Dynamic Halbach array magnet integrated microfluidic system for the continuous-flow separation of rare tumor cells

Abstract Studies have shown that primary tumor sites begin shedding cancerous cells into peripheral blood at early stages of cancer, and the presence and frequency of circulating tumor cells (CTCs) in blood is directly proportional to disease progression. The challenge is that the concentration of the CTCs in peripheral blood may be extremely low. In the past few years, several microfluidic-based concepts have been investigated to isolate CTCs from whole blood. However, these devices are generally hampered by complex fabrication processes and very low volumetric throughputs, which may not be practical for rapid clinical applications. This paper presents a high-performance yet simple magnetophoretic microfluidic chip for the enrichment and on-chip analysis of rare CTCs from blood. Microscopic and flow cytometric assays developed for selection of cancer cell lines, selection of monoclonal antibodies, and optimization of bead coupling are discussed. Additionally, on-chip characterization of rare cancer cells using high resolution immunofluorescence microscopy and modeling results for prediction of CTC capture length are presented. The device has the ability to interface directly with on-chip pre and post processing modules such as mixing, incubation, and automated image analysis systems. These features will enable us to isolate rare cancer cells from whole blood and detect them on the chip with subcellular resolution.

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Ex VivoDetection of Circulating Tumor Cells from Whole Blood by Direct Nanoparticle Visualization

ACS Nano ◽

10.1021/acsnano.7b08813 ◽

2018 ◽

Vol 12 (2) ◽

pp. 1902-1909 ◽

Cited By ~ 10

Author(s):

Regivaldo G. Sobral-Filho ◽

Lindsay DeVorkin ◽

Sarah Macpherson ◽

Andrew Jirasek ◽

Julian J. Lum ◽

...

Keyword(s):

Tumor Cells ◽

Circulating Tumor Cells ◽

Whole Blood

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Hybrid negative enrichment of circulating tumor cells from whole blood in a 3D-printed monolithic device

Lab on a Chip ◽

10.1039/c9lc00575g ◽

2019 ◽

Vol 19 (20) ◽

pp. 3427-3437 ◽

Cited By ~ 6

Author(s):

Chia-Heng Chu ◽

Ruxiu Liu ◽

Tevhide Ozkaya-Ahmadov ◽

Mert Boya ◽

Brandi E. Swain ◽

...

Keyword(s):

Tumor Cells ◽

Circulating Tumor Cells ◽

Microfluidic Device ◽

Whole Blood ◽

3D Printed

A monolithic 3D-printed microfluidic device integrated with stacked layers of functionalized leukodepletion channels and microfiltration for the negative enrichment of circulating tumor cells directly from clinically relevant volumes of whole blood.

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A microfluidic system based on the monoclonal antibody BCMab1 specifically captures circulating tumor cells from bladder cancer patients

Journal of Biomaterials Science Polymer Edition ◽

10.1080/09205063.2020.1748332 ◽

2020 ◽

Vol 31 (9) ◽

pp. 1199-1210 ◽

Cited By ~ 1

Author(s):

Yunchao Wang ◽

Qing Liu ◽

Tongyi Men ◽

Ye Liang ◽

Haitao Niu ◽

...

Keyword(s):

Monoclonal Antibody ◽

Bladder Cancer ◽

Cancer Patients ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Microfluidic System

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Functional profiling of circulating tumor cells with an integrated vortex capture and single-cell protease activity assay

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1803884115 ◽

2018 ◽

Vol 115 (40) ◽

pp. 9986-9991 ◽

Cited By ~ 45

Author(s):

Manjima Dhar ◽

Jeffrey Nam Lam ◽

Tonya Walser ◽

Steven M. Dubinett ◽

Matthew B. Rettig ◽

...

Keyword(s):

Tumor Cells ◽

Circulating Tumor Cells ◽

Activity Ratio ◽

Proteolytic Enzymes ◽

Microfluidic System ◽

Matrix Metalloprotease ◽

Rare Cancer ◽

Companion Diagnostics ◽

Functional Profiling ◽

Vortex Capture

Tumor cells are hypothesized to use proteolytic enzymes to facilitate invasion. Whether circulating tumor cells (CTCs) secrete these enzymes to aid metastasis is unknown. A quantitative and high-throughput approach to assay CTC secretion is needed to address this question. We developed an integrated microfluidic system that concentrates rare cancer cells >100,000-fold from 1 mL of whole blood into ∼50,000 2-nL drops composed of assay reagents within 15 min. The system isolates CTCs by size, exchanges fluid around CTCs to remove contaminants, introduces a matrix metalloprotease (MMP) substrate, and encapsulates CTCs into microdroplets. We found CTCs from prostate cancer patients possessed above baseline levels of MMP activity (1.7- to 200-fold). Activity of CTCs was generally higher than leukocytes from the same patient (average CTC/leukocyte MMP activity ratio, 2.6 ± 1.5). Higher MMP activity of CTCs suggests active proteolytic processes that may facilitate invasion or immune evasion and be relevant phenotypic biomarkers enabling companion diagnostics for anti-MMP therapies.

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