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Top 20 Most Cited Articles
The 20 most cited articles over time based on CrossRef data.
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Biomicrofluidics 1, 021503 (2007); http://dx.doi.org/10.1063/1.2723669 (15 pages) | Cited 96 times Online Publication Date: 10 May 2007
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Multi-target pathogen detection using heterogeneous medical samples require continuous filtering, sorting, and trapping of debris, bioparticles, and immunocolloids within a diagnostic chip. We present an integrated AC dielectrophoretic (DEP) microfluidic platform based on planar electrodes that form three-dimensional (3D) DEP gates. This platform can continuously perform these tasks with a throughput of 3 μL/min. Mixtures of latex particles, Escherichia coli Nissle, Lactobacillus, and Candida albicans are sorted and concentrated by these 3D DEP gates. Surface enhanced Raman scattering is used as an on-chip detection method on the concentrated bacteria. A processing rate of 500 bacteria was estimated when 100 μl of a heterogeneous colony of 107 colony forming units /ml was processed in a single pass within 30 min.
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Review Article—Dielectrophoresis: Status of the theory, technology, and applications Biomicrofluidics 4, 022811 (2010); http://dx.doi.org/10.1063/1.3456626 (35 pages) | Cited 85 times Online Publication Date: 29 June 2010
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A review is presented of the present status of the theory, the developed technology and the current applications of dielectrophoresis (DEP). Over the past 10 years around 2000 publications have addressed these three aspects, and current trends suggest that the theory and technology have matured sufficiently for most effort to now be directed towards applying DEP to unmet needs in such areas as biosensors, cell therapeutics, drug discovery, medical diagnostics, microfluidics, nanoassembly, and particle filtration. The dipole approximation to describe the DEP force acting on a particle subjected to a nonuniform electric field has evolved to include multipole contributions, the perturbing effects arising from interactions with other cells and boundary surfaces, and the influence of electrical double-layer polarizations that must be considered for nanoparticles. Theoretical modelling of the electric field gradients generated by different electrode designs has also reached an advanced state. Advances in the technology include the development of sophisticated electrode designs, along with the introduction of new materials (e.g., silicone polymers, dry film resist) and methods for fabricating the electrodes and microfluidics of DEP devices (photo and electron beam lithography, laser ablation, thin film techniques, CMOS technology). Around three-quarters of the 300 or so scientific publications now being published each year on DEP are directed towards practical applications, and this is matched with an increasing number of patent applications. A summary of the US patents granted since January 2005 is given, along with an outline of the small number of perceived industrial applications (e.g., mineral separation, micropolishing, manipulation and dispensing of fluid droplets, manipulation and assembly of micro components). The technology has also advanced sufficiently for DEP to be used as a tool to manipulate nanoparticles (e.g., carbon nanotubes, nano wires, gold and metal oxide nanoparticles) for the fabrication of devices and sensors. Most efforts are now being directed towards biomedical applications, such as the spatial manipulation and selective separation/enrichment of target cells or bacteria, high-throughput molecular screening, biosensors, immunoassays, and the artificial engineering of three-dimensional cell constructs. DEP is able to manipulate and sort cells without the need for biochemical labels or other bioengineered tags, and without contact to any surfaces. This opens up potentially important applications of DEP as a tool to address an unmet need in stem cell research and therapy.
