Engineering biophysical microtechnologies for hematologic applications in health and disease

项目摘要/摘要 复杂的生物物理细胞相互作用是许多血液过程不可或缺的一部分，从血小板 聚集成白细胞滚动，并通过内皮细胞外渗。虽然分子生物学导致了 大量致病基因和相关生化信号通路的发现，这只是 这幅画，类似于只知道戏剧中的演员，而不知道情节。要充分理解如何 我们血液中的这些细胞机器在血液循环的动态环境中协同工作，以及这些 在疾病状态下，物理相互作用会出错，需要在细胞和 亚细胞尺度。我是一名“内科医生-科学家-工程师”，受过临床血液学和 生物工程，特别关注微/纳米系统技术、微流体和细胞力学， 我的实验室稳步地将这些领域合并在一起，开发出回答生物物理血液学问题的工具 以前在技术上不可行的问题，然后我们立即将其转化为我的病人的 床边。特别关注血液过程和疾病，如止血，血栓形成和 针对镰状细胞疾病，我们的实验室利用我们独特的临床和工程专业知识发明了 突破性的微技术，既可以作为血液过程和疾病的体外模型 这些系统在生理上比当前的系统更相关，或者能够回答特定的生物物理问题 在血液学方面，目前的系统无法做到这一点。更具体地说，我们已经开发出：1)“芯片器官” 使微血管系统的微流体模型能够在生理上起作用的技术 止血、血栓形成和镰状细胞病病理生理学的相关模型和2)微工程 研究血小板如何对其生物物理微环境做出反应的细胞学平台。 总的来说，我们的微技术不仅带来了突破性的研究，解决了 在血液学方面，目前的分析无法回答，但也可以作为药物发现的平台， 用于新型诊断设备的先驱技术，甚至是改变范式的药物输送策略。搬家 展望未来，我们的研究计划在技术开发和应用方面都取得了进展， 从问基本的有影响力的问题到对病人的翻译。前者的例子包括 将更复杂的微工程功能融入我们的微流体中，如机械部件 和新的生物材料，使“内皮化”出血模型能够研究所有的主要成分 体外止血和基于胶原水凝胶的微血管芯片研究细胞-细胞 镰状细胞病中的相互作用分别导致内皮功能障碍。另一方面，我们也在 现在应用我们现有的微技术作为血液疾病的生物物理生物标记物，如免疫 血小板减少症。总体而言，我们实验室独特的从地下室到工作台再到床边的方法不仅将 影响血液学研究，但最重要的是，改善我的病人的生活。

Project Summary/Abstract Complex biophysical cellular interactions are integral to many hematological processes ranging from platelet aggregation to leukocyte rolling and extravasation through the endothelium. While molecular biology has led to the discovery of numerous causative genes and associated biochemical signaling pathways, that is only part of the picture, analogous to knowing only the actors in a play without knowing the plot. To fully comprehend how these cellular machines in our blood work in concert in the dynamic environment of the circulation and how these physical interactions go awry during disease states requires physical tools that operate at the cellular and subcellular scales. With my background as a “physician-scientist-engineer” trained in clinical hematology and bioengineering with specific focuses in micro/nanosystems technologies, microfluidics, and cellular mechanics, my laboratory has steadily merged these fields together to develop tools to answer biophysical hematologic questions that were previously technologically infeasible, which we then immediately translate to my patients' bedsides. With specific focuses on hematologic processes and diseases such as hemostasis, thrombosis and sickle cell disease, our laboratory has leveraged our unique combined clinical and engineering expertise to invent groundbreaking microtechnologies that either function as in vitro models of hematologic processes and disease that are more physiologically relevant than current systems or enable answering specific biophysical questions in hematology that current systems are incapable of. More specifically, we have developed: 1) “organ-on-chip” technologies to enable vascularized microfluidic models of the microvasculature that function as physiologically relevant models of hemostasis, thrombosis, and sickle cell disease pathophysiology and 2) microengineered platforms to study the cellular mechanics of how platelets respond to their biophysical microenvironment. Collectively, our microtechnologies have not only led to groundbreaking research that have addressed questions in hematology that were not answerable with current assays, but also serve as drug discovery platforms, precursor technologies for novel diagnostic devices, and even paradigm-shifting drug delivery strategies. Moving forward, our research program progresses both in terms of technology development and application thereof, from asking basic impactful questions as well as translation towards the patient. Examples of the former involve incorporating more complex microengineered features into our microfluidics, such as mechanical components and novel biomaterials, to enable an “endothelialized” bleeding model to study all of the principal components of hemostasis in vitro and a collagen hydrogel-based microvasculature-on-a-chip to investigate how cell-cell interactions in sickle cell disease causes endothelial dysfunction, respectively. On the other hand, we are also now applying our existing microtechnologies as biophysical biomarkers of hematologic diseases such as immune thrombocytopenia. Overall, our laboratory's unique “basement-to-bench-to-bedside” approach will not only will impact hematology research, but most importantly, improve the lives of my patients.