeutic agent IMS-70, which has demonstrated an intrinsic ability to inhibit neutrophil-derived proteases, will be evaluated as a healing component of our wound treatment(s). We predict that the majority of improvement will occur in the zone of stasis. Our hypothesis will be tested with the following specific aims: ? ? Specific Aim 1): Formulation and in vitro screening of IMS-70 & Derivatives ? ? IMS-70 will be chemically modified to incorporate the antibiotic and MMP inhibitor, doxycycline; the reactive oxygen species scavenger, glutathione; the antimicrobial cerium ion, and the nutrient arginine. In vitro screening will be performed to test the ability of these derivatives to inhibit proteases such as neutrophil-derived elastase, cathepsin G, MMP-8 and MMP-9 and neutrophil- derived myeloperoxidase. ? ? Specific Aim 2): In vivo testing of IMS-70 & Derivatives. ? ? The IMS-70 derivatives will be blended into a CMC amorphous hydrogel carrier and applied to a burn wound in the rat. This model generates areas of full- thickness burn separated by non-burned interspaces representing the zone of stasis. The efficacy of the dressings will be tested by comparing histology, protease activity, and inflammatory markers to a control group receiving only the hydrogel carrier. ? Successful completion of the specific aims outlined in this proposal will provide the necessary data to optimize topical therapies for use in larger surface area burns, potentially limiting the systemic effects that result in burn wound sepsis, burn wound conversion, and prolonged recovery.
Project Narrative: Thermal injury triggers a complex inflammatory response that can result in extensive damage to the unburned tissues. In this proposal we describe the development and testing of novel topical therapies designed to limit the inflammatory response and thereby reduce the extent of burn wound injury. These basic mechanisms will also apply to chemical burns and radiation induced injury, as well as other inflammatory diseases of the skin. ? ? ?
