Microfluidic devices to enrich and isolate circulating tumor cells.

Given the potential clinical impact of circulating tumor cells (CTCs) in blood as a clinical biomarker for the diagnosis and prognosis of various cancers, a myriad of detection methods for CTCs have been recently introduced. Among those, a series of microfluidic devices are particularly promising as they uniquely offer micro-scale analytical systems that are highlighted by low consumption of samples and reagents, high flexibility to accommodate other cutting-edge technologies, precise and well-defined flow behaviors, and automation capability, presenting significant advantages over conventional larger scale systems. In this review, we highlight the advantages of microfluidic devices and their potential for translation into CTC detection methods, categorized by miniaturization of bench-top analytical instruments, integration capability with nanotechnologies, and in situ or sequential analysis of captured CTCs. This review provides a comprehensive overview of recent advances in CTC detection achieved through application of microfluidic devices and the challenges that these promising technologies must overcome to be clinically impactful.

[1]  Dino Di Carlo,et al.  Microfluidic sample preparation for diagnostic cytopathology. , 2013, Lab on a chip.

[2]  Hong Chen,et al.  Vertical SiNWAs for biomedical and biotechnology applications. , 2014, Journal of materials chemistry. B.

[3]  Youli Zu,et al.  Detecting Circulating Tumor Cells: Current Challenges and New Trends , 2013, Theranostics.

[4]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[5]  László Hajba,et al.  Circulating tumor-cell detection and capture using microfluidic devices , 2014 .

[6]  E. Dmitrovsky,et al.  Effective capture of circulating tumor cells from a transgenic mouse lung cancer model using dendrimer surfaces immobilized with anti-EGFR. , 2015, Analytical chemistry.

[7]  Hong Wu,et al.  Three-dimensional nanostructured substrates toward efficient capture of circulating tumor cells. , 2009, Angewandte Chemie.

[8]  Jonathan W. Uhr,et al.  Tumor Cells Circulate in the Peripheral Blood of All Major Carcinomas but not in Healthy Subjects or Patients With Nonmalignant Diseases , 2004, Clinical Cancer Research.

[9]  Eugene J. Lim,et al.  Tunable Nanostructured Coating for the Capture and Selective Release of Viable Circulating Tumor Cells , 2015, Advanced materials.

[10]  Shirley Dex,et al.  JR 旅客販売総合システム（マルス）における運用及び管理について , 1991 .

[11]  Paul C. H. Li.  Microfluidic Lab-On-A-Chip for Chemical and Biological Analysis and Discovery , 2005 .

[12]  Bin-Da Chan,et al.  Circulating tumor cell detection using a parallel flow micro-aperture chip system. , 2015, Lab on a chip.

[13]  Siyang Zheng,et al.  Membrane microfilter device for selective capture, electrolysis and genomic analysis of human circulating tumor cells. , 2007, Journal of chromatography. A.

[14]  Seungpyo Hong,et al.  Dendrimer-mediated multivalent binding for the enhanced capture of tumor cells. , 2011, Angewandte Chemie.

[15]  Seungpyo Hong,et al.  Recent advances in nanotechnology-based detection and separation of circulating tumor cells. , 2016, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[16]  Seungpyo Hong,et al.  The Binding Avidity of a Nanoparticle-based Multivalent Targeted Drug Delivery Platform , 2022 .

[17]  Weian Zhao,et al.  Bioinspired multivalent DNA network for capture and release of cells , 2012, Proceedings of the National Academy of Sciences.

[18]  Peter R. C. Gascoyne,et al.  Isolation of Circulating Tumor Cells by Dielectrophoresis , 2014, Cancers.

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

[20]  B. Lim,et al.  Enrichment, detection and clinical significance of circulating tumor cells. , 2013, Lab on a chip.

[21]  Dino Di Carlo,et al.  Microfluidic Purification and Concentration of Malignant Pleural Effusions for Improved Molecular and Cytomorphological Diagnostics , 2013, PloS one.

[22]  Chunsheng Jiang,et al.  Microfluidics and circulating tumor cells. , 2013, The Journal of molecular diagnostics : JMD.

[23]  Hongshen Ma,et al.  Technologies for label-free separation of circulating tumor cells: from historical foundations to recent developments. , 2014, Lab on a chip.

[24]  Adam H Mepham,et al.  Nanoparticle-mediated binning and profiling of heterogeneous circulating tumor cell subpopulations. , 2015, Angewandte Chemie.

