Topical Modulation of Burn Wound Healing

烧伤伤口愈合的局部调节

基本信息

批准号：
7481972
负责人：
DAVID J VACHON
金额：
$ 19.77万
依托单位：
IASIS MOLECULAR SCIENCES, INC
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-05 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7481972
关键词：
Address Affect Alkanesulfonates Animals Anti-Bacterial Agents Antibiotics Antioxidants Area Arginine Biochemical Blood flow Burn injury Cathepsin G Cations Cerium Characteristics Chemical Burns Clinical Comb animal structure Complex Control Groups Coupled Data Depth Dermal Development Dialysis procedure Doxycycline Drug Formulations Effectiveness Elastases Endopeptidases Evaluation Functional disorder Gel Gelatinase B Glutathione Healed Histology Human Hydrogels Impaired wound healing In Vitro Individual Inflammation Inflammatory Inflammatory Response Injury Ion Exchange Ions Lipids Liquid substance MCC protocol Marketing Matrix Metalloproteinase Inhibitor Measurement Mediator of activation protein Metals Modeling Necrosis Neutrophil Collagenase Nitric Oxide Nutrient Outcome PSSO3 Pancreatic Elastase Peptide Hydrolases Peroxidase Persons Physical Dialysis Polymers Preparation Protease Inhibitor Proteins Public Health Purpose Radiation Rattus Reactive Oxygen Species Recovery Regulation Rodent Rodent Model Salts Screening procedure Sepsis Serine Protease Simulate Sodium Chloride Solutions Sterile coverings Surface Testing Therapeutic Therapeutic Agents Thick Time Tissues Toxin United States United States Food and Drug Administration Water Wound Healing Wounds and Injuries Zinc antimicrobial base clinically relevant cost effectiveness direct application healing heat injury improved in vivo inhibitor/antagonist leukocyte activation neutrophil novel prevent response skin disorder therapy design wound

项目摘要

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE 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.

描述（由申请人提供）：我们的中心假设是对热损伤的炎症反应导致内源性蛋白酶及其抑制剂的失衡，从而导致愈合受损。在这项合作的工作中，我们建议通过使用局部伤口敷料可以改善烧伤伤口愈合，并能够影响涉及炎症反应的关键介体的能力。治疗剂IMS-70表现出抑制嗜中性粒细胞蛋白酶的内在能力，将被评估为我们伤口治疗的愈合成分。我们预测，大多数改善将发生在停滞区。我们的假设将以以下特定目的进行检验：特定目标1）：IMS-70和衍生物的配方和体外筛选 IMS-70将进行化学修饰，以掺入抗生素和MMP抑制剂强力霉素。活性氧物种清除剂，谷胱甘肽；抗菌葡萄氏离子和营养精氨酸。将进行体外筛查，以测试这些衍生物抑制蛋白酶的能力，例如中性粒细胞衍生的弹性酶，组织蛋白酶G，MMP-8和MMP-9以及中性粒细胞衍生的髓质过氧化物酶。特定目标2）：IMS-70和衍生物的体内测试。 IMS-70衍生物将被混合到CMC无定形水凝胶载体中，并施加到大鼠燃烧的伤口上。该模型产生的区域具有全厚度燃烧的区域，该区域由代表停滞区域的非烧焦的空间分离。敷料的功效将通过将组织学，蛋白酶活性和炎症标记与仅接收水凝胶载体的对照组进行比较来测试。该提案中概述的特定目的的成功完成将提供必要的数据，以优化局部疗法，以用于较大的表面积燃烧，可能限制会导致灼伤伤口败血症，烧伤伤口转换和延长恢复的全身效应。公共卫生相关性项目叙事：热损伤会触发复杂的炎症反应，可能会对未烧伤组织造成广泛损害。在该提案中，我们描述了旨在限制炎症反应的新型局部疗法的发展和测试，从而减少了烧伤伤口损伤的程度。这些基本机制也将适用于化学灼伤和辐射引起的损伤以及皮肤的其他炎症性疾病。