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Jan 2013

Volume 7, Issue 1, Articles (01xxxx)

Issue Cover Spotlight Figure

Biomicrofluidics 7, 011809 (2013); http://dx.doi.org/10.1063/1.4788921 (12 pages)

Alireza Salmanzadeh, Michael B. Sano, Roberto C. Gallo-Villanueva, Paul C. Roberts, Eva M. Schmelz, and Rafael V. Davalos

"Investigating dielectric properties of different stages of syngeneic murine
ovarian cancer cells"

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Referee acknowledgment for 2012

Hsueh-Chia Chang and Leslie Y. Yeo, Editors

Biomicrofluidics 7, 010201 (2013); http://dx.doi.org/10.1063/1.4790814 (2 pages)

Online Publication Date: 4 February 2013

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Abstract Unavailable
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01.30.Tt Bibliographies
85.85.+j Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
87.80.Ek Mechanical and micromechanical techniques
87.85.Ox Biomedical instrumentation and transducers, including micro-electro-mechanical systems (MEMS)
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Editorial: Moving on in biomicrofluidics

Hsueh-Chia Chang and Leslie Yeo

Biomicrofluidics 7, 010401 (2013); http://dx.doi.org/10.1063/1.4775344 (3 pages)

Online Publication Date: 31 January 2013

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Abstract Unavailable
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01.30.Ww Editorials
07.10.Cm Micromechanical devices and systems
85.85.+j Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
87.80.Ek Mechanical and micromechanical techniques
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An integrated microfluidic device for rapid serodiagnosis of amebiasis

Wang Zhao, Li Zhang, Wenwen Jing, Sixiu Liu, Hiroshi Tachibana, Xunjia Cheng, and Guodong Sui

Biomicrofluidics 7, 011101 (2013); http://dx.doi.org/10.1063/1.4793222 (6 pages)

Online Publication Date: 21 February 2013

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A microfluidic device was successfully fabricated for the rapid serodiagnosis of amebiasis. A micro bead-based immunoassay was fabricated within integrated microfluidic chip to detect the antibody to Entamoeba histolytica in serum samples. In this assay, a recombinant fragment of C terminus of intermediate subunit of galactose and N-acetyl-D-galactosamine-inhibitable lectin of Entamoeba histolytica (C-Igl, aa 603-1088) has been utilized instead of the crude antigen. This device was validated with serum samples from patients with amebiasis and showed great sensitivity. The serodiagnosis can be completed within 20 min with 2 μl sample consumption. The device can be applied for the rapid and cheap diagnosis of other infectious disease, especially for the developing countries with very limited medical facilities.
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87.85.Ox Biomedical instrumentation and transducers, including micro-electro-mechanical systems (MEMS)
07.10.Cm Micromechanical devices and systems
85.85.+j Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
87.14.E- Proteins
87.19.X- Diseases
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Micro-/nanofluidics based cell electroporation

Shengnian Wang and L. James Lee

Biomicrofluidics 7, 011301 (2013); http://dx.doi.org/10.1063/1.4774071 (14 pages) | Cited 1 time

Online Publication Date: 7 January 2013

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Non-viral gene delivery has been extensively explored as the replacement for viral systems. Among various non-viral approaches, electroporation has gained increasing attention because of its easy operation and no restrictions on probe or cell type. Several effective systems are now available on the market with reasonably good gene delivery performance. To facilitate broader biological and medical applications, micro-/nanofluidics based technologies were introduced in cell electroporation during the past two decades and their advances are summarized in this perspective. Compared to the commercially available bulk electroporation systems, they offer several advantages, namely, (1) sufficiently high pulse strength generated by a very low potential difference, (2) conveniently concentrating, trapping, and regulating the position and concentration of cells and probes, (3) real-time monitoring the intracellular trafficking at single cell level, and (4) flexibility on cells to be transfected (from single cell to large scale cell population). Some of the micro-devices focus on cell lysis or fusion as well as the analysis of cellular properties or intracellular contents, while others are designed for gene transfection. The uptake of small molecules (e.g., dyes), DNA plasmids, interfering RNAs, and nanoparticles has been broadly examined on different types of mammalian cells, yeast, and bacteria. A great deal of progress has been made with a variety of new micro-/nanofluidic designs to address challenges such as electrochemical reactions including water electrolysis, gas bubble formation, waste of expensive reagents, poor cell viability, low transfection efficacy, higher throughput, and control of transfection dosage and uniformity. Future research needs required to advance micro-/nanofluidics based cell electroporation for broad life science and medical applications are discussed.
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87.85.Rs Nanotechnologies-applications
82.45.Tv Bioelectrochemistry
85.85.+j Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
87.15.Tt Electrophoresis
87.16.Wd Intracellular trafficking
87.80.Ek Mechanical and micromechanical techniques
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Chip in a lab: Microfluidics for next generation life science research