[25]  Mehmet Toner,et al.  Inertial Focusing for Tumor Antigen–Dependent and –Independent Sorting of Rare Circulating Tumor Cells , 2013, Science Translational Medicine.

[26]  Sridhar Ramaswamy,et al.  A microfluidic device for label-free, physical capture of circulating tumor cell-clusters , 2015, Nature Methods.

[27]  Dino Di Carlo,et al.  Automated cellular sample preparation using a Centrifuge-on-a-Chip. , 2011, Lab on a chip.

[28]  Samuel K Sia,et al.  Commercialization of microfluidic point-of-care diagnostic devices. , 2012, Lab on a chip.

[29]  Perry G. Schiro,et al.  Simultaneous and selective isolation of multiple subpopulations of rare cells from peripheral blood using ensemble-decision aliquot ranking (eDAR). , 2015, Lab on a chip.

[30]  Kazunori Hoshino,et al.  Microchip-based immunomagnetic detection of circulating tumor cells. , 2011, Lab on a chip.

[31]  Inertia-activated cell sorting of immune-specifically labeled cells in a microfluidic device , 2014 .

[32]  S. Lehmann,et al.  Protein biochip systems for the clinical laboratory , 2005, Clinical chemistry and laboratory medicine.

[33]  David T. Eddington,et al.  Channel surface patterning of alternating biomimetic protein combinations for enhanced microfluidic tumor cell isolation. , 2012, Analytical chemistry.

[34]  Eugene J. Lim,et al.  Microfluidic, marker-free isolation of circulating tumor cells from blood samples , 2014, Nature Protocols.

[35]  Kyung-A Hyun,et al.  Advances and critical concerns with the microfluidic enrichments of circulating tumor cells. , 2014, Lab on a chip.

[36]  Taisuke Masuda,et al.  Development of a New Rapid Isolation Device for Circulating Tumor Cells (CTCs) Using 3D Palladium Filter and Its Application for Genetic Analysis , 2014, PloS one.

[37]  W. Marsden.  I and J , 2012 .

[38]  Mateus Crespo,et al.  Reporting the Capture Efficiency of a Filter-Based Microdevice: A CTC Is Not a CTC Unless It Is CD45 Negative—Letter , 2011, Clinical Cancer Research.

[39]  A. Woolley,et al.  Advances in microfluidic materials, functions, integration, and applications. , 2013, Chemical reviews.

[40]  Ronan M. T. Fleming,et al.  Advantages and challenges of microfluidic cell culture in polydimethylsiloxane devices. , 2015, Biosensors & bioelectronics.

[41]  F. Olasagasti,et al.  Miniaturized technology for protein and nucleic acid point-of-care testing , 2012, Translational Research.

[42]  Alison M Thompson,et al.  Microfluidics for single-cell genetic analysis. , 2014, Lab on a chip.

[43]  A. Breman,et al.  High-recovery visual identification and single-cell retrieval of circulating tumor cells for genomic analysis using a dual-technology platform integrated with automated immunofluorescence staining , 2015, BMC Cancer.

[44]  S Paget,et al.  THE DISTRIBUTION OF SECONDARY GROWTHS IN CANCER OF THE BREAST. , 1889 .

[45]  Daniel T Chiu,et al.  Sensitive and high-throughput isolation of rare cells from peripheral blood with ensemble-decision aliquot ranking. , 2012, Angewandte Chemie.

[46]  Ciprian Iliescu,et al.  Label-free isolation of circulating tumor cells in microfluidic devices: Current research and perspectives. , 2013, Biomicrofluidics.

[47]  Jaap M J den Toonder,et al.  Circulating tumor cell isolation and diagnostics: toward routine clinical use. , 2011, Cancer research.

[48]  G. Whitesides,et al.  Fabrication of microfluidic systems in poly(dimethylsiloxane) , 2000, Electrophoresis.

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

[50]  B. Molnár,et al.  Circulating tumor cell clusters in the peripheral blood of colorectal cancer patients. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[52]  J. Tobias,et al.  Colony stimulating factor 1 is an extrinsic stimulator of mouse spermatogonial stem cell self-renewal , 2009, Development.

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

[54]  Brigitte Rack,et al.  Detection of Circulating Tumor Cells in Peripheral Blood of Patients with Metastatic Breast Cancer: A Validation Study of the CellSearch System , 2007, Clinical Cancer Research.

