Microfluidics and cancer: are we there yet?

More than two decades ago, microfluidics began to show its impact in biological research. Since then, the field of microfluidics has evolving rapidly. Cancer is one of the leading causes of death worldwide. Microfluidics holds great promise in cancer diagnosis and also serves as an emerging tool for understanding cancer biology. Microfluidics can be valuable for cancer investigation due to its high sensitivity, high throughput, less material-consumption, low cost, and enhanced spatio-temporal control. The physical laws on microscale offer an advantage enabling the control of physics, biology, chemistry and physiology at cellular level. Furthermore, microfluidic based platforms are portable and can be easily designed for point-of-care diagnostics. Developing and applying the state of the art microfluidic technologies to address the unmet challenges in cancer can expand the horizons of not only fundamental biology but also the management of disease and patient care. Despite the various microfluidic technologies available in the field, few have been tested clinically, which can be attributed to the various challenges existing in bridging the gap between the emerging technology and real world applications. We present a review of role of microlfuidcs in cancer research, including the history, recent advances and future directions to explore where the field stand currently in addressing complex clinical challenges and future of it. This review identifies four critical areas in cancer research, in which microfluidics can change the current paradigm. These include cancer cell isolation, molecular diagnostics, tumor biology and high-throughput screening for therapeutics. In addition, some of our lab’s current research is presented in the corresponding sections.

[1]  Kevin W Eliceiri,et al.  Transition to invasion in breast cancer: a microfluidic in vitro model enables examination of spatial and temporal effects. , 2011, Integrative biology : quantitative biosciences from nano to macro.

[2]  L. Hood,et al.  Integrated barcode chips for rapid, multiplexed analysis of proteins in microliter quantities of blood , 2008, Nature Biotechnology.

[3]  James R Heath,et al.  Nanotechnology and cancer. , 2008, Annual review of medicine.

[4]  Daniel B. Martin,et al.  Circulating microRNAs as stable blood-based markers for cancer detection , 2008, Proceedings of the National Academy of Sciences.

[5]  Jason P. Gleghorn,et al.  Capture of circulating tumor cells from whole blood of prostate cancer patients using geometrically enhanced differential immunocapture (GEDI) and a prostate-specific antibody. , 2010, Lab on a chip.

[6]  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.

[7]  A. Griffiths,et al.  High-resolution dose–response screening using droplet-based microfluidics , 2011, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Zhongliang Tang,et al.  Efficient capture of circulating tumor cells with a novel immunocytochemical microfluidic device. , 2011, Biomicrofluidics.

[9]  Francis Barany,et al.  High-throughput selection, enumeration, electrokinetic manipulation, and molecular profiling of low-abundance circulating tumor cells using a microfluidic system. , 2011, Analytical chemistry.

[10]  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.

[11]  A. Jayaraman,et al.  A programmable microfluidic cell array for combinatorial drug screening. , 2012, Lab on a chip.

[12]  Peter K Sorger,et al.  Microfluidics closes in on point-of-care assays , 2008, Nature Biotechnology.

[13]  P. Metalnikov,et al.  Droplet-Scale Estrogen Assays in Breast Tissue, Blood, and Serum , 2009, Science Translational Medicine.

[14]  A. Berg,et al.  Micro Total Analysis Systems , 1995 .

[15]  David J Beebe,et al.  Cellular observations enabled by microculture: paracrine signaling and population demographics. , 2009, Integrative biology : quantitative biosciences from nano to macro.

[16]  David J. Mooney,et al.  Label-free biomarker detection from whole blood , 2009, 2010 10th IEEE International Conference on Solid-State and Integrated Circuit Technology.

[17]  P. Csermely,et al.  Salivary Genomics, Transcriptomics and Proteomics: The Emerging Concept of the Oral Ecosystem and their Use in the Early Diagnosis of Cancer and other Diseases , 2008, Current genomics.

[18]  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.

[19]  Donald Wlodkowic,et al.  Biological implications of polymeric microdevices for live cell assays. , 2009, Analytical chemistry.

[20]  T. Wurdinger,et al.  Microfluidic isolation and transcriptome analysis of serum microvesicles. , 2010, Lab on a chip.

[21]  Darwin R. Reyes,et al.  Micro total analysis systems. 1. Introduction, theory, and technology. , 2002, Analytical chemistry.

[22]  M. Zborowski,et al.  Detection of rare MCF-7 breast carcinoma cells from mixtures of human peripheral leukocytes by magnetic deposition analysis. , 1999, Cytometry.

[23]  J. Turner,et al.  Circulating tumor cells: capture with a micromachined device , 2005 .

[24]  Mehmet Toner,et al.  Isolation and Characterization of Circulating Tumor Cells from Patients with Localized and Metastatic Prostate Cancer , 2010, Science Translational Medicine.

[25]  Ru-Fang Yeh,et al.  Molecular Biomarker Analyses Using Circulating Tumor Cells , 2010, PloS one.

[26]  Raquel Perez-Castillejos,et al.  Partitioning microfluidic channels with hydrogel to construct tunable 3-D cellular microenvironments. , 2008, Biomaterials.

