The potential of a dielectrophoresis activated cell sorter (DACS) as a next generation cell sorter
© The Author(s). 2016
Received: 7 March 2016
Accepted: 10 May 2016
Published: 20 May 2016
Originally introduced by H. A. Pohl in 1951, dielectrophoretic (DEP) force has been used as a striking tool for biological particle manipulation (or separation) for the last few decades. In particular, dielectrophoresis activated cell sorters (DACSes) have been developed for applications in various biomedical fields. These applications include cell replacement therapy, drug screening and medical diagnostics. Since a DACS does not require a specific bio-marker, it is able to function as a biological particle sorting tool with numerous configurations for various cells [e.g. red blood cells (RBCs), white blood cells (WBCs), circulating tumor cells, leukemia cells, breast cancer cells, bacterial cells, yeast cells and sperm cells]. This article explores current DACS capabilities worldwide, and it also looks at recent developments intended to overcome particular limitations. First, the basic theories are reviewed. Then, representative DACSes based on DEP trapping, traveling wave DEP systems, DEP field-flow fractionation and DEP barriers are introduced, and the strong and weak points of each DACS are discussed. Finally, for the purposes of commercialization, prerequisites regarding throughput, efficiency and recovery rates are discussed in detail through comparisons with commercial cell sorters (e.g. fluorescent activated and magnetic activated cell sorters).
Since dielectrophoresis was first reported by H. A. Pohl in 1951, it has been employed as a biological particle manipulating tool in various fields (e.g. cell replacement therapy, drug screening, medical diagnostics, particle filtration and microfluidics) [1–10]. Dielectrophoretic (DEP) phenomena occur when micro/nano-particles in a medium are exposed to a non-uniform electric field, causing polarization for particular particles according to their dielectric property [11, 12]. DEP force is classified into two types according to correlations of the dielectric properties of the particles and medium. Positive DEP (p-DEP) force pulls particles toward a higher electric gradient, and negative DEP (n-DEP) force repels particles away from the higher electric gradient. Therefore, various target cells with different dielectric properties can be manipulated by controlling the medium properties or the input voltage condition. In order to manipulate biological particles, consequently, various dielectrophoresis-based techniques, including DEP trapping, DEP field-flow fractionation (DEP-FFF), traveling wave DEP (TwDEP) force and DEP barrier, are performed within a micro fluid channel [13–21]. DEP trapping techniques are mainly used to isolate particles within a still fluid utilizing p-DEP force [22–25]. The TwDEP force, DEP-FFF and DEP barrier techniques are realized via angled or vertical electrode pairs, and they are generally implemented with n-DEP force within the micro channel with fluidic flow [26–32]. The latter techniques have a striking advantage in terms of throughput since the continuous loading of target cells along the fluidic flow allows for continuous cell separation. Therefore, there have been many studies on the separation of various biological particles, including blood cells [red blood cells (RBCs) and white blood cells (WBCs)], cancer cells [circulating tumor cells (CTCs), leukemia cells and breast cancer cells], submicron particles (bacteria, yeast cells), spermatozoa, stem cells, protein and DNA. Dielectrophoresis activated cell sorters (DACSes) differ from conventional fluorescent activated cell sorters (FACSes) and magnetic activated cell sorters (MACSes) in that they do not require the additional financial and time expenditure necessary for immune-labeling [33–38]. In addition, DACSes achieve high separation efficiency owing to the continuous separation in the micro fluid channel. Nevertheless, there are still big hurdles to be overcome with respect to their low throughputs and recovery rates.
In this article, therefore, we explore current DACS capabilities worldwide and look at recent developments intended to overcome particular limitations. First, the basic theories are reviewed. Then, the configurations and characteristics of four representative DACSes are compared, and the strong and weak points of each DACS are discussed. Finally, a commercialization strategy is suggested.
Traveling wave dielectrophoresis
DEP field flow fractionation
Comparative analysis with a commercial cell sorter
FACSes and MACSes are representative commercial cell sorters. FACSes show high separation efficiencies of over 97 %, throughputs of 10,000 cells/s and recovery rates of over 55 % [55–57]. MACSes show similar performance characteristics—separation efficiencies of over 90 %, throughputs of 1010 cells/h and recovery rates near 50 % [58–60]. The results do not include the time-consuming labeling process that takes over an hour. The aforementioned DACS employing DEP-FFF and DEP barrier immediately achieved competitive results when compared to FACSes and MACSes in terms of separation efficiency. However, the throughput and recovery rate are still not at commercial levels. Even though Hu et al.  reported a striking throughput employing dielectrophoresis at over 10,000 cells/s, similar to that of a FACS, their sorter required a specific marker and a labeling process as prerequisites, which are also required for FACSes and MACSes. Consequently, it can be said that a DACS without immune-labelling cannot produce the levels of performance in terms of efficiency, throughput and recovery rate when compared to FACSes and MACSes. Nevertheless, a DACS employing the intrinsic dielectric material properties of a particle obtained a high separation efficiency and high recovery rate without the labeling process. Once a high throughput can be achieved through an optimization process (e.g. employing a modular system consisting of a few of the same features as those used by MACSes, applying a higher flow rate and so on), DACSes will be sufficiently competitive with FACSes and MACSes.
Conclusion and prospects
Tissue engineering to rebuild damaged organs.
Stem cell separation for cell replacement treatment.
In vitro fertilization or intracytoplasmic sperm injection; superior sperm selection.
DL carried out the research work and wrote the manuscript. BH carried out a survey of dielectrohporesis-based particle sorting systems. BK supervised all research work. All authors read and approved the final manuscript.
Dongkyu Lee received his B.S. and M.S. degrees from Korea Aerospace University in 2012 and 2014, respectively, and is now a Ph.D. candidate at Korea Aerospace University. His current research interests include microelectromechanical systems (MEMS) for bio particle sorting systems.
Bohyun Hwang received his B.S. degree from Korea Aerospace University in 2015, and is now in a Master’s course at Korea Aerospace University. His current research interests include the development of cell sorting systems based on dielectrophoresis.
Byungkyu Kim received his Ph.D. in mechanical engineering from the University of Wisconsin, Madison, in 1997. From 1997 to 2000, he was a technical staff member at the Center for X-ray Lithography (CXrL) at the University of Wisconsin where he developed a computer code for the thermal modeling of a mask membrane and wafer during beam exposure. From 2000 to 2005, he worked for the Microsystem Center at KIST as a principal research scientist. He was in charge of developing the microrobot for a microcapsule-type endoscope. Currently, he is a professor in the School of Aerospace and Mechanical Engineering at Korea Aerospace University. His research interests include microelectromechanical systems (MEMS) for cell separation.
This research was supported by the Bio & Medical Technology Development Program (NRF-2005-2000206) and the Basic Science Research Program (NRF-2015R1D1A01057714) of the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology.
The authors declare that they have no competing interests.
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