[55]  Yi-Kuen Lee,et al.  Highly efficient capture of circulating tumor cells by using nanostructured silicon substrates with integrated chaotic micromixers. , 2011, Angewandte Chemie.

[56]  Sridhar Ramaswamy,et al.  RNA sequencing of pancreatic circulating tumour cells implicates WNT signaling in metastasis , 2012, Nature.

[57]  Joshua Balsam,et al.  Webcam-based flow cytometer using wide-field imaging for low cell number detection at high throughput. , 2014, The Analyst.

[58]  J. Nieva,et al.  Case study of the morphologic variation of circulating tumor cells. , 2007, Human pathology.

[59]  Andrew J Armstrong,et al.  Angiogenesis , Metastasis , and the Cellular Microenvironment Circulating Tumor Cells from Patients with Advanced Prostate and Breast Cancer Display Both Epithelial and Mesenchymal Markers , 2011 .

[60]  Shashi K Murthy,et al.  Engineered alginate hydrogels for effective microfluidic capture and release of endothelial progenitor cells from whole blood. , 2011, Langmuir : the ACS journal of surfaces and colloids.

[61]  François-Clément Bidard,et al.  High purity microfluidic sorting and analysis of circulating tumor cells: towards routine mutation detection. , 2015, Lab on a chip.

[62]  Mo Chao Huang,et al.  Microsieve lab-chip device for rapid enumeration and fluorescence in situ hybridization of circulating tumor cells. , 2012, Lab on a chip.

[63]  Cha-Mei Tang,et al.  The systematic study of circulating tumor cell isolation using lithographic microfilters. , 2014, RSC advances.

[64]  H. Tseng,et al.  Capture and Stimulated Release of Circulating Tumor Cells on Polymer‐Grafted Silicon Nanostructures , 2013, Advanced materials.

[65]  Kazunori Hoshino,et al.  Multiscale immunomagnetic enrichment of circulating tumor cells: from tubes to microchips. , 2014, Lab on a chip.

[66]  L. Terstappen,et al.  Self-seeding microwell chip for the isolation and characterization of single cells. , 2015, Lab on a chip.

[67]  Jean Salamero,et al.  Microfluidic sorting and multimodal typing of cancer cells in self-assembled magnetic arrays , 2010, Proceedings of the National Academy of Sciences.

[68]  George M Whitesides,et al.  Polyvalent Interactions in Biological Systems: Implications for Design and Use of Multivalent Ligands and Inhibitors. , 1998, Angewandte Chemie.

[69]  Utkan Demirci,et al.  Nanostructured substrates for isolation of circulating tumor cells. , 2013, Nano today.

[70]  Mehmet Toner,et al.  Biopolymer system for cell recovery from microfluidic cell capture devices. , 2012, Analytical chemistry.

[71]  Seungpyo Hong,et al.  Direct measurements on CD24-mediated rolling of human breast cancer MCF-7 cells on E-selectin. , 2011, Analytical chemistry.

[72]  K. Jensen,et al.  Cells on chips , 2006, Nature.

[73]  Seungpyo Hong,et al.  The role of polymers in detection and isolation of circulating tumor cells , 2012 .

[74]  Sridhar Ramaswamy,et al.  Circulating Tumor Cell Clusters Are Oligoclonal Precursors of Breast Cancer Metastasis , 2014, Cell.

[75]  Seungpyo Hong,et al.  Enhanced tumor cell isolation by a biomimetic combination of E-selectin and anti-EpCAM: implications for the effective separation of circulating tumor cells (CTCs). , 2010, Langmuir : the ACS journal of surfaces and colloids.

[76]  Rui Liu,et al.  Lectin‐aided separation of circulating tumor cells and assay of their response to an anticancer drug in an integrated microfluidic device , 2010, Electrophoresis.

[77]  N. Morgenthaler,et al.  A novel method for the in vivo isolation of circulating tumor cells from peripheral blood of cancer patients using a functionalized and structured medical wire , 2012, International journal of oncology.

[78]  Seungpyo Hong,et al.  Differential Detection of Tumor Cells Using a Combination of Cell Rolling, Multivalent Binding, and Multiple Antibodies , 2014, Analytical chemistry.

[79]  Donald E Ingber,et al.  A combined micromagnetic-microfluidic device for rapid capture and culture of rare circulating tumor cells. , 2012, Lab on a chip.

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