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Ultrafast microfluidics using surface acoustic waves Biomicrofluidics 3, 012002 (2009); http://dx.doi.org/10.1063/1.3056040 (23 pages) | Cited 71 times Online Publication Date: 2 January 2009
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We demonstrate that surface acoustic waves (SAWs), nanometer amplitude Rayleigh waves driven at megahertz order frequencies propagating on the surface of a piezoelectric substrate, offer a powerful method for driving a host of extremely fast microfluidic actuation and micro/bioparticle manipulation schemes. We show that sessile drops can be translated rapidly on planar substrates or fluid can be pumped through microchannels at 1–10 cm/s velocities, which are typically one to two orders quicker than that afforded by current microfluidic technologies. Through symmetry-breaking, azimuthal recirculation can be induced within the drop to drive strong inertial microcentrifugation for micromixing and particle concentration or separation. Similar micromixing strategies can be induced in the same microchannel in which fluid is pumped with the SAW by merely changing the SAW frequency to rapidly switch the uniform through-flow into a chaotic oscillatory flow by exploiting superpositioning of the irradiated sound waves from the sidewalls of the microchannel. If the flow is sufficiently quiescent, the nodes of the transverse standing wave that arises across the microchannel also allow for particle aggregation, and hence, sorting on nodal lines. In addition, the SAW also facilitates other microfluidic capabilities. For example, capillary waves excited at the free surface of a sessile drop by the SAW underneath it can be exploited for micro/nanoparticle collection and sorting at nodal points or lines at low powers. At higher powers, the large accelerations off the substrate surface as the SAW propagates across drives rapid destabilization of the drop free surface giving rise to inertial liquid jets that persist over 1–2 cm in length or atomization of the entire drop to produce 1–10 μm monodispersed aerosol droplets, which can be exploited for ink-jet printing, mass spectrometry interfacing, or pulmonary drug delivery. The atomization of polymer/protein solutions can also be used for the rapid synthesis of 150–200 nm polymer/protein particles or biodegradable polymeric shells in which proteins, peptides, and other therapeutic molecules are encapsulated within for controlled release drug delivery. The atomization of thin films behind a translating drop containing polymer solutions also gives rise to long-range spatial ordering of regular polymer spots whose size and spacing are dependent on the SAW frequency, thus offering a simple and powerful method for polymer patterning without requiring surface treatment or physical/chemical templating.
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Real-time detection, control, and sorting of microfluidic droplets Biomicrofluidics 1, 044101 (2007); http://dx.doi.org/10.1063/1.2795392 (12 pages) | Cited 37 times Online Publication Date: 3 October 2007
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We report the design and implementation of capacitive detection and control of microfluidic droplets in microfluidic devices. Integrated microfluidic chip(s) with detection/control circuit enables us to monitor in situ the individual volume of droplets, ranging from nanoliter to picoliter, velocity and even composition, with an operation frequency of several kilohertz. Through electronic feedback, we are able to easily count, sort, and direct the microfluidic droplets. Potential applications of this approach can be employed in the areas of biomicrofluidic processing, microchemical reactions as well as digital microfluidics.
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Biomicrofluidics 2, 034105 (2008); http://dx.doi.org/10.1063/1.2973661 (11 pages) | Cited 35 times Online Publication Date: 11 August 2008
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The conventional microfluidic H filter is modified with multi-insulating blocks to achieve a flow-through manipulation and separation of microparticles. The device transports particles by exploiting electro-osmosis and electrophoresis, and manipulates particles by utilizing dielectrophoresis (DEP). Polydimethylsiloxane (PDMS) blocks fabricated in the main channel of the PDMS H filter induce a nonuniform electric field, which exerts a negative DEP force on the particles. The use of multi-insulating blocks not only enhances the DEP force generated, but it also increases the controllability of the motion of the particles, facilitating their manipulation and separation. Experiments were conducted to demonstrate the controlled flow direction of particles by adjusting the applied voltages and the separation of particles by size under two different input conditions, namely (i) a dc electric field mode and (ii) a combined ac and dc field mode. Numerical simulations elucidate the electrokinetic and hydrodynamic forces acting on a particle, with theoretically predicted particle trajectories in good agreement with those observed experimentally. In addition, the flow field was obtained experimentally with fluorescent tracer particles using the microparticle image velocimetry (μ-PIV) technique.