Aaron M. Streets and Yanyi Huang

Biomicrofluidics 7, 011302 (2013); http://dx.doi.org/10.1063/1.4789751 (23 pages) | Cited 1 time

Online Publication Date: 31 January 2013

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Microfluidic circuits are characterized by fluidic channels and chambers with a linear dimension on the order of tens to hundreds of micrometers. Components of this size enable lab-on-a-chip technology that has much promise, for example, in the development of point-of-care diagnostics. Micro-scale fluidic circuits also yield practical, physical, and technological advantages for studying biological systems, enhancing the ability of researchers to make more precise quantitative measurements. Microfluidic technology has thus become a powerful tool in the life science research laboratory over the past decade. Here we focus on chip-in-a-lab applications of microfluidics and survey some examples of how small fluidic components have provided researchers with new tools for life science research.
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85.85.+j Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
87.85.Ox Biomedical instrumentation and transducers, including micro-electro-mechanical systems (MEMS)
47.85.Np Fluidics
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Biomimetic tumor microenvironment on a microfluidic platform

Huipeng Ma, Hui Xu, and Jianhua Qin

Biomicrofluidics 7, 011501 (2013); http://dx.doi.org/10.1063/1.4774070 (13 pages)

Online Publication Date: 7 January 2013

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Tumor microenvironment is a highly complex system consisting of non-cancerous cells, soluble factors, signaling molecules, extracellular matrix, and mechanical cues, which provides tumor cells with integrated biochemical and biophysical cues. It has been recognized as a significant regulator in cancer initiation, progression, metastasis, and drug resistance, which is becoming a crucial component of cancer biology. Modeling microenvironmental conditions of such complexity in vitro are particularly difficult and technically challenging. Significant advances in microfluidic technologies have offered an unprecedented opportunity to closely mimic the physiological microenvironment that is normally encountered by cancer cells in vivo. This review highlights the recent advances of microfluidic platform in recapitulating many aspects of tumor microenvironment from biochemical and biophysical regulations. The major events relevant in tumorigenesis, angiogenesis, and spread of cancer cells dependent on specific combinations of cell types and soluble factors present in microenvironmental niche are summarized. The questions and challenges that lie ahead if this field is expected to transform the future cancer research are addressed as well.
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87.85.G- Biomechanics
07.10.Cm Micromechanical devices and systems
85.85.+j Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
87.16.-b Subcellular structure and processes
87.17.-d Cell processes
89.75.-k Complex systems
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Preface to Special Topic: Microfluidics in Cancer Research

Suman Chakraborty

Biomicrofluidics 7, 011701 (2013); http://dx.doi.org/10.1063/1.4790815 (3 pages)

Online Publication Date: 4 February 2013

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Abstract Unavailable
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87.85.Ox Biomedical instrumentation and transducers, including micro-electro-mechanical systems (MEMS)
01.30.Rr Surveys and tutorial papers; resource letters
85.85.+j Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
87.19.xj Cancer

Rapid isolation of cancer cells using microfluidic deterministic lateral displacement structure

Zongbin Liu, Fei Huang, Jinghui Du, Weiliang Shu, Hongtao Feng, Xiaoping Xu, and Yan Chen

Biomicrofluidics 7, 011801 (2013); http://dx.doi.org/10.1063/1.4774308 (10 pages) | Cited 2 times

Online Publication Date: 7 January 2013

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This work reports a microfluidic device with deterministic lateral displacement (DLD) arrays allowing rapid and label-free cancer cell separation and enrichment from diluted peripheral whole blood, by exploiting the size-dependent hydrodynamic forces. Experiment data and theoretical simulation are presented to evaluate the isolation efficiency of various types of cancer cells in the microfluidic DLD structure. We also demonstrated the use of both circular and triangular post arrays for cancer cell separation in cell solution and blood samples. The device was able to achieve high cancer cell isolation efficiency and enrichment factor with our optimized design. Therefore, this platform with DLD structure shows great potential on fundamental and clinical studies of circulating tumor cells.
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87.85.Ox Biomedical instrumentation and transducers, including micro-electro-mechanical systems (MEMS)
07.10.Cm Micromechanical devices and systems
85.85.+j Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
87.16.-b Subcellular structure and processes
87.19.xj Cancer
87.85.G- Biomechanics

Size-based hydrodynamic rare tumor cell separation in curved microfluidic channels

Jiashu Sun, Chao Liu, Mengmeng Li, Jidong Wang, Yunlei Xianyu, Guoqing Hu, and Xingyu Jiang

Biomicrofluidics 7, 011802 (2013); http://dx.doi.org/10.1063/1.4774311 (11 pages) | Cited 1 time

