Abstract
Exploration of active manipulation of bioparticles has been impacted by the development of micro-/nanofluidic technologies, enabling evident observation of particle responses by means of applied tunable external force field, namely, dielectrophoresis (DEP), magnetophoresis (MAG), acoustophoresis (ACT), thermophoresis (THM), and optical tweezing or trapping (OPT). In this chapter, each mechanism is presented in brief yet concise, for broad range of readers, as strong foundation for amateur as well as brainstorming source for experts. The discussion covers the fundamental mechanism that underlying the phenomenon, presenting the theoretical and schematic description; how the response being tuned; and utmost practical, the understanding by specific implementation into bioparticles manipulation engaging from micron-sized material down to molecular level particles.
Keywords
- microfluidics
- nanofluidics
- dielectrophoresis
- magnetophoresis
- acoustophoresis
- thermophoresis
- optical tweezing
- optical trapping
1. Introduction
Progress in biomedical technologies has emerged into miniaturization of biomedical devices. The main features in miniaturized biomedical devices are establishment of controlled microenvironment that promotes predictive micro-/nanoparticle behaviors and reduction in required sample volume for characterization of scarce materials, e.g., patient-derived samples, which help to reduce the cost and time for diagnosis and therapy [1]. Miniaturization of these biomedical devices demands for implementation of particular procedures in precise approach, which has been extensively studied in micro-/nanofluidic system integrated with active manipulation mechanisms [2, 3, 4].
Micro-/nanofluidic system facilitates researchers in creating well-controlled micro-/nanoscale environment and at the same time enables the analysis of micro-/nanoparticles including biological particle (bioparticle) behaviors and responses toward active manipulation mechanisms, in addition to particle-particle reactions and external stimuli [5]. Active manipulation mechanisms make possible the control of bioparticle displacement and motional trajectories in a highly predictable and consistent fashion [2], by introducing tunable external force systems such as dielectrophoresis (DEP) [6, 7], magnetophoresis (MAG) [8], acoustophoresis (ACT) [9], thermophoresis (THM) [10], and/or optical tweezing/trapping (OPT) [11, 12].
In this chapter, description of the fundamental mechanism underlying the phenomenon is presented, covering the theoretical and schematic description, as well as specific implementation into bioparticle manipulation covering from micron-sized material down to molecular-level particles. Conclusion and future perspectives of this multidisciplinary field are provided at the end of this chapter.
2. Bioparticles in biomedical studies
Manipulation of bioparticles has been a major concern in recent development of micro−/nanofluidic studies due to their potential in biomedical application. Those particles, according to their biological structure and physical properties, can be categorized as (1) model organisms; (2) body cells, which include blood cells, tumor and cancer cells, and stem or progenitor cells; (3) bacteria; (4) viruses; (5) nucleic acids; and (6) proteins.
Model organisms, either unicellular (e.g., yeast) or multicellular (e.g.,
3. Dielectrophoresis
Dielectrophoresis (DEP) is the motion of polarizable particles under a spatially nonuniform electric field that cause momentary polarization of the particle by dipole establishment within, with an unequal Columbic forces at both ends of the particles, causing the particles to move [2, 6, 7].
3.1. Fundamentals of DEP
Dielectrophoretic force,
where
For a spherical particle,
where
where
The dielectrophoretic force direction is determined by the sign of the
Moreover, for an AC field with spatial variation, the dielectrophoretic force is given by
where Re[
In general, the traveling wave DEP is created by application of 90° phase-shifted electric signal, i.e., 0, 90, 180, and 270°, on an array of planar parallel electrodes, causing generation of a traveling wave of electrostatic potential which can vertically suspend a lossy dielectric sphere while at the same time propels it along the array. The Re[
As bioparticles are typically multilayered with the presence of multilayer membranes, Clausius-Mossotti factor calculation needs to consider total permittivity of the bioparticle comprising of the permittivity of all layers. Total permittivity,
where
Transition between the pDEP and nDEP responses of bioparticle happens across the point when the polarization of the particle and the suspending medium are equal, which occurs at a particular frequency known as crossover frequency,
where
3.2. Dielectrophoretic manipulation of bioparticles
Manipulation of model organism has been demonstrated by Chen et al. [18], who perform detection and trapping of
4. Magnetophoresis
Magnetophoresis (MAG) is the motion of particles under the influence of a nonuniform magnetic field, as the particles being magnetized cause them to be attracted toward the regions of high magnetic flux density or repelled away [8]. Magnetic field is generated by either a permanent magnet or an electromagnetic coil.
