Creating a capture zone in microfluidic flow greatly enhances the throughput and efficiency of cancer detection.

Efficient capture of rare circulating tumor cells (CTCs) from blood samples is valuable for early cancer detection to improve the management of cancer. In this work, we developed a highly efficient microfluidics-based method for detecting CTCs in human blood. This is achieved by creating separate capture and flow zones in the microfluidic device (ZonesChip) and using patterned dielectrophoretic force to direct cells from the flow zone into the capture zone. This separation of the capture and flow zones minimizes the negative impact of high flow speed (and thus high throughput) and force in the flow zone on the capture efficiency, overcoming a major bottleneck of contemporary microfluidic approaches using overlapping flow and capture zones for CTC detection. When the flow speed is high (≥0.58 mm/s) in the flow zone, the separation of capture and flow zones in our ZonesChip could improve the capture efficiency from ∼0% (for conventional device without separating the two zones) to ∼100%. Our ZonesChip shows great promise as an effective platform for the detection of CTCs in blood from patients with early/localized-stage colorectal tumors.

[1]  Hongshen Ma,et al.  Size and deformability based separation of circulating tumor cells from castrate resistant prostate cancer patients using resettable cell traps. , 2015, Lab on a chip.

[2]  D. Haber,et al.  Microfluidic isolation of platelet-covered circulating tumor cells. , 2017, Lab on a chip.

[3]  Peter C. Y. Chen,et al.  Slanted spiral microfluidics for the ultra-fast, label-free isolation of circulating tumor cells. , 2014, Lab on a chip.

[4]  Sharmeela Kaushal,et al.  Fluorescently labeled chimeric anti‐CEA antibody improves detection and resection of human colon cancer in a patient‐derived orthotopic xenograft (PDOX) nude mouse model , 2014, Journal of surgical oncology.

[5]  M. Toner,et al.  Enhanced Isolation and Release of Circulating Tumor Cells Using Nanoparticle Binding and Ligand Exchange in a Microfluidic Chip. , 2017, Journal of the American Chemical Society.

[6]  A. Jemal,et al.  Colorectal cancer statistics, 2014 , 2014, CA: a cancer journal for clinicians.

[7]  R. Pethig,et al.  ApoStream(™), a new dielectrophoretic device for antibody independent isolation and recovery of viable cancer cells from blood. , 2012, Biomicrofluidics.

[8]  D. Weitz,et al.  An RNA-based signature enables high specificity detection of circulating tumor cells in hepatocellular carcinoma , 2017, Proceedings of the National Academy of Sciences.

[9]  E. Gunter,et al.  Hematological and iron-related analytes--reference data for persons aged 1 year and over: United States, 1988-94. , 2005, Vital and health statistics. Series 11, Data from the National Health Survey.

[10]  D. Haber,et al.  Whole blood stabilization for the microfluidic isolation and molecular characterization of circulating tumor cells , 2017, Nature Communications.

[11]  Daniel F. Hayes,et al.  Sensitive capture of circulating tumour cells by functionalised graphene oxide nanosheets , 2013, Nature nanotechnology.

[12]  Andreas Manz,et al.  A facile in situ microfluidic method for creating multivalent surfaces: toward functional glycomics. , 2012, Lab on a chip.

[13]  D. Jayne,et al.  Carcinoembryonic antigen is the preferred biomarker for in vivo colorectal cancer targeting , 2013, British Journal of Cancer.

[14]  Sharon S. Hori,et al.  Detection and Quantitation of Circulating Tumor Cell Dynamics by Bioluminescence Imaging in an Orthotopic Mammary Carcinoma Model , 2014, PloS one.

[15]  Xiongbin Lu,et al.  Continuous On-Chip Cell Separation Based on Conductivity-Induced Dielectrophoresis with 3D Self-Assembled Ionic Liquid Electrodes. , 2016, Analytical chemistry.

[16]  Subra Suresh,et al.  Circulating Tumor Cell Phenotyping via High-Throughput Acoustic Separation. , 2018, Small.