Online Publication Date: 7 January 2013

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In this work, we propose a rapid and continuous rare tumor cell separation based on hydrodynamic effects in a label-free manner. The competition between the inertial lift force and Dean drag force inside a double spiral microchannel results in the size-based cell separation of large tumor cells and small blood cells. The mechanism of hydrodynamic separation in curved microchannel was investigated by a numerical model. Experiments with binary mixture of 5- and 15-μm-diameter polystyrene particles using the double spiral channel showed a separation purity of more than 95% at the flow rate above 30 ml/h. High throughput (2.5 × 108 cells/min) and efficient cell separation (more than 90%) of spiked HeLa cells and 20 × diluted blood cells was also achieved by the double spiral channel.
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87.85.Ox Biomedical instrumentation and transducers, including micro-electro-mechanical systems (MEMS)
07.10.Cm Micromechanical devices and systems
85.85.+j Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
87.17.-d Cell processes

Separation of tumor cells with dielectrophoresis-based microfluidic chip

Mohammed Alshareef, Nicholas Metrakos, Eva Juarez Perez, Fadi Azer, Fang Yang, Xiaoming Yang, and Guiren Wang

Biomicrofluidics 7, 011803 (2013); http://dx.doi.org/10.1063/1.4774312 (12 pages) | Cited 1 time

Online Publication Date: 9 January 2013

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The present work demonstrates the use of a dielectrophoretic lab-on-a-chip device in effectively separating different cancer cells of epithelial origin for application in circulating tumor cell (CTC) identification. This study uses dielectrophoresis (DEP) to distinguish and separate MCF-7 human breast cancer cells from HCT-116 colorectal cancer cells. The DEP responses for each cell type were measured against AC electrical frequency changes in solutions of varying conductivities. Increasing the conductivity of the suspension directly correlated with an increasing frequency value for the first cross-over (no DEP force) point in the DEP spectra. Differences in the cross-over frequency for each cell type were leveraged to determine a frequency at which the two types of cell could be separated through DEP forces. Under a particular medium conductivity, different types of cells could have different DEP behaviors in a very narrow AC frequency band, demonstrating a high specificity of DEP. Using a microfluidic DEP sorter with optically transparent electrodes, MCF-7 and HCT-116 cells were successfully separated from each other under a 3.2 MHz frequency in a 0.1X PBS solution. Further experiments were conducted to characterize the separation efficiency (enrichment factor) by changing experimental parameters (AC frequency, voltage, and flow rate). This work has shown the high specificity of the described DEP cell sorter for distinguishing cells with similar characteristics for potential diagnostic applications through CTC enrichment.
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87.85.Ox Biomedical instrumentation and transducers, including micro-electro-mechanical systems (MEMS)
82.70.Kj Emulsions and suspensions
85.85.+j Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
87.16.-b Subcellular structure and processes

Sequentially pulsed fluid delivery to establish soluble gradients within a scalable microfluidic chamber array

Edward S. Park, Michael A. DiFeo, Jacqueline M. Rand, Matthew M. Crane, and Hang Lu

Biomicrofluidics 7, 011804 (2013); http://dx.doi.org/10.1063/1.4774313 (16 pages) | Cited 2 times

Online Publication Date: 9 January 2013

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This work presents a microfluidic chamber array that generates soluble gradients using sequentially pulsed fluid delivery (SPFD). SPFD produces stable gradients by delivering flow pulses to either side of a chamber. The pulses on each side contain different signal concentrations, and they alternate in sequence, providing the driving force to establish a gradient via diffusion. The device, herein, is significant because it demonstrates the potential to simultaneously meet four important needs that can accelerate and enhance the study of cellular responses to signal gradients. These needs are (i) a scalable chamber array, (ii) low complexity fabrication, (iii) a non-shearing microenvironment, and (iv) gradients with low (near zero) background concentrations. The ability to meet all four needs distinguishes the SPFD device from flow-based and diffusion-based designs, which can only achieve a subset of such needs. Gradients are characterized using fluorescence measurements, which reveal the ability to change the curvature of concentration profiles by simple adjustments to pulsing sequence and flow rate. Preliminary experiments with MDA-MB-231 cancer cells demonstrate cell viability and indicate migrational and morphological responses to a fetal bovine serum gradient. Improved and expanded versions of this technology could form the basis of high-throughput screening tools to study cell migration, development, and cancer.
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87.17.Rt Cell adhesion and cell mechanics
87.80.Ek Mechanical and micromechanical techniques
87.85.Ox Biomedical instrumentation and transducers, including micro-electro-mechanical systems (MEMS)
85.85.+j Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
87.14.E- Proteins
87.15.mq Luminescence

Empirical chemosensitivity testing in a spheroid model of ovarian cancer using a microfluidics-based multiplex platform

