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.

循环肿瘤细胞被认为是癌症早期检测的预测生物标志物，因此检测患者外周血中的循环肿瘤细胞对临床应用具有重要意义，包括癌症的早期检测以及对癌症进展的诊断和预测。如果可以从全血中分离出活的未经修饰的循环肿瘤细胞，那么随后对这些细胞的临床分析可以导致个性化的癌症治疗。然而，由于循环肿瘤细胞的极端稀缺性，成功的分离技术必须同时满足高通量、高灵敏度、高纯度和高活性的性能指标才能有用--这是一个从未实现的目标。为了解决这些性能指标，该项目使用了一种新的三重方法，称为三维确定介电泳法。目前，在细胞分离过程中，三维几何、确定性侧向位移和介电泳法的综合效应是研究的一个空白。通过这项研究，将全面了解流体力学、细胞变形、介电泳力和确定性的横向位移结构之间的相互作用，这将大大提高灵敏度、纯度和高通量下的细胞存活率-所有这些要求都将同时得到满足。此外，该项目将对伊利诺伊大学芝加哥分校(联邦指定的少数族裔服务机构)和华盛顿州立大学温哥华分校(符合条件的本科院校研究机构，也是华盛顿州西南部唯一的四年制研究型大学)在技术领域的大量代表不足的学生产生重大影响。三维确定性介电泳法通过在以前未连接的想法和领域知识之间创建有意义和有价值的链接-即确定性横向位移、介电泳法和三维打印-带来了革命性的影响，潜在地颠覆了所有现有的替代方案，并超越了所有现有的替代方案。然而，为了使该方法真正用于医疗实践，必须获得关于分离过程的基本知识。本研究分为三个研究目标：1)使用预测模型研究周期性障碍阵列中的细胞传输、细胞-障碍碰撞动力学和细胞介电；2)制作三维确定性介电设备，并表征不同障碍形状、几何形状、障碍阵列模式、介电泳场参数、载液和流速对细胞分离性能的影响；3)以上述四个性能指标表征肺肿瘤细胞的循环肿瘤细胞分离性能。这项研究具有重要意义，因为多物理数值模型将阐明该方法复杂分离原理的科学机制，这将指导高通量无标记循环肿瘤细胞分离的微流控装置的实验实现。这项研究的独特之处在于，通过最先进的纳米三维打印技术，将首次在三维微结构中将介电泳与确定的横向位移相结合。这里的研究成果对临床应用具有重要的影响，包括早期癌症检测以及癌症进展的诊断和预测，因为循环肿瘤细胞越来越多地被认为是早期癌症的预测生物标志物。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。

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