Cell Separation by Non-Inertial Force Fields in Microfluidic Systems

Abstract

Cell and microparticle separation in microfluidic systems has recently gained significant attention in sample preparations for biological and chemical studies. Microfluidic separation is typically achieved by applying differential forces on the target particles to guide them into different paths. This paper reviews basic concepts and novel designs of such microfluidic separators with emphasis on the use of non-inertial force fields, including dielectrophoretic force, optical gradient force, magnetic force, and acoustic primary radiation force. Comparisons of separation performances with discussions on physiological effects and instrumentation issues toward point-of-care devices are provided as references for choosing appropriate separation methods for various applications.

Figure 1

Particle separation with cross flow filtration and laminar flow. (A) Cross flow filtration. Particles smaller than the micro pores on the side walls are continuously extracted into the side channels. The flow in the main channel perpendicular to the micro pores prevents fouling of larger particles on the pores. (B) Asymmetric pinched flow fractionation. Particles introduced from inlet 1 are hydrodynamically aligned against sidewall 1 of the pinched segment, where the centers of mass of the particles are dictated by the radii. Particles are then separated into different trajectories in the diverging section. Reproduced from Takagi et al., 2005 by permission of The Royal Society of Chemistry. (C) Deterministic lateral displacement. In a laminar flow around staggered arrays of posts, small particles stay within a band stream (between two adjacent dashed lines) and come back to the same lateral position every three rows. Large particles, however, are forced to laterally shift after each row as the center of mass needs to cross the boundary of the two adjacent streams. Adapted from Davis et al., 2006, Copyright 2006 National Academy of Sciences, U.S.A.

Figure 2

Particle separation by DEP forces. (A) A DEP deflector by the trapezoidal electrode array. Polystyrene beads immersed in a separation buffer experience nDEP force upon encountering each of the trapezoidal electrodes. This nDEP force on the particle is size dependent, resulting in particle fractionation in the transverse direction. Reproduced from Choi and Park, 2005 by permission of The Royal Society of Chemistry. (B) A schematic representation of the electric field strength contours near the oil droplet and the nDEP force on a particle. (C) Superposed trajectories of the 5.7 μm and 15.7 μm particles separated by DC-iDEP. Reproduced from Barbulovic-Nad et al., 2006 by permission of The Royal Society of Chemistry.

Figure 3

Particle separation by optical forces. (A) Binary fractionation with an optical lattice. A three-dimensional optical lattice formed in the fractionation chamber (FC) exerts the optical gradient force, guiding one species of the particles into the upper flow field. Adapted by permission from Macmillan Publishers Ltd: Nature, MacDonald et al., 2003, copyright 2003. (B) Fractionation of polydisperse particles. The acousto-optically generated optical guide (inset) traps all the particles, then releases them in a size-increasing order, achieving lateral fractionation of four different sizes. Reproduced from Milne et al., 2007 by permission from Optical Society of America, Copyright 2007. (C) A microscale fluorescent activated cell sorter with optical force switching. After being aligned to the center of the channel by flow focusing, cells are analyzed and then switched based on their detected fluorescence. Target cells are directed by the laser to the collection outlet while all the other cells flow to the waste outlet. Adapted by permission from Macmillan Publishers Ltd: Nature Biotechnology, Wang et al., 2005, copyright 2005.

Figure 4

Particle separation by magnetic forces. (A) The two laminar streams, the source stream containing both magnetic and non-magnetic particles and the collection stream without particles, flow through a strong magnetic field gradient produced by the microfabricated NiFe microcomb. Magnetic particles are extracted into the collection stream by magnetic force in the direction perpendicular to the flow. Adapted from Xia et al., 2006, Copyright 2006, with kind permission of Springer Science and Business Media. (B) In free-flow magnetophoresis, particles are laterally fractionated in the separation chamber, then collected into different outlet channels. Reprinted from Pamme et al., 2006, Copyright 2006, with permission from Elsevier.

Figure 5

Particle separation by acoustic forces. (A) Two particle types of opposite ϕ are positioned, by the acoustic forces, in the pressure nodal and anti-nodal planes of a standing wave. (B) The top view of a continuous separation of two particle types from each other. Reproduced from Petersson et al., 2004 by permission of The Royal Society of Chemistry. (C) Free-flow acoustophoresis. A stream of mixed particles was fractionated as it passes through the acoustic standing wave section. In this case, the acoustic force differentially deflects particles in a size-dependent manner.