4.1. Fundamentals of MAG
Magnetophoretic force experienced by a particle is governed by
where
The motional direction is controlled by the difference of magnetic susceptibility between the particle and the medium, i.e.,
Common practices in magnetophoretic manipulation of bioparticle employ either (1) immunomagnetic manipulation [28] or (2) diamagnetic manipulation [29], in which paramagnetic bounded to bioparticle is exploited in the former, while in the latter, paramagnetic- or ferrofluid-suspending medium is utilized. In immunomagnetic bioparticle manipulation, paramagnetic micro-/nanoparticles, e.g., iron oxide microparticles and streptavidin paramagnetic particles, which have higher susceptibility compared to suspending medium are used. Target bioparticles are bounded to paramagnetic micro-/nanoparticles through antibodies, benefiting from binding affinity with bioparticles. Under influence of magnetic field, the microparticle-bioparticle complexes can be manipulated. While in diamagnetic bioparticle manipulation, a suspending medium with higher magnetic susceptibility compared to target bioparticle is utilized. In this method, the magnetic field manipulates the suspending medium rather than the bioparticles themselves.
4.2. Magnetophoretic manipulation of bioparticles
Lee et al. [27] magnetically functionalize living yeast cells,
5. Acoustophoresis
Acoustophoresis (ACT) is the motion of particles when experiencing a surface acoustic wave (SAW) radiation pressure, either by standing surface acoustic wave or traveling surface acoustic wave [36, 37].
5.1. Fundamentals of ACT
Acoustophoretic force,
where
The direction of the particle motion, either toward the pressure node or the antinode, is governed by the sign of the acoustic contrast factor,
where
Mainstream applications of ACT in particle manipulation employ either (1) traveling surface acoustic wave (TSAW) [37] or standing surface acoustic wave (SSAW) [36]. A TSAW is a condition when a surface acoustic wave (SAW) is propagating from interdigitated transducer (IDT) electrodes, while SSAW occurs when two TSAWs constructively interfere and form a standing or stationary SAW. TSAW can be generated by a single IDT electrode, while the SSAW can be generated either by a pair of IDT electrodes or a combination of a single IDT and wave reflectors. In TSAW acoustophoresis, bioparticles move together with the wave propagation, while in SSAW acoustophoresis, they are pushed toward the SAW pressure node or the antinode. Pressure node is the region of constant pressure, while pressure antinodes are regions alternating between maximum and minimum pressure values.
5.2. Acoustophoretic manipulation of bioparticles
Acoustophoretic manipulation of model organism has been demonstrated by Sundvik et al. [39]. They study levitation of zebrafish embryos using acoustic radiation force in a noncontact wall-less platform for a period of less than 2000 s, while the embryos still in development at 2–14 hours postfertilization, and they found that the levitation does not interfere the development, though it might influence mortality rate. Urbansky et al. [40] perform the manipulation of peripheral blood progenitor cells (PBPCs) with the focus on sorting out CD8 lymphocytes (target cells) from the mixture that contains CD4, CD19, CD34, and CD56 lymphocytes as well. They label the CD8 with affinity beads, forming bead-cell complex, to modify the acoustic mobility of the target cells. Furthermore, they modify the medium properties of central buffer, using Ficoll wash buffer, to adjust the acoustic force on different particles, so that bead-CD8 complexes are pushed into central buffer under acoustophoretic force exerted by piezoceramic transducer, while other unbounded cells remain flowing at the side due to lower acoustic mobility. Urbansky et al. [41] further perform separation of mononuclear cells (MNCs) from diluted whole blood using acoustophoretic microfluidic device. They managed to overcome the behavior similarity of MNCs and RBCs in acoustic standing wave by optimizing the buffer conditions to modify the acoustophoretic mobility of the cells. Antfolk et al. [42] accomplish separation of spiked prostate cancer cells (DU145) from whole blood using ACT-DEP-integrated platform consisting of acoustophoretic pre-alignment, separation, and concentration of targeted DU145 cells, prior to single-cell array trapping using DEP microwell. Bacteria manipulation has been accomplished by Ohlsson et al. [38], who developed a microsystem for bacteria separation, enrichment, and detection from blood, as demonstrated in Figure 3b. The system is integrated with acoustic separation to remove RBCs from blood sample, with subsequent enrichment of bacteria from plasma by acoustic trapping to polystyrene seed particles, and polymerase chain reaction (PCR) for detection and identification of the bacteria at the final stage. They demonstrate the system using whole blood samples, which, respectively, spiked with
6. Thermophoresis
Thermophoresis (THM) is the motion of particles driven by thermal gradients in the suspending medium. Thermal gradients are commonly generated by local absorption of infrared (IR) laser. The thermal gradients induce diffusional motion of the particles, either toward higher or lower temperature regions [10].
6.1. Fundamentals of THM
Thermophilic particles diffused to the region with higher temperature, while thermophobic particles move to the opposite direction, as shown in Figure 4a.