Tamal Das, Liliane Meunier, Laurent Barbe, Diane Provencher, Olivier Guenat, Thomas Gervais, and Anne-Marie Mes-Masson

Biomicrofluidics 7, 011805 (2013); http://dx.doi.org/10.1063/1.4774309 (15 pages) | Cited 2 times

Online Publication Date: 10 January 2013

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The use of biomarkers to infer drug response in patients is being actively pursued, yet significant challenges with this approach, including the complicated interconnection of pathways, have limited its application. Direct empirical testing of tumor sensitivity would arguably provide a more reliable predictive value, although it has garnered little attention largely due to the technical difficulties associated with this approach. We hypothesize that the application of recently developed microtechnologies, coupled to more complex 3-dimensional cell cultures, could provide a model to address some of these issues. As a proof of concept, we developed a microfluidic device where spheroids of the serous epithelial ovarian cancer cell line TOV112D are entrapped and assayed for their chemoresponse to carboplatin and paclitaxel, two therapeutic agents routinely used for the treatment of ovarian cancer. In order to index the chemoresponse, we analyzed the spatiotemporal evolution of the mortality fraction, as judged by vital dyes and confocal microscopy, within spheroids subjected to different drug concentrations and treatment durations inside the microfluidic device. To reflect microenvironment effects, we tested the effect of exogenous extracellular matrix and serum supplementation during spheroid formation on their chemotherapeutic response. Spheroids displayed augmented chemoresistance in comparison to monolayer culturing. This resistance was further increased by the simultaneous presence of both extracellular matrix and high serum concentration during spheroid formation. Following exposure to chemotherapeutics, cell death profiles were not uniform throughout the spheroid. The highest cell death fraction was found at the center of the spheroid and the lowest at the periphery. Collectively, the results demonstrate the validity of the approach, and provide the basis for further investigation of chemotherapeutic responses in ovarian cancer using microfluidics technology. In the future, such microdevices could provide the framework to assay drug sensitivity in a timeframe suitable for clinical decision making.
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87.85.Ox Biomedical instrumentation and transducers, including micro-electro-mechanical systems (MEMS)
07.10.Cm Micromechanical devices and systems
85.85.+j Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
87.16.-b Subcellular structure and processes
87.14.E- Proteins
87.64.M- Optical microscopy

Probing the mechanical properties of brain cancer cells using a microfluidic cell squeezer device

Z. S. Khan and S. A. Vanapalli

Biomicrofluidics 7, 011806 (2013); http://dx.doi.org/10.1063/1.4774310 (15 pages) | Cited 2 times

Online Publication Date: 10 January 2013

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Despite being invasive within surrounding brain tissues and the central nervous system, little is known about the mechanical properties of brain tumor cells in comparison with benign cells. Here, we present the first measurements of the peak pressure drop due to the passage of benign and cancerous brain cells through confined microchannels in a “microfluidic cell squeezer” device, as well as the elongation, speed, and entry time of the cells in confined channels. We find that cancerous and benign brain cells cannot be differentiated based on speeds or elongation. We have found that the entry time into a narrow constriction is a more sensitive indicator of the differences between malignant and healthy glial cells than pressure drops. Importantly, we also find that brain tumor cells take a longer time to squeeze through a constriction and migrate more slowly than benign cells in two dimensional wound healing assays. Based on these observations, we arrive at the surprising conclusion that the prevailing notion of extraneural cancer cells being more mechanically compliant than benign cells may not apply to brain cancer cells.
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87.85.G- Biomechanics
87.85.Ox Biomedical instrumentation and transducers, including micro-electro-mechanical systems (MEMS)
85.85.+j Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
87.16.-b Subcellular structure and processes
87.19.L- Neuroscience

Antibody-independent isolation of circulating tumor cells by continuous-flow dielectrophoresis

Sangjo Shim, Katherine Stemke-Hale, Apostolia M. Tsimberidou, Jamileh Noshari, Thomas E. Anderson, and Peter R. C. Gascoyne

Biomicrofluidics 7, 011807 (2013); http://dx.doi.org/10.1063/1.4774304 (12 pages) | Cited 3 times

Online Publication Date: 16 January 2013

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Circulating tumor cells (CTCs) are prognostic markers for the recurrence of cancer and may carry molecular information relevant to cancer diagnosis. Dielectrophoresis (DEP) has been proposed as a molecular marker-independent approach for isolating CTCs from blood and has been shown to be broadly applicable to different types of cancers. However, existing batch-mode microfluidic DEP methods have been unable to process 10 ml clinical blood specimens rapidly enough. To achieve the required processing rates of 106 nucleated cells/min, we describe a continuous flow microfluidic processing chamber into which the peripheral blood mononuclear cell fraction of a clinical specimen is slowly injected, deionized by diffusion, and then subjected to a balance of DEP, sedimentation and hydrodynamic lift forces. These forces cause tumor cells to be transported close to the floor of the chamber, while blood cells are carried about three cell diameters above them. The tumor cells are isolated by skimming them from the bottom of the chamber while the blood cells flow to waste. The principles, design, and modeling of the continuous-flow system are presented. To illustrate operation of the technology, we demonstrate the isolation of circulating colon tumor cells from clinical specimens and verify the tumor origin of these cells by molecular analysis.
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87.85.Ox Biomedical instrumentation and transducers, including micro-electro-mechanical systems (MEMS)
87.14.-g Biomolecules: types
87.15.-v Biomolecules: structure and physical properties
87.15.Tt Electrophoresis
87.17.Rt Cell adhesion and cell mechanics