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High-throughput size-based rare cell enrichment using microscale vortices Biomicrofluidics 5, 022206 (2011); http://dx.doi.org/10.1063/1.3576780 (10 pages) | Cited 35 times Online Publication Date: 29 June 2011
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Cell isolation in designated regions or from heterogeneous samples is often required for many microfluidic cell-based assays. However, current techniques have either limited throughput or are incapable of viable off-chip collection. We present an innovative approach, allowing high-throughput and label-free cell isolation and enrichment from heterogeneous solution using cell size as a biomarker. The approach utilizes the irreversible migration of particles into microscale vortices, developed in parallel expansion-contraction trapping reservoirs, as the cell isolation mechanism. We empirically determined the critical particle/cell diameter Dcrt and the operational flow rate above which trapping of cells/particles in microvortices is initiated. Using this approach we successfully separated larger cancer cells spiked in blood from the smaller blood cells with processing rates as high as 7.5×106 cells/s. Viable long-term culture was established using cells collected off-chip, suggesting that the proposed technique would be useful for clinical and research applications in which in vitro culture is often desired. The presented technology improves on current technology by enriching cells based on size without clogging mechanical filters, employing only a simple single-layered microfluidic device and processing cell solutions at the ml/min scale.
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Understanding electrokinetics at the nanoscale: A perspective Biomicrofluidics 3, 012001 (2009); http://dx.doi.org/10.1063/1.3056045 (15 pages) | Cited 35 times Online Publication Date: 2 January 2009
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Electrokinetics promises to be the microfluidic technique of choice for portable diagnostic chips and for nanofluidic molecular detectors. However, despite two centuries of research, our understanding of ion transport and electro-osmotic flow in and near nanoporous membranes, whose pores are natural nanochannels, remains woefully inadequate. This short exposition reviews the various ion-flux and hydrodynamic anomalies and speculates on their potential applications, particularly in the area of molecular sensing. In the process, we revisit several old disciplines, with some unsolved open questions, and we hope to create a new one.
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Biomicrofluidics 1, 044102 (2007); http://dx.doi.org/10.1063/1.2818767 (5 pages) | Cited 29 times Online Publication Date: 27 November 2007
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We report an interesting buffer electric relaxation time tuning technique, coupled with a glutaraldehyde cross-linking cell fixation reaction, which allows for sensitive dielectrophoretic analysis and discrimination of bovine red blood cell (bRBC) starvation age. The buffer composition is selected such that two easily accessible dielectrophoretic crossover frequencies (cof) exist. Low concentration glutaraldehyde fixation was observed to produce a threefold decrease in the higher cof with a comparable increase in the lower cof also witnessed. More importantly, increased glutaraldehyde fixation concentration significantly increased the higher cof by a factor found to be sensitive to the bRBC starvation age.
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Dielectrophoretic separation of colorectal cancer cells Biomicrofluidics 4, 013204 (2010); http://dx.doi.org/10.1063/1.3279786 (13 pages) | Cited 25 times Online Publication Date: 12 January 2010
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Separation of colorectal cancer cells from other biological materials is important for stool-based diagnosis of colorectal cancer. In this paper, we use conventional dielectrophoresis in a microfluidic chip to manipulate and isolate HCT116 colorectal cancer cells. It is noticed that at a particular alternating current frequency band, the HCT116 cells are clearly deflected to a side channel from the main channel after the electric activation of an electrode pair. This motion caused by negative dielectrophoresis can be used to simply and rapidly separate cancer cells from other cells. In this manuscript, we report the chip design, flow conditions, dielectrophoretic spectrum of the cancer cells, and the enrichment factor of the colorectal cancer cells from other cells.
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Electrokinetic focusing and filtration of cells in a serpentine microchannel Biomicrofluidics 3, 044109 (2009); http://dx.doi.org/10.1063/1.3267098 (10 pages) | Cited 25 times Online Publication Date: 24 November 2009
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Focusing cells into a single stream is usually a necessary step prior to counting and separating them in microfluidic devices such as flow cytometers and cell sorters. This work presents a sheathless electrokinetic focusing of yeast cells in a planar serpentine microchannel using dc-biased ac electric fields. The concurrent pumping and focusing of yeast cells arise from the dc electrokinetic transport and the turn-induced ac/dc dielectrophoretic motion, respectively. The effects of electric field (including ac to dc field ratio and ac field frequency) and concentration (including buffer concentration and cell concentration) on the cell focusing performance were studied experimentally and numerically. A continuous electrokinetic filtration of E. coli cells from yeast cells was also demonstrated via their differential electrokinetic focusing in a serpentine microchannel.
