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 皮肤是针对外国侮辱和病原体的第一道防线，是第一个受到影响的器官 辐射事件。意外暴露，战时危害或与恐怖主义有关的事件的威胁已经存在 由于在行业，医疗设施和军事中使用放射性材料的使用增加而加剧 安装。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。当前，辐射引起的皮肤损伤的对策非常有限，而那些则有限 可用显示有限的功效。阻碍有效对策的关键因素是 缺乏具有特定转换性的方便和健壮的模型。因此，这是我们的 长期目标以开发便携式组织培养物生物反应器，能够维持全厚度的生存能力 人皮襟翼通过动脉灌注。使用此生物反应器，我们将建立一个体外人类皮肤模型 研究辐射引起的皮肤损伤的潜在机制，并随后测试效力 医疗对策。我们的中心假设是由灌注生物反应器支撑的人皮肤 将实现RI的临床相关，长期（约4周）的表征和潜在的评估 疗法。 RI有望通过局部诱导DNA损伤，炎症以及凋亡和治疗 JP4-039的应用有望减轻人类皮肤灌注模型中的这些影响。支持我们 假设，我们的初步工作导致成功地制造了可再现的灌注生物反应器。这 生物反应器能够控制整个血管化皮肤组织的连续流体流动，并通过动脉进入 插管。该系统配备了对静脉和动脉压力的实时监控，可以 基于解剖学上的输入动态调节流体流。此外，实时反馈系统 为了维持常规温度，已经安装了 测量气态二氧化碳，气态O2和灌注液。使用此灌注生物反应器，我们已经显示 成功灌注人皮瓣。我们计划通过追求以下两个来检验中心假设 具体目标。 AIM 1-表征辐射诱发的损伤，在体内全厚度人体皮肤灌注中 文化。目标2-测试抗氧化剂JP4-039减轻辐射引起的皮肤损伤的能力。这本小说 使用丢弃的人皮组织进行机械研究并发展医学对策的方法 反对辐射诱发的伤害有很多希望。我们的团队在机器上有丰富的经验 发育，塑料和重建手术，辐射诱导损害的研究以及发展 医疗对策。我们预计该项目的成功完成将大大完成 促进我们对辐射引起的皮肤损伤涉及的机制的理解以及验证 使用我们的灌注文化模型作为测试医学对策的平台。

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