Collaborative Research: Towards High-Throughput Label-Free Circulating Tumor Cell Separation using 3D Deterministic Dielectrophoresis (D-Cubed)

合作研究：利用 3D 确定性介电泳 (D-Cubed) 实现高通量无标记循环肿瘤细胞分离

• 批准号: 1917295
• 负责人: Jie Xu
• 金额: $ 27.77万
• 依托单位: University of Illinois at Chicago
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1917295&HistoricalAwards=false
• 关键词: Collaborative; Research; Towards; Throughput; Label

Circulating tumor cells are increasingly recognized as predictive biomarkers in early cancer detection; therefore, detecting circulating tumor cells in the peripheral blood of patients has important implications for clinical applications, which include early cancer detection as well as diagnoses and prediction of cancer progression. If viable unmodified circulating tumor cells can be separated from whole blood, then subsequent clinical analysis of these cells can lead to personalized cancer treatment. However, due to the extreme rarity of circulating tumor cells, a successful separation technology must meet the performance metrics of high-throughput, high-sensitivity, high-purity, and high-viability simultaneously to be useful - a goal that has never been achieved. To tackle these performance metrics, this project utilizes a novel threefold method called Three-Dimensional Deterministic Dielectrophoresis. Currently, the combined effects of three-dimensional geometry, deterministic lateral displacement and dielectrophoresis in a cell separation process represent a gap in research. Through this research, comprehensive understanding of the interplay between fluid mechanics, cell deformation, dielectrophoretic forces, and deterministic lateral displacement structures will be gained, which will lead to much improved sensitivity, purity, and cell viability at high-throughput - all requirements to be met at the same time. Additionally, the project will have a significant impact on a large number of underrepresented students in technical fields at both University of Illinois at Chicago (a federally designated Minority Serving Institution) and Washington State University Vancouver (a Research in Undergraduate Institutions eligible institution and the only four-year research university in southwest Washington). The Three-Dimensional Deterministic Dielectrophoresis method brings a transformative impact by creating meaningful and valuable links between previously unconnected ideas and domain knowledge - namely deterministic lateral displacement, dielectrophoresis, and three-dimensional printing - potentially disrupting and outperforming all existing alternatives. However, in order to make the method truly useful for medical practice, fundamental knowledge about the separation process must be gained. This breaks down into three research objectives: 1) Study cell transport, cell-obstacle collision dynamics, and cell dielectrophoresis in periodic obstacle arrays using predictive models with experimental validations; 2) Fabricate Three-Dimensional Deterministic Dielectrophoresis devices and characterize how different obstacle shapes, geometries, obstacle array patterns, dielectrophoresis field parameters, carrier fluids and flow rates influence the cell separation performance; 3) Characterize circulating tumor cell separation performance for lung tumor cells against the four performance metrics above. This proposed research is significant because the multiphysics numerical models will elucidate scientific mechanisms of the complex separation principles of this method, which will guide experimental realization of a microfluidic device for high-throughput label-free circulating tumor cell separation. The research is unique in that dielectrophoresis will be combined with deterministic lateral displacement in a three-dimensional micro-structure for the first time, which is enabled by state-of-the-art nano three-dimensional printing technology. The research outcomes here have important implications for clinical applications including early cancer detection as well as diagnosis and prediction of cancer progression, as circulating tumor cells are increasingly recognized as predictive biomarkers in early stage cancer.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.

在早期癌症检测中，循环肿瘤细胞越来越多地被认为是预测性生物标志物。因此，检测患者外周血中循环肿瘤细胞对临床应用具有重要意义，其中包括早期癌症检测以及诊断和预测癌症的进展。如果可以将无效的未修饰的循环肿瘤细胞与全血分离，那么这些细胞的随后临床分析可能会导致个性化的癌症治疗。但是，由于循环肿瘤细胞的极端稀有性，成功的分离技术必须满足高通量，高敏感性，高纯度和高可变性的高率指标，同时有用 - 这一目标是从未实现的目标。为了应对这些性能指标，该项目采用了一种新型的三倍方法，称为三维确定性介电性电泳。当前，在细胞分离过程中，三维几何形状，确定性侧向位移和介电的综合作用代表了研究中的差距。通过这项研究，将获得对流体力学，细胞变形，介电摄取力和确定性的侧向位移结构之间相互作用的全面了解，这将导致高通量的灵敏度，纯度和细胞活力，同时满足所有需求。此外，该项目将对伊利诺伊大学芝加哥大学（联邦指定的少数民族服务机构）和华盛顿州立大学温哥华的伊利诺伊大学技术领域的大量代表性不足的学生产生重大影响。三维确定性的介电性方法通过在先前未连接的思想和领域知识之间建立有意义的有价值的联系（即确定性确定性的侧向位移，介电型和三维印刷），从而带来了变革性的影响 - 潜在的破坏和超越了所有现有替代方案。但是，为了使该方法对医学实践真正有用，必须获得有关分离过程的基本知识。这将分为三个研究目标：1）使用具有实验验证的预测模型研究细胞运输，细胞孔碰撞动力学和细胞介电的细胞介电流体； 2）制造三维确定性的介电性电泳设备，并表征不同的障碍物形状，几何形状，障碍物阵列模式，介电型电池磁场参数，载体流体和流速如何影响细胞分离性能； 3）表征肺部肿瘤细胞的循环肿瘤细胞分离性能与上述四个性能指标。这项提出的研究具有重要意义，因为多物理数值模型将阐明该方法的复杂分离原理的科学机制，该机制将指导微流体设备的实验实现，以实现高通量标记的无循环肿瘤细胞分离。这项研究的独特之处在于，电介型将首次与三维微型结构中的确定性横向位移相结合，这是由最先进的纳米三维印刷技术启用的。这里的研究结果对临床应用具有重要意义，包括早期癌症检测以及诊断和预测癌症的进展，因为循环肿瘤细胞越来越被认为是早期癌症的预测性生物标志物。这项奖项反映了NSF的法定任务，并通过使用该基金会的知识优点和广泛影响来评估来表现出值得通过评估来进行评估。

项目成果

Separation of Non-Viable Chinese Hamster Ovary (CHO) Cells Using Dielectrophoresis in a Deterministic Lateral Displacement Ratchet

使用确定性横向位移棘轮中的介电泳分离无活力的中国仓鼠卵巢 (CHO) 细胞

• DOI: 10.1115/imece2020-23520
• 发表时间: 2020
• 期刊: Proceedings of ASME 2020 International Mechanical Engineering Congress and Exposition
• 作者: Khan, Mohammed;Chen, Xiaolin;Xu, Jie
• 通讯作者: Xu, Jie

AC electroosmosis micromixing on a lab-on-a-foil electric microfluidic device

• DOI: 10.1016/j.snb.2022.131611
• 发表时间: 2022-02
• 期刊: Sensors and Actuators B: Chemical
• 作者: Mengren Wu;Yuan Gao;A. Ghaznavi;Weiqi Zhao;Jie Xu