Liquid flow density,
where
Steady-state concentration changes for a given spatial temperature difference,
where
Studies prove that a temperature difference between 2 and 8 K in the beam center with a 1/
6.2. Thermophoretic manipulation of bioparticles
Thermophoretic manipulation of yeast cells has been demonstrated by Lin et al. [46] using low-power and flexible all-optical manipulation method, which presented in Figure 4b. They generate light-controlled temperature gradient field thus to trap the suspended cells due to permittivity gradient in the electric double layer of the cell membrane-charged surface. In fact, they manage to realize arbitrary spatial arrangement, as well as precise rotation of single-cell assemblies, with resolution down to 100 nm. J. Chen et al. [48] demonstrate thermophoretic manipulation of
7. Optical tweezing/trapping
Optical tweezing or trapping (OPT) indicates the manipulation of particles using optical forces, referring to the exploitation of light radiation pressure to displace and demobilize target particles [11, 12].
7.1. Fundamentals of OPT
Emission of light by a light source induces scattering and gradient forces, which affect particle in the light propagation axis. Scattering force,
Optical tweezing or trapping depends on the dimension range of the particle under manipulation, which is governed by two physical principles, i.e., (1)
where
where
OPT can be created by light emission through a high numerical aperture number (NA) of microscope objective (MO), which focuses light tightly and results in a force along the highest intensity axis, but in the backward direction, which causes the bioparticle to be demobilized, as presented in Figure 5a.
7.2. Optical tweezing or trapping of bioparticles
Favre-Bulle et al. [53] use optical trapping in vivo to manipulate otoliths in larval zebrafish to stimulate the vestibular system. Lateral and medial forces upon the otolith cause complementary corrective tail motion, while lateral force on either otolith causes a rolling correction in both eyes. Fascinating manipulation of blood has been demonstrated by Zhong et al. [54], who perform manipulation of RBCs in vivo, i.e., within subdermal capillaries in living mice, using infrared optical tweezers. They demonstrate the optical trapping and three-dimensional manipulation of single RBC in the capillary, as well as multiple RBC trapping, forming capillary blockage and clearance, by turning on and off the optical tweezer. Pradhan et al. [55] use optical trapping to bring a single cell of neural tumor cell lines into close proximity of another and measure the time required for cell-cell adhesion to form, as this method can be used to assess the differentiation status of cancerous cells. They perform the measurement for human neuroblastoma SK-N-SH and rat C6 glioma cells. Stem cell manipulation has been performed by Kirkham et al. [56]. They develop remarkable holographic optical tweezer and demonstrate the micromanipulation of several stem cells, including mouse embryonic stem cells, mouse mesenchymal stem cells, and mouse primary calvarea cells, as well as microstructures, such as poly(DL-lactic-co-glycolic acid) microparticles and electrospun fiber fragments. They succeeded in accurately construct three-dimensional architecture with varying geometries from cocultured cells and microstructure and then stabilized them using hydrogels and cell-cell adhesion methods. Zakrisson et al. [57] perform the optical trapping of nonpiliated strain of
8. Conclusion and future perspectives
Manipulation of bioparticles in micro-/nanofluidic, integrated with active manipulation mechanisms, i.e., dielectrophoresis, magnetophoresis, acoustophoresis, thermophoresis, and optical tweezing/trapping, has been discussed in this chapter. Description of the underlying fundamental theory is provided at the beginning, and state-of-the-art implementations into a wide range of bioparticles are carefully introduced. DEP has shown rapid progress into exploration of extremely small bioparticle manipulation, i.e., virus, nucleic acids, and protein. In particular, demonstration of DNA sorting [23] and impedance-based protein capturing [25] prove the potential for nanoscale application, as well as genetic and molecular biology studies. MAG is advantageous in selective manipulation benefited by biofunctionalization of magnetic micro-/nanoparticle for affinity binding to target bioparticles. Novel achievement in customization of target bioparticle magnetization using predefined multiple layers of magnetic particles [27] is promising for application into heterogeneous suspension manipulation, such as whole blood, progenitor, and cancerous cell detection and sorting. ACT’s greatest progress is in the integration with other mechanisms, e.g., DEP, to establish a complete biomedical device [42], showing that transformation from conventional devices to microfluidic biomedical devices which are superfast, precise, and portable is soon to be realized. THM technology particularly is matured enough in extremely small bioparticle manipulation, i.e., protein and nucleic acids, specifically as a measurement tool for binding interaction between molecules. In fact, the recent exploration of thermal gradient-based DNA translocation [50], as well as cell arbitrary manipulation benefited from permittivity gradient in the electric double layer of cell membrane [47], potentially open for new path in THM research. OPT has emerged into in vivo studies [53, 54], indicating that the clinical application is promising and soon to be achieved. In addition, OPT capability in application to genetic and stem cell studies is of high potential, as demonstrated in construction of three-dimensional bioparticle assemblies [55, 56]. Rapid progress of studies on these micro-/nanofluidic active manipulation mechanisms toward bioparticles has a significant impact to biomedical research and technology development. Evolution into high-precision, superfast, and portable miniaturized biomedical devices is pretty soon to be achieved.
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