This proposal is in response to the mission of the Office of Research Infrastructure Programs (ORIP) to "Develop and provide access to critical animal models that offer essential clues to a broad range of human disorders". Our goal is to develop a universal animal model that best recapitulates non-healing human chronic wounds. The burden of chronic wounds is growing rapidly due to increasing health care costs, an aging population and a sharp rise in the incidence of obesity and diabetes. Despite more than a century of extensive research and thousands of dressings developed, even the best treatments achieve only a 50% healing rate-and this healing is often only temporary with high recurrence rate. A statement made in one of the first papers describing chronic wound treatment-that "Old ulcers in 1830 will be older ulcers in 1860"-unfortunately still applies today. Unless some dramatic measures are taken, old ulcers in 2014 will be older ulcers in 2044. It is expensive and time consuming to develop new wound care drugs. The ability to translate experimental findings into clinical usage relies heavily on animal models that serve as surrogates of the human condition. Human chronic wounds are defined as wounds that heal with a significant delay, usually over a period of more than 2-3 months. However, all current animal models have problems, such as being acute in nature, with very short or no ischemic time, and mostly created in young animals. No current model is able to recapitulate human chronic wounds. Although multiple factors are involved in nonhealing chronic wounds, our unifying hypothesis is that tissue ischemia is the most critical factor hindering healing. Persistent tissue ischemia in te vicinity of the wound is an important underlying feature of chronic wounds that severely impairs the healing process. For many chronic wounds, ischemia may not be the initiating factor because many ulcers start from a combination of repeated trauma, neuropathy, pressure loading, and infection. However, tissue ischemia is the main cause that hinders healing-wounds do not heal in tissue that does not bleed, whereas they always heal in tissue that bleeds extensively. We have developed an ischemic rabbit ear model using a minimally invasive surgical procedure. This model has the advantages of being simple, safe, economical, and very flexible, with minimal skin contraction. The duration of ischemia is about one month-the longest of all currently available models. This procedure has been used in more than one hundred rabbits without complications. However, ischemia finally disappears after one month-which is still too short a duration to match human chronic wounds. This project aims at further improvements in this model that will make it more closely approximate human chronic wounds with various pathophysiologic origins. The following goals are planned: 1) to extend the ischemic time up to 2-3 months, 2) to use this model in aged animals; and 3) to ensure that the model remains simple, safe, and easy to create. For the phase I project, our goal is to obtain the proof-of-concept that the ischemic time can be extended further by subcutaneous tissue separation with minimal or no side effects. The minimally invasive surgery developed by our group has provided the longest ischemic wound model. The success of the current project will build a critical infrastructure program to fill a major gap in scientific research and provide a simple and easy to use animal model for wound dressing development.
Public Health Relevance Statement: Public Health Relevance: The most critical deficiency in wound research and drug development is a lack of suitable animal model that can recapitulate the clinical features of chronic wounds. A minimally invasive technique to create an animal model with the longest ischemic time has been developed by our group. This project will further extend the ischemic time to reflect the most critical feature of non-healing chronic wounds. The success of this project will build a critical infrastructure program to fill a major gap in scientific research andprovide a simple and easy to use animal model for wound dressing development.
Project Terms: Acute; Adverse effects; Affect; aged; aging population; Animal Model; Animals; base; Caring; Chronic; Clinical; cost; Development; Diabetes Mellitus; Disease; drug development; Ear structure; Ensure; flexibility; Goals; Healed; healing; Health Care Costs; Hemorrhage; Human; Impaired wound healing; Incidence; Infection; Ischemia; juvenile animal; Length; Measures; minimally invasive; Minimally Invasive Surgical Procedures; Mission; Modeling; Nature; Neuropathy; Obesity; Operative Surgical Procedures; Oryctolagus cuniculus; Paper; Pathology; Patients; Pharmaceutical Preparations; Phase; pressure; Procedures; Process; programs; Protocols documentation; public health relevance; Recurrence; Research; research and development; Research Infrastructure; response; Silicone Gels; Skin; Sterile coverings; subcutaneous; Subcutaneous Tissue; success; Techniques; Testing; Time; Tissues; Translating; Trauma; Ulcer; United States; Venous; wound; Wound Healing
