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: 10380774
• 负责人: Asim Ejaz
• 金额: $ 17.97万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380774
• 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; 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.

项目摘要 皮肤作为抵御外来侵袭和病原体的第一道防线，是第一个受到感染的器官。 辐射事件。意外暴露、战时危险或与恐怖主义有关的事件的威胁， 由于工业、医疗设施和军事中放射性物质的使用增加， 装置.皮肤对电离辐射的反应对局部和全身治疗具有重要意义， 保护目前，针对辐射引起的皮肤损伤的对策非常有限， 已经显示出有限的功效。阻碍制定有效对策的一个关键因素是 缺乏一个方便和强大的模型，具有特定的翻译人类。因此我们 长期目标是开发一种能够维持全层细胞活力的便携式组织培养生物反应器， 通过动脉灌注的人体皮瓣。利用该生物反应器，我们将建立体外人皮肤模型， 研究辐射引致皮肤损伤的基本机制，并随后测试 医学对策。我们的中心假设是，由灌注生物反应器支持的人类皮肤 将能够对RI进行临床相关的长期（约4周）表征，并评估 治疗预期RI诱导DNA损伤、炎症和细胞凋亡，并且通过局部给药进行治疗。 JP 4 -039的应用有望减轻人皮肤灌注模型中的这些影响。为支持我们的 假设，我们的初步工作导致了可重复灌注生物反应器的成功制造。这 生物反应器能够控制通过动脉进入的贯穿血管化皮肤组织的连续流体流动 插管该系统配备了静脉和动脉压力的实时监测， 基于解剖学相关的输入来动态地调节所述流体流。此外，实时反馈系统 用于维持正常温度的设备，沿着负责 测量气态CO2、气态O2和灌注液pH。使用这种灌注生物反应器，我们已经表明， 成功灌注人体皮瓣。我们计划通过以下两个方面来检验我们的中心假设 具体目标。目的1-表征离体全层人皮肤灌注中的辐射诱导损伤 文化目的2-测试抗氧化剂JP 4 -039减轻辐射诱导的皮肤损伤的能力。这本小说 利用废弃人体皮肤组织进行机理研究和开发医学对策的方法 防止辐射引起的伤害有很大的希望。我们的团队在机器制造方面有着丰富的经验 发展，整形和重建手术，辐射损伤的研究，以及发展 医学对策。我们预计，该项目的成功完成将大大 推进我们对辐射引起的皮肤损伤机制的理解，并验证 使用我们的灌注培养模型作为测试医疗对策的平台。

项目成果

Nicotinamide Riboside Improves Stemness of Human Adipose-Derived Stem Cells and Inhibits Terminal Adipocyte Differentiation.

• DOI: 10.3390/ph16081134
• 发表时间: 2023-08-10
• 期刊: PHARMACEUTICALS
• 影响因子: 4.6
• 作者: Chinnapaka, Somaiah;Malekzadeh, Hamid;Tirmizi, Zayaan;Arellano, Jose A.;Ejaz, Asim
• 通讯作者: Ejaz, Asim

Application of Adipose-Tissue Derived Products for Burn Wound Healing.

• DOI: 10.3390/ph16091302
• 发表时间: 2023-09-14
• 期刊: Pharmaceuticals (Basel, Switzerland)
• 作者: Malekzadeh H;Tirmizi Z;Arellano JA;Egro FM;Ejaz A
• 通讯作者: Ejaz A

Metformin and adipose-derived stem cell combination therapy alleviates radiation-induced skin fibrosis in mice.

• DOI: 10.1186/s13287-023-03627-7
• 发表时间: 2024-01-08
• 期刊: Stem cell research & therapy
• 影响因子: 7.5