[17]  Rajan P Kulkarni,et al.  Label-free enumeration, collection and downstream cytological and cytogenetic analysis of circulating tumor cells , 2016, Scientific Reports.

[18]  Paolo A. Netti,et al.  Cell rolling and adhesion on surfaces in shear flow. A model for an antibody-based microfluidic screening system , 2012 .

[19]  A Manz,et al.  Protein-carbohydrate complex reveals circulating metastatic cells in a microfluidic assay. , 2013, Small.

[20]  T. Huang,et al.  Acoustic separation of circulating tumor cells , 2015, Proceedings of the National Academy of Sciences.

[21]  T. Toth,et al.  Label-Free On-Chip Selective Extraction of Cell-Aggregate-Laden Microcapsules from Oil into Aqueous Solution with Optical Sensor and Dielectrophoresis. , 2018, ACS sensors.

[22]  K. Isselbacher,et al.  Isolation of circulating tumor cells using a microvortex-generating herringbone-chip , 2010, Proceedings of the National Academy of Sciences.

[23]  P. Gascoyne,et al.  Antibody-independent isolation of circulating tumor cells by continuous-flow dielectrophoresis. , 2013, Biomicrofluidics.

[24]  Mengxi Wu,et al.  High-throughput acoustic separation of platelets from whole blood. , 2016, Lab on a chip.

[25]  H. Friess,et al.  Characterization of cytokeratin 20 expression in pancreatic and colorectal cancer. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[26]  R. Cote,et al.  Identification and Quantitation of Circulating Tumor Cells. , 2017, Annual review of analytical chemistry.

[27]  Alison Stopeck,et al.  Circulating tumor cells, disease progression, and survival in metastatic breast cancer. , 2004, The New England journal of medicine.

[28]  A. Jemal,et al.  Cancer statistics, 2018 , 2018, CA: a cancer journal for clinicians.

[29]  K. Pienta,et al.  Circulating Tumor Cells Predict Survival Benefit from Treatment in Metastatic Castration-Resistant Prostate Cancer , 2008, Clinical Cancer Research.

[30]  Xiling Shen,et al.  A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells. , 2013, Cell stem cell.

[31]  J. Massagué,et al.  Metastatic colonization by circulating tumour cells , 2016, Nature.

[32]  S. Digumarthy,et al.  Isolation of rare circulating tumour cells in cancer patients by microchip technology , 2007, Nature.

[33]  Thomas J George,et al.  Capture, release and culture of circulating tumor cells from pancreatic cancer patients using an enhanced mixing chip. , 2014, Lab on a chip.

[34]  Feng Zhang,et al.  Nanoroughened surfaces for efficient capture of circulating tumor cells without using capture antibodies. , 2013, ACS nano.

[35]  Z. Werb,et al.  Circulating Tumor Cells , 2013, Science.

[36]  J. Pollard,et al.  Immune cell promotion of metastasis , 2015, Nature Reviews Immunology.

[37]  J. Volakis,et al.  Stiffness-Independent Highly Efficient On-Chip Extraction of Cell-Laden Hydrogel Microcapsules from Oil Emulsion into Aqueous Solution by Dielectrophoresis. , 2015, Small.

[38]  Michael B. Sano,et al.  Isolation of rare cancer cells from blood cells using dielectrophoresis , 2012, 2012 Annual International Conference of the IEEE Engineering in Medicine and Biology Society.

[39]  H. Jung,et al.  Continuous separation of breast cancer cells from blood samples using multi-orifice flow fractionation (MOFF) and dielectrophoresis (DEP). , 2011, Lab on a chip.

[40]  S. Kyo,et al.  Circulating tumour cells detected by a novel adenovirus-mediated system may be a potent therapeutic marker in gynaecological cancers , 2012, British Journal of Cancer.

[41]  Ronald C. Chen,et al.  Multivalent Binding and Biomimetic Cell Rolling Improves the Sensitivity and Specificity of Circulating Tumor Cell Capture , 2018, Clinical Cancer Research.

[42]  Dino Di Carlo,et al.  Biophysical isolation and identification of circulating tumor cells. , 2017, Lab on a chip.