Engineering biophysical microtechnologies for hematologic applications in health and disease

工程生物物理微技术在健康和疾病中的血液学应用

• 批准号: 10579951
• 负责人: Wilbur A Lam
• 金额: $ 78.45万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-22 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579951
• 关键词: Address; Adopted; Biochemical; Biocompatible Materials; Biological Assay; Biological Markers; Biology; Biomedical Engineering; Biophysics; Blood; Blood Platelets; Cell Communication; Cells; Circulation; Clinical; Clinical assessments; Collagen; Complex; Diagnostic; Diagnostic Equipment; Disease; Disease model; Drug Delivery Systems; Endothelium; Engineering; Environment; Extravasation; Functional disorder; Genes; Goals; Health; Hematological Disease; Hematology; Hemorrhage; Hemostatic function; Hydrogels; Idiopathic Thrombocytopenic Purpura; In Vitro; Laboratories; Leukocyte Rolling; Mechanics; Medicine; Microfluidics; Modeling; Molecular Biology; Patients; Physicians; Physics; Physiological; Platelet aggregation; Play; Process; Research; Scientist; Sickle Cell Anemia; Signal Pathway; System; Technology; Therapeutic; Thrombosis; Training; Translating; Translations; Vascularization; Work; bench to bedside; clinical diagnostics; drug discovery; endothelial dysfunction; improved; in vitro Model; interdisciplinary approach; interest; invention; microdevice; nanoscale; nanosystems; new technology; novel; organ on a chip; pre-clinical; programs; technology development; technology platform; tool

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.

项目摘要/摘要 复杂的生物物理细胞相互作用是许多血液学过程不可或缺的一部分 通过内皮的白细胞滚动和渗出的聚集。虽然分子生物学已导致 发现了许多休闲基因和相关的生化信号传导途径，这只是 图片类似于仅知道戏剧中的演员而不知道情节。充分理解如何 我们的血液中的这些细胞机在循环的动态环境中共同进行，以及如何 身体相互作用在疾病状态下出现问题，需要在细胞中运行的物理工具， 亚细胞尺度。以我的背景为“医师科学家工程师”，接受了临床血液学和 在微/纳米系统技术，微流体和细胞力学方面具有特定重点的生物工程， 我的实验室稳步合并了这些领域，以开发用于回答生物物理血液学的工具 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患者 床旁。特别关注血液学过程和疾病，例如止血，血栓形成和 镰状细胞疾病，我们的实验室利用了我们独特的临床和工程专业知识来发明 开创性的微技术，它们可以用作血液学过程和疾病的体外模型 比当前系统更有意义，或启用回答特定的生物物理问题 在血液学中，当前系统无力。更具体地说，我们已经开发了：1）“片上器官” 能够启用微脉管系统的血管化微流体模型的技术 止血，血栓形成和镰状细胞病理生理学的相关模型和2）微工程 研究血小板如何应对其生物物理微环境的平台。 总体而言，我们的微技术不仅导致了开创性的研究，从而解决了问题 在血液学中对当前测定不起的血液学，但也充当药物发现平台， 用于新型诊断设备的前体技术，甚至是范式转移药物输送策略。移动 向前看，我们的研究计划在技术开发及其应用方面取得了进步， 从提出基本有影响力的问题以及对患者的翻译。前者的例子涉及 将更复杂的微工程特征纳入我们的微流体，例如机械组件 和新型的生物材料，以实现“内皮化”出血模型来研究所有主要成分 体外止血和基于胶原水凝胶基于芯片的胶原蛋白的微瘤，以研究细胞细胞如何 镰状细胞疾病的相互作用分别引起内皮功能障碍。另一方面，我们也是 现在将我们现有的微技术作为血液学疾病的生物物理生物标志物，例如免疫 血小板减少症。总体而言，我们实验室独特的“地下室到卧铺”的方法不仅会 影响血液学研究，但最重要的是，改善了患者的生活。