CAREER: Modeling human veins and venous pathology with organ-on-chip engineering for basic, translational and educational research

静脉疾病(如静脉血栓形成)是全球最大的心血管疾病死亡原因之一。对这些疾病的了解相对较少，治疗这些疾病的治疗方法也非常有限。这些不足之处的存在是因为发现和治疗计划严重依赖动物模型的结果，而这些静脉疾病模型(特别是啮齿动物模型)在预测人类病理生理学方面往往表现不佳。这个NSF职业项目的目标是检验这样一个假设，即静脉的结构、功能和病理(深静脉血栓形成)可以用新设计的芯片上器官(Vin-on-Chip)技术自下而上地重建，在临床前和临床心血管研究中可以作为动物模型的替代品。该项目将被用来创建一个名为“没有动物但有工程的生物学”的教育项目，该项目将针对高中生，让本科生参与研究并担任导师，并为研究生提供当代交流策略。该计划旨在刺激STEM教育的兴奋，并有助于培养一支关键和多样化的生物医学工程师队伍，他们可以通过药物发现管道的创新来加速和节约医疗保健。研究人员的长期目标是通过FDA批准的生物工程建模系统为复杂血管疾病提供机械理解和治疗评估，从而积极影响人类医疗保健。为了实现这一目标，这个职业项目将建立在Investigator设计的完全人类芯片上静脉(包括瓣膜和内皮)的可调模型上，用于体外分析静脉血栓形成、相关病理和治疗。研究计划旨在建立这个芯片上静脉平台，对控制静脉血栓形成及其治疗的已知但未被探索的因素进行可剖析的分析。第一步是利用该平台依次剖析Virchow三位一体的因素(内皮、血液和血流)，并确定它们在DVT发生和传播中的单独和协同贡献。然后，芯片上的静脉将被用于系统地剖析免疫因素。血液成分(中性粒细胞、单核细胞或血小板)将被系统地添加或减去，以确定单独或共同在DVT发病及其后果中的协同或抑制作用。最后，芯片上的静脉将被用来建议解决DVT的新策略。工作假设是DVT-on-Chip系统将揭示抗凝剂、抗炎和他汀类药物的组合如何解决DVT。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Venous diseases (such as venous thrombosis) are ranked amongst the top cardiovascular causes of death worldwide. These diseases are relatively poorly understood and the therapeutic approaches to treat these disorders are very limited. These inadequacies exist because discovery and therapeutic programs rely heavily on results from animal models, whereas these models (particularly rodent models) of venous diseases often perform poorly in terms of predicting human pathophysiology. The goal of this NSF CAREER project is to test the hypothesis that venous architecture, function and pathology (deep vein thrombosis) can be recreated bottom-up with a newly designed organ-on-chip (vein-on-chip) technology, which can serve as a replacement to animal models in preclinical and clinical cardiovascular research. The project will be leveraged to create an educational program titled "Biology WITHOUT Animals But WITH Engineering" that will target high school students, involve undergraduates in research and as mentors, and provide contemporary communication strategies to graduate students. The program is designed to stimulate excitement in STEM education and contribute to creating a critical and diverse workforce of biomedical engineers who can accelerate and economize healthcare through innovation in drug discovery pipelines.The Investigator’s long-term goal is to positively impact human healthcare by providing both mechanistic understanding as well as therapeutic assessment for complex vascular diseases with FDA-approved bioengineered modeling systems. Toward this goal, this CAREER project will build on the Investigator’s engineered tunable model of a fully human vein-on-chip (including valves and endothelium) for the analysis of venous thrombosis, related pathologies and therapeutics in vitro. The Research Plan is designed to establish this vein-on-chip platform to perform dissectible analysis of the known but underexplored factors that govern venous thrombosis and its treatment. The first step is to leverage the platform to dissect the factors of Virchow’s triad sequentially (endothelium, blood and flow) and determine their individual and collaborative contributions in the onset and propagation of DVT. The vein-on-a-chip will then be applied to dissect the immune factors systematically. Blood constituents (neutrophils, monocytes or platelets) will be added or subtracted systematically to determine the synergistic or inhibitory role, individually or collectively, in onset of DVT and its consequences. Finally, the vein-on-chip will be used to suggest new strategies to resolve DVT. The working hypothesis is that the DVT-on-chip system will reveal how combinations of anticoagulant, anti-inflammatory and statin drugs may resolve DVT.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.