Dielectrophoresis has broad applicability to marker-free isolation of tumor cells from blood by microfluidic systems

Sangjo Shim, Katherine Stemke-Hale, Jamileh Noshari, Frederick F. Becker, and Peter R. C. Gascoyne

Biomicrofluidics 7, 011808 (2013); http://dx.doi.org/10.1063/1.4774307 (12 pages) | Cited 4 times

Online Publication Date: 16 January 2013

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The number of circulating tumor cells (CTCs) found in blood is known to be a prognostic marker for recurrence of primary tumors, however, most current methods for isolating CTCs rely on cell surface markers that are not universally expressed by CTCs. Dielectrophoresis (DEP) can discriminate and manipulate cancer cells in microfluidic systems and has been proposed as a molecular marker-independent approach for isolating CTCs from blood. To investigate the potential applicability of DEP to different cancer types, the dielectric and density properties of the NCI-60 panel of tumor cell types have been measured by dielectrophoretic field-flow fractionation (DEP-FFF) and compared with like properties of the subpopulations of normal peripheral blood cells. We show that all of the NCI-60 cell types, regardless of tissue of origin, exhibit dielectric properties that facilitate their isolation from blood by DEP. Cell types derived from solid tumors that grew in adherent cultures exhibited dielectric properties that were strikingly different from those of peripheral blood cell subpopulations while leukemia-derived lines that grew in non-adherent cultures exhibited dielectric properties that were closer to those of peripheral blood cell types. Our results suggest that DEP methods have wide applicability for the surface-marker independent isolation of viable CTCs from blood as well as for the concentration of leukemia cells from blood.
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87.85.-d Biomedical engineering
85.85.+j Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
87.16.-b Subcellular structure and processes
87.19.U- Hemodynamics
87.19.xj Cancer

Investigating dielectric properties of different stages of syngeneic murine ovarian cancer cells

Alireza Salmanzadeh, Michael B. Sano, Roberto C. Gallo-Villanueva, Paul C. Roberts, Eva M. Schmelz, and Rafael V. Davalos

Biomicrofluidics 7, 011809 (2013); http://dx.doi.org/10.1063/1.4788921 (12 pages) | Cited 1 time

Online Publication Date: 23 January 2013

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In this study, the electrical properties of four different stages of mouse ovarian surface epithelial (MOSE) cells were investigated using contactless dielectrophoresis (cDEP). This study expands the work from our previous report describing for the first time the crossover frequency and cell specific membrane capacitance of different stages of cancer cells that are derived from the same cell line. The specific membrane capacitance increased as the stage of malignancy advanced from 15.39 ± 1.54 mF m−2 for a non-malignant benign stage to 26.42 ± 1.22 mF m−2 for the most aggressive stage. These differences could be the result of morphological variations due to changes in the cytoskeleton structure, specifically the decrease of the level of actin filaments in the cytoskeleton structure of the transformed MOSE cells. Studying the electrical properties of MOSE cells provides important information as a first step to develop cancer-treatment techniques which could partially reverse the cytoskeleton disorganization of malignant cells to a morphology more similar to that of benign cells.
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87.85.jc Electrical, thermal, and mechanical properties of biological matter
87.85.Ox Biomedical instrumentation and transducers, including micro-electro-mechanical systems (MEMS)
85.85.+j Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
87.16.Ln Cytoskeleton
87.19.xj Cancer
87.80.Kc Electrochemical techniques

Label-free isolation of circulating tumor cells in microfluidic devices: Current research and perspectives

Igor Cima, Chay Wen Yee, Florina S. Iliescu, Wai Min Phyo, Kiat Hon Lim, Ciprian Iliescu, and Min Han Tan

Biomicrofluidics 7, 011810 (2013); http://dx.doi.org/10.1063/1.4780062 (16 pages) | Cited 2 times