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Design and integration of an all-in-one biomicrofluidic chip Biomicrofluidics 2, 034103 (2008); http://dx.doi.org/10.1063/1.2966453 (8 pages) | Cited 24 times Online Publication Date: 21 July 2008
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We demonstrate a highly integrated microfluidic chip with the function of DNA amplification. The integrated chip combines giant electrorheological-fluid actuated micromixer and micropump with a microheater array, all formed using soft lithography. Internal functional components are based on polydimethylsiloxane (PDMS) and silver/carbon black-PDMS composites. The system has the advantages of small size with a high degree of integration, high polymerase chain reaction efficiency, digital control and simple fabrication at low cost. This integration approach shows promise for a broad range of applications in chemical synthesis and biological sensing/analysis, as different components can be combined to target desired functionalities, with flexible designs of different microchips easily realizable through soft lithography.
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Biomicrofluidics 2, 024103 (2008); http://dx.doi.org/10.1063/1.2930817 (14 pages) | Cited 23 times Online Publication Date: 6 May 2008
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In this paper, we demonstrate for the first time that insulative dielectrophoresis can induce size-dependent trajectories of DNA macromolecules. We experimentally use λ (48.5 kbp) and T4GT7 (165.6 kbp) DNA molecules flowing continuously around a sharp corner inside fluidic channels with a depth of 0.4 μm. Numerical simulation of the electrokinetic force distribution inside the channels is in qualitative agreement with our experimentally observed trajectories. We discuss a possible physical mechanism for the DNA polarization and dielectrophoresis inside confining channels, based on the observed dielectrophoresis responses due to different DNA sizes and various electric fields applied between the inlet and the outlet. The proposed physical mechanism indicates that further extensive investigations, both theoretically and experimentally, would be very useful to better elucidate the forces involved at DNA dielectrophoresis. When applied for size-based sorting of DNA molecules, our sorting method offers two major advantages compared to earlier attempts with insulative dielectrophoresis: Its continuous operation allows for high-throughput analysis, and it only requires electric field strengths as low as ∼ 10 V/cm.
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Microfluidics as a functional tool for cell mechanics Biomicrofluidics 3, 012006 (2009); http://dx.doi.org/10.1063/1.3067820 (15 pages) | Cited 22 times Online Publication Date: 5 January 2009
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Living cells are a fascinating demonstration of nature’s most intricate and well-coordinated micromechanical objects. They crawl, spread, contract, and relax—thus performing a multitude of complex mechanical functions. Alternatively, they also respond to physical and chemical cues that lead to remodeling of the cytoskeleton. To understand this intricate coupling between mechanical properties, mechanical function and force-induced biochemical signaling requires tools that are capable of both controlling and manipulating the cell microenvironment and measuring the resulting mechanical response. In this review, the power of microfluidics as a functional tool for research in cell mechanics is highlighted. In particular, current literature is discussed to show that microfluidics powered by soft lithographic techniques offers the following capabilities that are of significance for understanding the mechanical behavior of cells: (i) Microfluidics enables the creation of in vitro models of physiological environments in which cell mechanics can be probed. (ii) Microfluidics is an excellent means to deliver physical cues that affect cell mechanics, such as cell shape, fluid flow, substrate topography, and stiffness. (iii) Microfluidics can also expose cells to chemical cues, such as growth factors and drugs, which alter their mechanical behavior. Moreover, these chemical cues can be delivered either at the whole cell or subcellular level. (iv) Microfluidic devices offer the possibility of measuring the intrinsic mechanical properties of cells in a high throughput fashion. (v) Finally, microfluidic methods provide exquisite control over drop size, generation, and manipulation. As a result, droplets are being increasingly used to control the physicochemical environment of cells and as biomimetic analogs of living cells. These powerful attributes of microfluidics should further stimulate novel means of investigating the link between physicochemical cues and the biomechanical response of cells. Insights from such studies will have implications in areas such as drug delivery, medicine, tissue engineering, and biomedical diagnostics.
