Development of Full Thickness Human Skin Perfusion Model for Testing Medical Countermeasures against Radiation Induced Skin Injuries

开发全层人体皮肤灌注模型，用于测试辐射引起的皮肤损伤的医疗对策

• 批准号: 10216778
• 负责人: Asim Ejaz
• 金额: $ 22.63万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216778
• 关键词: Acute; Advanced Development; Affect; Anatomy; Animal Experimentation; Animal Model; Animal Testing; Antioxidants; Apoptosis; Biopsy; Bioreactors; Blood Substitutes; Blood Vessels; Burn injury; CASP3 gene; CD3 Antigens; Cannulations; Carbon Dioxide; Cell Death; Cellular biology; Chemical Injury; Cleaved cell; Creatinine; DNA; DNA Damage; Development; Dose; Electrolytes; Feedback; Foundations; Future; Genetic Variation; Glucose; HMGB1 gene; Health; Heat-Shock Proteins 70; Histologic; Human; IL8 gene; Immunology; In Situ Nick-End Labeling; In Vitro; Industry; Inflammation; Inflammatory; Injury; Interleukin-1; Interleukin-10; Interleukin-12; Interleukin-6; Ionizing radiation; Liquid substance; MAPK8 gene; Maintenance; Measures; Medical; Microfluidics; Military Personnel; Mission; Mitochondria; Modeling; Monitor; Mus; Nutritional; Organ; Oxidative Stress; Pathway interactions; Perfusion; Phase I Clinical Trials; Plastic Surgical Procedures; Proteins; Public Health; Radiation; Radiation Accidents; Radiation Dose Unit; Radiation Injuries; Radiation induced damage; Radioactive; Recipe; Reconstructive Surgical Procedures; Reproducibility; Research; Research Personnel; Signal Transduction; Skin; Skin Tissue; Skin injury; Source; Study models; Surgical Flaps; System; TNF gene; Temperature; Terrorism; Testing; Thick; Time; Tissues; Topical application; Transforming Growth Factor beta; United States National Institutes of Health; Up-Regulation; Urea; Uric Acid; Venous; Western Blotting; Work; base; cancer therapy; clinically relevant; design; drug development; efficacy testing; experience; fluid flow; hazard; innovation; irradiation; medical countermeasure; novel strategies; oxidation; p38 Mitogen Activated Protein Kinase; pathogen; portability; preservation; pressure; radiation countermeasure; radiation mitigation; radiation mitigator; radiation-induced injury; real time monitoring; research and development; response; sharing platform; skin damage; tissue culture; tool; tumor-immune system interactions

Project Summary Skin, being the first line of defense against foreign insults and pathogens, is the first organ to be affected by radiation incidents. The threat of accidental exposures, wartime hazards, or terrorism-related incidents has been intensified due to the increased use of radioactive materials in industry, medical facilities, and military installations. Skin response to ionizing radiations has important implications for local and systemic treatment and protection. Currently, there are very limited countermeasures for radiation-induced skin damage, and those that are available have shown limited efficacy. A key factor hindering development of effective countermeasures is the absence of a convenient and robust model possessing specific translatability to humans. It is therefore our long-term objective to develop a portable tissue culture bioreactor capable of maintaining viability of full-thickness human skin flaps via arterial perfusion. With this bioreactor, we will establish an in vitro human skin model for studying the underlying mechanism of radiation-induced skin damage and will subsequently test the efficacies of medical countermeasures. Our central hypothesis is that human skin supported by the perfusion bioreactor will enable clinically relevant, long-term (~4 weeks) characterization of RI and the assessment of potential therapies. RI is expected to induce DNA damage, inflammation, and apoptosis and treatment via topical application of JP4-039 is expected to mitigate these effects in human skin perfusion model. In support of our hypothesis, our preliminary work resulted in the successful fabrication of reproducible perfusion bioreactor. This bioreactor is capable of controlling continuous fluid flow throughout vascularized skin tissue, accessed via arterial cannulation. The system is equipped with real-time monitoring of venous and arterial pressures and can dynamically adjust the fluid flow based on anatomically-relevant inputs. Additionally, real-time feedback systems for maintenance of normothermic temperature have been installed, along with components responsible for measuring gaseous CO2, gaseous O2, and perfusate pH. Using this perfusion bioreactor, we have shown successful perfusion of human skin flap. We plan to test our central hypothesis by pursuing the following two specific aims. Aim 1- Characterize radiation induced injury in an ex vivo full-thickness human skin perfusion culture. Aim 2- Test the ability of antioxidant JP4-039 to mitigate radiation-induced skin damage. This novel approach to use discarded human skin tissue for mechanistic studies and develop medical countermeasures against radiation induced injuries holds a lot of promise. Our team has extensive experience in machine development, plastic and reconstructive surgeries, the study of radiation induced damage, and the development of medical countermeasures. We anticipate that the successful completion of this project will significantly advance our understanding of the mechanisms involved in radiation-induced skin damage as well as validate the use of our perfusion culture model as a platform of testing medical countermeasures.

项目总结