Online Publication Date: 24 January 2013

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This review will cover the recent advances in label-free approaches to isolate and manipulate circulating tumor cells (CTCs). In essence, label-free approaches do not rely on antibodies or biological markers for labeling the cells of interest, but enrich them using the differential physical properties intrinsic to cancer and blood cells. We will discuss technologies that isolate cells based on their biomechanical and electrical properties. Label-free approaches to analyze CTCs have been recently invoked as a valid alternative to “marker-based” techniques, because classical epithelial and tumor markers are lost on some CTC populations and there is no comprehensive phenotypic definition for CTCs. We will highlight the advantages and drawbacks of these technologies and the status on their implementation in the clinics.
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87.85.Ox Biomedical instrumentation and transducers, including micro-electro-mechanical systems (MEMS)
07.10.Cm Micromechanical devices and systems
85.85.+j Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
87.17.Rt Cell adhesion and cell mechanics
87.19.R- Mechanical and electrical properties of tissues and organs
87.19.xj Cancer

Perspective: Flicking with flow: Can microfluidics revolutionize the cancer research?

Tamal Das and Suman Chakraborty

Biomicrofluidics 7, 011811 (2013); http://dx.doi.org/10.1063/1.4789750 (20 pages) | Cited 1 time

Online Publication Date: 31 January 2013

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According to the World Health Organization, cancer is one of the leading causes of death worldwide. Cancer research, in its all facets, is truly interdisciplinary in nature, cutting across the fields of fundamental and applied sciences, as well as biomedical engineering. In recent years, microfluidics has been applied successfully in cancer research. There remain, however, many elusive features of this disease, where microfluidic systems could throw new lights. In addition, some inherent features of microfluidic systems remain unexploited in cancer research. In this article, we first briefly review the advancement of microfluidics in cancer biology. We then describe the biophysical aspects of cancer and outline how microfluidic system could be useful in developing a deeper understanding on the underlying mechanisms. We next illustrate the effects of the confined environment of microchannel on cellular dynamics and argue that the tissue microconfinement could be a crucial facet in tumor development. Lastly, we attempt to highlight some of the most important problems in cancer biology, to inspire next level of microfluidic applications in cancer research.
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85.85.+j Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
07.10.Cm Micromechanical devices and systems
87.17.-d Cell processes
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Fabrication of hexagonally packed cell culture substrates using droplet formation in a T-shaped microfluidic junction

Chiun Peng Lee, Yi Hsin Chen, and Zung Hang Wei

Biomicrofluidics 7, 014101 (2013); http://dx.doi.org/10.1063/1.4774315 (10 pages)

Online Publication Date: 7 January 2013

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A method is here proposed to fabricate ordered hexagonally packed cell culture substrates with hexagonally arranged cell patterning areas. We generated photo-sensitive polymeric microdroplets in a T-shaped microfluidic junction by an immiscible liquid, and then solidified the collective self-assembled hexagonal droplet array to obtain the cell culture substrate, on which we took the grooves formed between the solidified droplets as the hexagonally arranged cell patterning areas. The most promising advantage of our method is that we can actively tune the droplet size by simply adopting different volumetric flow rates of the two immiscible fluids to form cell culture substrates with differently sized cell patterning areas. Besides, the examination results of the cell culture substrate's characteristics validate whether our method is capable of creating substrates with high spatial uniformity. To verify the cell patterning function of our cell culture substrates, we used the semi-adherent RAW cells to demonstrate the effectiveness of patterning of suspended/adherent cells before/after adhesion. Over 90% cell viability and cell patterning rate suggest that our method may be a promising approach for future applications of cell patterning on biochips.
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87.80.Ek Mechanical and micromechanical techniques
85.85.+j Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
87.17.Rt Cell adhesion and cell mechanics

A pillar-based microfilter for isolation of white blood cells on elastomeric substrate

Jafar Alvankarian, Alireza Bahadorimehr, and Burhanuddin Yeop Majlis

Biomicrofluidics 7, 014102 (2013); http://dx.doi.org/10.1063/1.4774068 (16 pages) | Cited 1 time

Online Publication Date: 9 January 2013

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Our goal is to design, fabricate, and characterize a pillar-based microfluidic device for size-based separation of human blood cells on an elastomeric substrate with application in the low-cost rapid prototyping of lab-chip devices. The single inlet single outlet device is using parallel U-shape arrays of pillars with cutoff size of 5.5 μm for trapping white blood cells (WBCs) in a pillar chamber with internal dead-volume of less than 1.0 μl. The microstructures are designed to limit the elastomeric deformation against fluid pressures. Numerical analysis showed that at maximum pressure loss of 15 kPa which is lower than the device conformal bonding strength, the pillar elastomeric deformation is less than 5% for flow rates of up to 1.0 ml min−1. Molding technique was employed for device prototyping using polyurethane methacrylate (PUMA) resin and polydimethylsiloxane (PDMS) mold. Characterization of the dual-layer device with beads and blood samples is performed. Tests with blood injection showed that ∼18%–25% of WBCs are trapped and ∼84%–89% of red blood cells (RBCs) are passed at flow rates of 15–50 μl min−1 with a slight decrease of WBCs trap and improve of the RBCs pass at higher flow rates. Similar results were obtained by separation of mixed microspheres of different size injected at flow rates of up to 400 μl min−1. Tests with blood samples stained by fluorescent gel demonstrated that the WBCs are accumulated in the arrays of pillars that later end up to blockage of the device. Filtration results of using elastomeric substrate present a good consistency with the trend of separation efficiencies of the similar silicon-based filters.
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87.80.-y Biophysical techniques (research methods)
47.85.-g Applied fluid mechanics