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Biomicrofluidics 1, 014106 (2007); http://dx.doi.org/10.1063/1.2710191 (13 pages) | Cited 21 times Online Publication Date: 16 February 2007
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Rapid concentration and detection of bacteria in integrated chips and microfluidic devices is needed for the advancement of lab-on-a-chip devices because current detection methods require high concentrations of bacteria which render them impractical. We present a new chip-scale rapid bacteria concentration technique combined with surface-enhanced Raman scattering (SERS) to enhance the detection of low bacteria count samples. This concentration technique relies on convection by a long-range converging vortex to concentrate the bacteria into a packed mound of 200 μm in diameter within 15 min. Concentration of bioparticle samples as low as 104 colony forming units (CFU)/ml are presented using batch volumes as large as 150 μl. Mixtures of silver nanoparticles with Saccharomyces cerevisiae, Escherichia coli F-amp, and Bacillus subtilis produce distinct and noticeably different Raman spectra, illustrating that this technique can be used as a detection and identification tool.
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A perspective on paper-based microfluidics: Current status and future trends Biomicrofluidics 6, 011301 (2012); http://dx.doi.org/10.1063/1.3687398 (13 pages) | Cited 20 times Online Publication Date: 2 March 2012
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“Paper-based microfluidics” or “lab on paper,” as a burgeoning research field with its beginning in 2007, provides a novel system for fluid handling and fluid analysis for a variety of applications including health diagnostics, environmental monitoring as well as food quality testing. The reasons why paper becomes an attractive substrate for making microfluidic systems include: (1) it is a ubiquitous and extremely cheap cellulosic material; (2) it is compatible with many chemical/biochemical/medical applications; and (3) it transports liquids using capillary forces without the assistance of external forces. By building microfluidic channels on paper, liquid flow is confined within the channels, and therefore, liquid flow can be guided in a controlled manner. A variety of 2D and even 3D microfluidic channels have been created on paper, which are able to transport liquids in the predesigned pathways on paper. At the current stage of its development, paper-based microfluidic system is claimed to be low-cost, easy-to-use, disposable, and equipment-free, and therefore, is a rising technology particularly relevant to improving the healthcare and disease screening in the developing world, especially for those areas with no- or low-infrastructure and limited trained medical and health professionals. The research in paper-based microfluidics is experiencing a period of explosion; most published works have focused on: (1) inventing low-cost and simple fabrication techniques for paper-based microfluidic devices; and (2) exploring new applications of paper-based microfluidics by incorporating efficient detection methods. This paper aims to review both the fabrication techniques and applications of paper-based microfluidics reported to date. This paper also attempts to convey to the readers, from the authors’ point of view the current limitations of paper-based microfluidics which require further research, and a few perspective directions this new analytical system may take in its development.
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Extracting the hydrodynamic resistance of droplets from their behavior in microchannel networks Biomicrofluidics 3, 012804 (2009); http://dx.doi.org/10.1063/1.3109686 (16 pages) | Cited 19 times Online Publication Date: 30 March 2009
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The overall traffic of droplets in a network of microfluidic channels is strongly influenced by the liquid properties of the moving droplets. In particular, the effective hydrodynamic resistance of individual droplets plays a key role in their global behavior. Here we propose two simple and low-cost experimental methods for measuring this parameter by analyzing the dynamics of a regular sequence of droplets injected into an “asymmetric loop” network. The choice of a droplet taking either route through the loop is influenced by the presence of previous droplets that modulate the hydrodynamic resistance of the branches they are sitting in. We propose to extract the effective resistance of a droplet from easily observable time series, namely, from the choices the droplets make at junctions and from the interdroplet distances. This becomes possible when utilizing a recently proposed theoretical model based on a number of simplifying assumptions. Here we present several sets of measurements of the hydrodynamic resistance of droplets, expressed in terms of a “resistance length.” The aim is twofold: (1) to reveal its dependence on a number of parameters, such as the viscosity, the volume of droplets, their velocity as well as the spacing between them. At the same time (2), by using a standard measurement technique, we compare the limitations of the proposed methods. As an important result of this comparison, we obtain the range of validity of the simplifying assumptions made in the theoretical model.
