Mechanobiology of Hemoglobin-Based Artificial Oxygen Carriers

人工氧载体（AOC）最初是作为输血的红细胞替代品开发的，最近作为氧治疗剂开发的。它们可以减少输血的有害副作用，例如捐献血液的免疫反应和炎症，或者在捐献血液变得稀缺时为患者进行挽救生命的手术。然而，开发安全有效的AOC来替代生理性人类红细胞是具有挑战性的。该奖项支持对AOC的研究，以更好地了解它们进入血液循环后的行为和表现。该项目的结果将为开发更安全的AOCs产品提供有用的知识。该研究方法可用于预测输血后血液替代品的性能或评估药物治疗对血液循环的影响。这项研究是高度跨学科的，涉及微加工，生物化学，微流体，生物工程和材料科学的知识和培训。这将有助于扩大代表性不足的群体对研究的参与。该项目的研究成果将纳入本科生和研究生生物工程课程，以及与K-12学生和科学教师的外联活动。延长AOC的存活时间和预防输血相关并发症是输血医学面临的重大挑战。AOC的机械生物学，将生物化学和输血后的系统反应联系起来，尚未得到充分研究。该项目的目标是使用多尺度实验方法解决关于AOC的输血后行为和对血管的潜在影响的几个重要问题。首先，AOCs的疲劳将通过使用独特和通用的生物力学测试平台在单细胞水平上使其经受循环缺氧和剪切应力来表征。然后，AOCs和生理细胞之间的动态相互作用将研究氧化损伤和一氧化氮治疗下，使用体外模型的血液循环复制细胞，血液动力学和气体微环境的毛细血管和小动脉。最后，在基于微流体的肺微血管模型中，当AOC与生理血细胞一起循环时，将测量血流行为、血管损伤的发作和进展。这项研究将提供一个基本的理解的生物力学机制的失败AOCs，炎症反应，和相关的治疗干预。这个奖项反映了NSF的法定使命，并已被认为是值得通过评估使用基金会的智力价值和更广泛的影响审查标准的支持。

Artificial oxygen carriers (AOCs) were initially developed as red blood cell substitutes for transfusion and recently as oxygen therapeutics. They can reduce the harmful side effects of transfusion, such as immunoreaction and inflammation from the donated blood, or to enable life-saving surgeries in patients when donated blood becomes a sparse source. However, development of safe and effective AOCs to replace physiological human red blood cells is challenging. This award supports the research on AOCs to better understand their behavior and performance after entering blood circulation. The results from this project will provide useful knowledge that can be used to develop of safer AOCs products. The research methods can be used to predict the post-transfusion performance of blood substitutes or evaluate the effects of drug treatment on blood circulation. This research is highly interdisciplinary, involving knowledge and training in microfabrication, biochemistry, microfluidics, bioengineering and materials science. It will help broaden participation of underrepresented groups in research. Research findings from this project will be integrated into undergraduate and graduate bioengineering courses, as well as the outreach activities with K-12 students and science teachers. Prolongation of AOCs survival and prevention of transfusion-associated complications are grand challenges in transfusion medicine. Mechanobiology of AOCs, linking biochemistry and systematic response post transfusion, has not been well-studied. The goal of this project is to address several important questions regarding the post-transfusion behavior of AOCs and the potential impacts on the blood vessels, using a multi-scale experimental approach. First, the fatigue of AOCs will be characterized by subjecting them to cyclic hypoxia and shear stresses at single-cell level using a unique and general biomechanical testing platform. Then, the dynamic interactions between AOCs and physiological cells will be studied under oxidative damage and nitric oxide treatments, using in vitro models of blood circulation replicating cellular, hemodynamic and gaseous microenvironment of capillaries and arterioles. Finally, he blood flow behavior, onset and progression of vessel injury will be measured while AOCs circulate in concert with physiological blood cells in a microfluidics-based pulmonary microvasculature model. This study will provide a fundamental understanding of the biomechanical mechanisms underlying the failure of AOCs, inflammatory response, and relevant therapeutic interventions.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.