Production rate and diameter analysis of spherical monodisperse microbubbles from two-dimensional, expanding-nozzle flow-focusing microfluidic devices

Shiying Wang, Ali H. Dhanaliwala, Johnny L. Chen, and John A. Hossack

Biomicrofluidics 7, 014103 (2013); http://dx.doi.org/10.1063/1.4774069 (12 pages) | Cited 1 time

Online Publication Date: 16 January 2013

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Flow-focusing microfluidic devices (FFMDs) can produce microbubbles (MBs) with precisely controlled diameters and a narrow size distribution. In this paper, poly-dimethyl-siloxane based, rectangular-nozzle, two-dimensional (2-D) planar, expanding-nozzle FFMDs were characterized using a high speed camera to determine the production rate and diameter of Tween 20 (2% v/v) stabilized MBs. The effect of gas pressure and liquid flow rate on MB production rate and diameter was analyzed in order to develop a relationship between FFMD input parameters and MB production. MB generation was observed to transition through five regimes at a constant gas pressure and increasing liquid flow rate. Each MB generation event (i.e., break-off to break-off) was further separated into two characteristic phases: bubbling and waiting. The duration of the bubbling phase was linearly related to the liquid flow rate, while the duration of the waiting phase was related to both liquid flow rate and gas pressure. The MB production rate was found to be inversely proportional to the sum of the bubbling and waiting times, while the diameter was found to be proportional to the product of the gas pressure and bubbling time.
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87.80.Ek Mechanical and micromechanical techniques
07.10.Cm Micromechanical devices and systems
47.55.db Drop and bubble formation
47.61.Fg Flows in micro-electromechanical systems (MEMS) and nano-electromechanical systems (NEMS)
47.85.Np Fluidics
85.85.+j Micro- and nano-electromechanical systems (MEMS/NEMS) and devices

Design criteria for developing low-resource magnetic bead assays using surface tension valves

Nicholas M. Adams, Amy E. Creecy, Catherine E. Majors, Bathsheba A. Wariso, Philip A. Short, David W. Wright, and Frederick R. Haselton

Biomicrofluidics 7, 014104 (2013); http://dx.doi.org/10.1063/1.4788922 (15 pages) | Cited 1 time

Online Publication Date: 18 January 2013

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Many assays for biological sample processing and diagnostics are not suitable for use in settings that lack laboratory resources. We have recently described a simple, self-contained format based on magnetic beads for extracting infectious disease biomarkers from complex biological samples, which significantly reduces the time, expertise, and infrastructure required. This self-contained format has the potential to facilitate the application of other laboratory-based sample processing assays in low-resource settings. The technology is enabled by immiscible fluid barriers, or surface tension valves, which stably separate adjacent processing solutions within millimeter-diameter tubing and simultaneously permit the transit of magnetic beads across the interfaces. In this report, we identify the physical parameters of the materials that maximize fluid stability and bead transport and minimize solution carryover. We found that fluid stability is maximized with ≤0.8 mm i.d. tubing, valve fluids of similar density to the adjacent solutions, and tubing with ≤20 dyn/cm surface energy. Maximizing bead transport was achieved using ≥2.4 mm i.d. tubing, mineral oil valve fluid, and a mass of 1-3 mg beads. The amount of solution carryover across a surface tension valve was minimized using ≤0.2 mg of beads, tubing with ≤20 dyn/cm surface energy, and air separators. The most favorable parameter space for valve stability and bead transport was identified by combining our experimental results into a single plot using two dimensionless numbers. A strategy is presented for developing additional self-contained assays based on magnetic beads and surface tension valves for low-resource diagnostic applications.
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87.80.Ek Mechanical and micromechanical techniques
07.10.Cm Micromechanical devices and systems
68.03.Cd Surface tension and related phenomena
87.14.E- Proteins
87.14.gk DNA
87.14.gn RNA
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Continual collection and re-separation of circulating tumor cells from blood using multi-stage multi-orifice flow fractionation

Hui-Sung Moon, Kiho Kwon, Kyung-A Hyun, Tae Seok Sim, Jae Chan Park, Jeong-Gun Lee, and Hyo-Il Jung

