Immunomagnetic nanoscreening of circulating tumor cells with a motion controlled microfluidic system

Combining the power of immunomagnetic assay and microfluidic microchip operations, we successfully detected rare CTCs from clinical blood samples. The microfluidic system is operated in a flip-flop mode, where a computer-controlled rotational holder with an array of microfluidic chips inverts the microchannels. We have demonstrated both theoretically and experimentally that the direction of red blood cell (RBC) sedimentation with regards to the magnetic force required for cell separation is important for capture efficiency, throughput, and purity. The flip-flop operation reduces the stagnation of RBCs and non-specific binding on the capture surface by alternating the direction of the magnetic field with respect to gravity. The developed immunomagnetic microchip-based screening system exhibits high capture rates (more than 90%) for SkBr3, PC3, and Colo205 cell lines in spiked screening experiments and successfully isolates CTCs from patient blood samples. The proposed motion controlled microchip-based immunomagnetic system shows great promise as a clinical tool for cancer diagnosis and prognosis.

[1]  A. Al-Mehdi,et al.  Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis , 2000, Nature Medicine.

[2]  Tanja Fehm,et al.  Cytogenetic evidence that circulating epithelial cells in patients with carcinoma are malignant. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[3]  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.

[4]  Leon W.M.M. Terstappen,et al.  Circulating Tumor Cells versus Imaging—Predicting Overall Survival in Metastatic Breast Cancer , 2006, Clinical Cancer Research.

[5]  P. Pilarski,et al.  FISH and chips: chromosomal analysis on microfluidic platforms. , 2007, IET nanobiotechnology.

[6]  H. Scher,et al.  Circulating Tumor Cell Analysis in Patients with Progressive Castration-Resistant Prostate Cancer , 2007, Clinical Cancer Research.

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

[8]  Stefan Sleijfer,et al.  Circulating tumor cells (CTCs): detection methods and their clinical relevance in breast cancer. , 2009, Cancer treatment reviews.

[9]  D. Ingber,et al.  Micromagnetic-microfluidic blood cleansing device. , 2009, Lab on a chip.

[10]  Anne-Michelle Noone,et al.  Circulating tumor cells: a useful predictor of treatment efficacy in metastatic breast cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  L. Terstappen,et al.  Characterization of circulating tumor cells by fluorescence in situ hybridization , 2009, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[12]  Oscar Lin,et al.  Fluorescence In situ Hybridization Analysis of Circulating Tumor Cells in Metastatic Prostate Cancer , 2009, Clinical Cancer Research.

[13]  Mark M Davis,et al.  Isolating highly enriched populations of circulating epithelial cells and other rare cells from blood using a magnetic sweeper device , 2009, Proceedings of the National Academy of Sciences.

[14]  Chong H. Ahn,et al.  Isolation of prostate cancer cell subpopulations of functional interest by use of an on-chip magnetic bead-based cell separator , 2009 .

[15]  K. Brehm,et al.  Characterization of S3Pvac Anti-Cysticercosis Vaccine Components: Implications for the Development of an Anti-Cestodiasis Vaccine , 2010, PLoS ONE.

[16]  A. Tutt,et al.  Comparative Membranome Expression Analysis in Primary Tumors and Derived Cell Lines , 2010, PloS one.

[17]  Jocelyn Kaiser,et al.  Medicine. Cancer's circulation problem. , 2010, Science.

[18]  Chang Lu,et al.  Microfluidic electroporation of tumor and blood cells: observation of nucleus expansion and implications on selective analysis and purging of circulating tumor cells. , 2010, Integrative biology : quantitative biosciences from nano to macro.

[19]  Tomoko Yoshino,et al.  Size-selective microcavity array for rapid and efficient detection of circulating tumor cells. , 2010, Analytical chemistry.

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

[21]  G. Doyle,et al.  Significance of Circulating Tumor Cells Detected by the CellSearch System in Patients with Metastatic Breast Colorectal and Prostate Cancer , 2009, Journal of oncology.

[22]  Dino Di Carlo,et al.  High-throughput size-based rare cell enrichment using microscale vortices. , 2011, Biomicrofluidics.

[23]  Jonathan W. Uhr,et al.  Controversies in clinical cancer dormancy , 2011, Proceedings of the National Academy of Sciences.

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

[25]  Bo Lu,et al.  3D microfilter device for viable circulating tumor cell (CTC) enrichment from blood , 2011, Biomedical microdevices.

[26]  Han Wei Hou,et al.  Pinched flow coupled shear-modulated inertial microfluidics for high-throughput rare blood cell separation. , 2011, Lab on a chip.

[27]  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.

[28]  M. Gross,et al.  Cytometric comparisons between circulating tumor cells from prostate cancer patients and the prostate-tumor-derived LNCaP cell line , 2012, Physical biology.

[29]  Peng Chen,et al.  Computational analysis of microfluidic immunomagnetic rare cell separation from a particulate blood flow. , 2012, Analytical chemistry.

[30]  Mainul Hossain,et al.  X-ray enabled detection and eradication of circulating tumor cells with nanoparticles. , 2012, Biosensors & bioelectronics.