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

[28]  Gengfeng Zheng,et al.  Multiplexed electrical detection of cancer markers with nanowire sensor arrays , 2005, Nature Biotechnology.

[29]  A. Jemal,et al.  Cancer statistics, 2011 , 2011, CA: a cancer journal for clinicians.

[30]  Mieke Schutte,et al.  Anti-Epithelial Cell Adhesion Molecule Antibodies and the Detection of Circulating Normal-Like Breast Tumor Cells , 2009, Journal of the National Cancer Institute.

[31]  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.

[32]  Jong Wook Hong,et al.  Integrated nanoliter systems , 2003, Nature Biotechnology.

[33]  Shuichi Takayama,et al.  Microfluidic system for formation of PC-3 prostate cancer co-culture spheroids. , 2009, Biomaterials.

[34]  R. Kamm,et al.  Cell migration into scaffolds under co-culture conditions in a microfluidic platform. , 2009, Lab on a chip.

[35]  D. Taylor,et al.  Tumour-derived exosomes and their role in cancer-associated T-cell signalling defects , 2005, British Journal of Cancer.

[36]  Jong Hwan Sung,et al.  Microtechnology for Mimicking In Vivo Tissue Environment , 2012, Annals of Biomedical Engineering.

[37]  Darwin R. Reyes,et al.  Micro total analysis systems. 2. Analytical standard operations and applications. , 2002, Analytical chemistry.

[38]  Robert Langer,et al.  New frontiers in nanotechnology for cancer treatment. , 2008, Urologic oncology.

[39]  David J Beebe,et al.  Hedgehog signaling in myofibroblasts directly promotes prostate tumor cell growth. , 2012, Integrative biology : quantitative biosciences from nano to macro.

[40]  Shuichi Takayama,et al.  Selective chemical treatment of cellular microdomains using multiple laminar streams. , 2003, Chemistry & biology.

[41]  Mehmet Toner,et al.  Detection of mutations in EGFR in circulating lung-cancer cells. , 2008, The New England journal of medicine.

[42]  Donald Wlodkowic,et al.  Microfluidic single-cell array cytometry for the analysis of tumor apoptosis. , 2009, Analytical chemistry.

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

[44]  Jaap M. J. den Toonder,et al.  Circulating tumor cells: the Grand Challenge. , 2011, Lab on a chip.

[45]  Donald Wlodkowic,et al.  Microfluidics: Emerging prospects for anti-cancer drug screening. , 2010, World journal of clinical oncology.

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

[47]  Han Wei Hou,et al.  Microfluidic Devices for Blood Fractionation , 2011, Micromachines.

[48]  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.

[49]  Elinore M Mercer,et al.  Microfluidic sorting of mammalian cells by optical force switching , 2005, Nature Biotechnology.

[50]  Evelyn Wenkel,et al.  Circulating Micro-RNAs as Potential Blood-Based Markers for Early Stage Breast Cancer Detection , 2012, PloS one.

[51]  Donald Wlodkowic,et al.  Cytometry in cell necrobiology revisited. Recent advances and new vistas , 2010, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[52]  D. Ichikawa,et al.  Circulating microRNAs in plasma of patients with gastric cancers , 2010, British Journal of Cancer.

[53]  Shuichi Takayama,et al.  Microfluidic Endothelium for Studying the Intravascular Adhesion of Metastatic Breast Cancer Cells , 2009, PloS one.

[54]  A. Lee,et al.  Engineering microscale cellular niches for three-dimensional multicellular co-cultures. , 2009, Lab on a chip.

[55]  Chang-Yu Chen,et al.  Separation and detection of rare cells in a microfluidic disk via negative selection. , 2011, Lab on a chip.

[56]  Giovanni De Gasperis,et al.  Microfluidic Cell Separation by 2-dimensional Dielectrophoresis , 1999 .

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

[58]  M Vasei,et al.  Frequent high-level expression of the immunotherapeutic target Ep-CAM in colon, stomach, prostate and lung cancers , 2006, British Journal of Cancer.

[59]  E. Finot,et al.  From nanotechnology to nanomedicine: applications to cancer research. , 2010, Current molecular medicine.

[60]  Daniel T Chiu,et al.  Deformability considerations in filtration of biological cells. , 2010, Lab on a chip.

[61]  M. Manimaran,et al.  Multi-step microfluidic device for studying cancer metastasis. , 2007, Lab on a chip.

[62]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[63]  Brian N. Johnson,et al.  An integrated microfluidic device for influenza and other genetic analyses. , 2005, Lab on a chip.

[64]  D. Haber,et al.  Circulating tumor cells: a window into cancer biology and metastasis. , 2010, Current opinion in genetics & development.

[65]  Jesse V Jokerst,et al.  Nano-bio-chips for high performance multiplexed protein detection: determinations of cancer biomarkers in serum and saliva using quantum dot bioconjugate labels. , 2009, Biosensors & bioelectronics.

[66]  R. Weinberg,et al.  The Biology of Cancer , 2006 .

[67]  Tobias Preckel,et al.  Cytometric analysis of protein expression and apoptosis in human primary cells with a novel microfluidic chip‐based system , 2003, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[68]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[69]  J. Massagué,et al.  Genetic determinants of cancer metastasis , 2007, Nature Reviews Genetics.