Biomicrofluidics 7, 014105 (2013); http://dx.doi.org/10.1063/1.4788914 (9 pages)

Online Publication Date: 24 January 2013

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Circulating tumor cells (CTCs) are highly correlated with the invasive behavior of cancer; as such, the ability to isolate and quantify CTCs is of great biomedical importance. This research presents a multi-stage multi-orifice flow fractionation (MS-MOFF) device formed by combining three single-stage multi-orifice segments designed for separating breast cancer cells from blood. The structure and dimensions of the MS-MOFF were determined by hydrodynamic principles to have consistent Reynolds numbers (Re) at each multi-orifice segment. From this device, we achieved improved separation efficiency by collecting and re-separating non-selected target cells in comparison with the single-stage multi-orifice flow fractionation (SS-MOFF). The recovery of breast cancer cells increased from 88.8% to greater than 98.9% through the multi-stage multi-orifice segments. This device can be utilized to isolate rare cells from human blood, such as CTCs, in a label-free manner solely through the use of hydrodynamic forces.
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87.85.Ox Biomedical instrumentation and transducers, including micro-electro-mechanical systems (MEMS)
85.85.+j Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
87.17.Uv Biotechnology of cell processes
87.19.xj Cancer
87.85.gf Fluid mechanics and rheology

Experimental validation of numerical study on thermoelectric-based heating in an integrated centrifugal microfluidic platform for polymerase chain reaction amplification

Mary Amasia, Seok-Won Kang, Debjyoti Banerjee, and Marc Madou

Biomicrofluidics 7, 014106 (2013); http://dx.doi.org/10.1063/1.4789756 (13 pages)

Online Publication Date: 30 January 2013

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A comprehensive study involving numerical analysis and experimental validation of temperature transients within a microchamber was performed for thermocycling operation in an integrated centrifugal microfluidic platform for polymerase chain reaction (PCR) amplification. Controlled heating and cooling of biological samples are essential processes in many sample preparation and detection steps for micro-total analysis systems. Specifically, the PCR process relies on highly controllable and uniform heating of nucleic acid samples for successful and efficient amplification. In these miniaturized systems, the heating process is often performed more rapidly, making the temperature control more difficult, and adding complexity to the integrated hardware system. To gain further insight into the complex temperature profiles within the PCR microchamber, numerical simulations using computational fluid dynamics and computational heat transfer were performed. The designed integrated centrifugal microfluidics platform utilizes thermoelectrics for ice-valving and thermocycling for PCR amplification. Embedded micro-thermocouples were used to record the static and dynamic thermal responses in the experiments. The data collected was subsequently used for computational validation of the numerical predictions for the system response during thermocycling, and these simulations were found to be in agreement with the experimental data to within ∼97%. When thermal contact resistance values were incorporated in the simulations, the numerical predictions were found to be in agreement with the experimental data to within ∼99.9%. This in-depth numerical modeling and experimental validation of a complex single-sided heating platform provide insights into hardware and system design for multi-layered polymer microfluidic systems. In addition, the biological capability along with the practical feasibility of the integrated system is demonstrated by successfully performing PCR amplification of a Group B Streptococcus gene.
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85.85.+j Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
07.10.Cm Micromechanical devices and systems
02.60.-x Numerical approximation and analysis
87.85.Ox Biomedical instrumentation and transducers, including micro-electro-mechanical systems (MEMS)
47.85.Np Fluidics
87.19.Pp Biothermics and thermal processes in biology

Paper pump for passive and programmable transport

Xiao Wang, Joshua A. Hagen, and Ian Papautsky

Biomicrofluidics 7, 014107 (2013); http://dx.doi.org/10.1063/1.4790819 (11 pages)

Online Publication Date: 6 February 2013

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In microfluidic systems, a pump for fluid-driving is often necessary. To keep the size of microfluidic systems small, a pump that is small in size, light-weight and needs no external power source is advantageous. In this work, we present a passive, simple, ultra-low-cost, and easily controlled pumping method based on capillary action of paper that pumps fluid through conventional polymer-based microfluidic channels with steady flow rate. By using inexpensive cutting tools, paper can be shaped and placed at the outlet port of a conventional microfluidic channel, providing a wide range of pumping rates. A theoretical model was developed to describe the pumping mechanism and aid in the design of paper pumps. As we show, paper pumps can provide steady flow rates from 0.3 μl/s to 1.7 μl/s and can be cascaded to achieve programmable flow-rate tuning during the pumping process. We also successfully demonstrate transport of the most common biofluids (urine, serum, and blood). With these capabilities, the paper pump has the potential to become a powerful fluid-driving approach that will benefit the fielding of microfluidic systems for point-of-care applications.
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87.80.Ek Mechanical and micromechanical techniques
07.10.Cm Micromechanical devices and systems
85.85.+j Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
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