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Biomicrofluidics 4, 034104 (2010); http://dx.doi.org/10.1063/1.3474638 (11 pages) | Cited 19 times Online Publication Date: 5 August 2010
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We present an analysis of the results of in situ surface-enhanced Raman scattering (SERS) of bacteria using a microfluidic chip capable of continuously sorting and concentrating bacteria via three-dimensional dielectrophoresis (DEP). Microchannels were made by sandwiching DEP microelectrodes between two glass slides. Avoiding the use of a metal nanoparticle suspension, a roughened metal surface is integrated into the DEP-based microfluidic chip for on-chip SERS detection of bacteria. On the upper surface of the slide, a roughened metal shelter was settled in front of the DEP concentrator to enhance Raman scattering. Similarly, an electrode-patterned bottom layer fabricated on a thin cover-slip was used to reduce fluorescence noise from the glass substrate. Gram positive (Staphylococcus aureus) and Gram negative (Pseudomonas aeruginosa) bacteria were effectively distinguished in the SERS spectral data. Staphylococcus aureus (concentration of 106 CFU/ml) was continuously separated and concentrated via DEP out of a sample of blood cells. At a flow rate of 1 μl/min, the bacteria were highly concentrated at the roughened surface and ready for on-chip SERS analysis within 3 min. The SERS data were successfully amplified by one order of magnitude and analyzed within a few minutes, resulting in the detection of signature peaks of the respective bacteria.
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Long-range and superfast trapping of DNA molecules in an ac electrokinetic funnel Biomicrofluidics 2, 044103 (2008); http://dx.doi.org/10.1063/1.3037326 (10 pages) | Cited 19 times Online Publication Date: 5 December 2008
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In this work we report a microfluidic platform capable of trapping and concentrating a trace amount of DNA molecules efficiently. Our strategy invokes nonlinear electro-osmotic flow induced by charge polarization under high-frequency ac fields. With the asymmetric quadrupole electrode design, a unique converging flow structure can be created for generating focusing effects on DNA molecules. This focusing in turn transforms into a robust funnel that can collect DNA molecules distantly from the bulk and pack them into a compact cone with the aid of short-range dipole-induced self-attraction and dielectrophoresis. Our results reveal that not only can DNA molecules be concentrated within just a few seconds, but also they can be focused into threads of 1 mm in length, demonstrating the superfast and long-range trapping capability of this funnel. In addition, pico M DNA solutions can be concentrated with several decades of enhancement without any continuous feeding. Alternating concentration and release of DNA molecules is also illustrated, which has potentials in concentrating and transporting biomolecules in a continuous fashion using microdevices.
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Enhanced discrimination of normal oocytes using optically induced pulling-up dielectrophoretic force Biomicrofluidics 3, 014103 (2009); http://dx.doi.org/10.1063/1.3086600 (10 pages) | Cited 19 times Online Publication Date: 17 February 2009
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We present a method to discriminate normal oocytes in an optoelectrofluidic platform based on the optically induced positive dielectrophoresis (DEP) for in vitro fertilization. By combining the gravity with a pulling-up DEP force that is induced by dynamic image projected from a liquid crystal display, the discrimination performance could be enhanced due to the reduction in friction force acting on the oocytes that are relatively large and heavy cells being affected by the gravity field. The voltage condition of 10 V bias at 1 MHz was applied for moving normal oocytes. The increased difference of moving velocity between normal and starved abnormal oocytes allows us to discriminate the normal ones spontaneously under the moving image pattern. This approach can be useful to develop an automatic and interactive selection tool of fertilizable oocytes.
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