[70]  S. Takayama,et al.  Microfluidics for flow cytometric analysis of cells and particles , 2005, Physiological measurement.

[71]  Mehmet Toner,et al.  Visualization of microscale particle focusing in diluted and whole blood using particle trajectory analysis. , 2012, Lab on a chip.

[72]  O. Gires,et al.  EpCAM (CD326) finding its role in cancer , 2007, British Journal of Cancer.

[73]  Justin C. Williams,et al.  Evaluation of Cancer Stem Cell Migration Using Compartmentalizing Microfluidic Devices and Live Cell Imaging , 2011, Journal of visualized experiments : JoVE.

[74]  Hanno Langen,et al.  Identification of Nicotinamide N-Methyltransferase as a Novel Serum Tumor Marker for Colorectal Cancer , 2005, Clinical Cancer Research.

[75]  Francis Lin,et al.  Differential effects of EGF gradient profiles on MDA-MB-231 breast cancer cell chemotaxis. , 2004, Experimental cell research.

[76]  Peter Kuhn,et al.  A rare-cell detector for cancer. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[77]  Samuel Aparicio,et al.  High-throughput microfluidic single-cell RT-qPCR , 2011, Proceedings of the National Academy of Sciences.

[78]  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.

[79]  Luke P. Lee,et al.  Continuous perfusion microfluidic cell culture array for high-throughput cell-based assays. , 2005, Biotechnology and bioengineering.

[80]  J Ratajczak,et al.  Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication , 2006, Leukemia.

[81]  M. Ferrari Cancer nanotechnology: opportunities and challenges , 2005, Nature Reviews Cancer.

[82]  T. Mok,et al.  Single-Molecule Detection of Epidermal Growth Factor Receptor Mutations in Plasma by Microfluidics Digital PCR in Non–Small Cell Lung Cancer Patients , 2009, Clinical Cancer Research.

[83]  J P Landers,et al.  Rapid detection of deletion, insertion, and substitution mutations via heteroduplex analysis using capillary- and microchip-based electrophoresis. , 2000, Genome research.

[84]  Paul I. Okagbare,et al.  Highly efficient capture and enumeration of low abundance prostate cancer cells using prostate‐specific membrane antigen aptamers immobilized to a polymeric microfluidic device , 2009, Electrophoresis.

[85]  M. Heller,et al.  Isolation of cultured cervical carcinoma cells mixed with peripheral blood cells on a bioelectronic chip. , 1998, Analytical chemistry.

[86]  Nicole K Henderson-Maclennan,et al.  Deformability-based cell classification and enrichment using inertial microfluidics. , 2011, Lab on a chip.

[87]  Mehmet Toner,et al.  Spontaneous migration of cancer cells under conditions of mechanical confinement. , 2009, Integrative biology : quantitative biosciences from nano to macro.

[88]  Alessandro Lugli,et al.  Frequent EpCam protein expression in human carcinomas. , 2004, Human pathology.

[89]  L. Penland,et al.  Use of a cDNA microarray to analyse gene expression patterns in human cancer , 1996, Nature Genetics.

[90]  L. Mazutis,et al.  Quantitative and sensitive detection of rare mutations using droplet-based microfluidics. , 2011, Lab on a chip.

[91]  D. Beebe,et al.  Microenvironment design considerations for cellular scale studies. , 2004, Lab on a chip.

[92]  M. Caggana,et al.  Development of a rare cell fractionation device: application for cancer detection , 2004, IEEE Transactions on NanoBioscience.

[93]  G. Whitesides,et al.  Patterned deposition of cells and proteins onto surfaces by using three-dimensional microfluidic systems. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[94]  Francis E H Tay,et al.  A quantitative observation and imaging of single tumor cell migration and deformation using a multi-gap microfluidic device representing the blood vessel. , 2006, Microvascular research.

[95]  N. Perrimon,et al.  Droplet microfluidic technology for single-cell high-throughput screening , 2009, Proceedings of the National Academy of Sciences.

[96]  Luke P. Lee,et al.  Dynamic single cell culture array. , 2006, Lab on a chip.

[97]  G. Whitesides The origins and the future of microfluidics , 2006, Nature.

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

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

[100]  George M. Whitesides,et al.  Laminar flows: Subcellular positioning of small molecules , 2001, Nature.

[101]  F. Slack,et al.  Oncomirs — microRNAs with a role in cancer , 2006, Nature Reviews Cancer.

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

[103]  G. Whitesides,et al.  Microfluidic devices fabricated in Poly(dimethylsiloxane) for biological studies , 2003, Electrophoresis.

[104]  Guillaume Lambert,et al.  A microfluidic device for continuous cancer cell culture and passage with hydrodynamic forces. , 2010, Lab on a chip.

[105]  A. Villa,et al.  Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T lymphocytes. , 2006, Cancer research.

[106]  D. J. Harrison,et al.  Planar chips technology for miniaturization and integration of separation techniques into monitoring systems. Capillary electrophoresis on a chip , 1992 .