Three types of magnetic flux sources are commonly used for micro- and nano-object handling: electromagnets, soft magnets and permanent magnets. Both electromagnets and soft magnets present the advantage of allowing on/off switching, although they usually require cumbersome side-equipment to perform this task. Electromagnets also have the disadvantage of Joule heating, which can be a major inconvenient for microfluidics. Permanent magnets on the other hand cannot be turned off. In some cases this is a great advantage, especially if they are down-scaled and integrated to microsystems, which then are autonomous.
One of the earliest works in magnetic capturing using bulk magnets was reported by Miltenyi in [1]. In this work, a Magnetic Cell Sorter (MACS) from Miltenyi Biotec is used to separate cells labeled with magnetic particles from non-labeled cells. Three basic steps can be observed: the objects of interest are labeled with magnetic particles; the solution passes through the MACS Column, in which the labeled cells are captured by the magnets while the others are collected on the outlet of the column; the captured cells are removed from the action range of the magnetic field and collected.[2]
The popularity of magnetism to control particles and samples has increased these last few years. Two of its main advantages are contactless actuation and the possibility to actuate in attraction and/or repulsion. Micro- and nano-particle fabrication is also boosting the use of magnetophoretic methods. Precisely controlled magnetic particles can be produced and functionalized with specific proteins, antibodies or surfactant compounds, for instance. Thus, they can be rendered stable in a certain medium and, more importantly, reactive to very specific target objects. More recently, microfluidics has appeared as a very interesting technology for this field. Its numerous advantages even made it classified as “almost too good to be true” [3]. This review presents a few examples of applications where magnetic flux sources, magnetic particles and microfluidics are combined in order to perform particle sorting and handling.
Other interesting review is reference [4].
The same principle was used by Hoshino et al. to develop microfluidic systems in which bulk magnets with antiparallel magnetization are disposed side by side in order to create a higher field gradient[5]. This system is used to capture magnetically labeled cancer cells and to observe them inside the microfluidic channel. Other research groups worked on similar ideas for blocking and unblocking particles. Bulk permanent magnets have also been used, for instance, to give magnetically labeled cells a specific spatial arrangement[6] and to create hair-like structures of magnetic particles [7].
A schematic of the attraction of magnetic objects above soft magnetic elements is shown by Tseng et al. in [8]. A macroscopic source of magnetic field polarizes micro- or nanoscaled soft magnetic elements, which generate both fields and field gradients that attract the round magnetically labelled objects. These elements have been widely used to capture magnetic particles, to concentrate them into determined locations and separate them from mixed solutions [9-11].
Guo et al. have shown in [12] the standard steps used to capture and release magnetic particles. The four frames in the picture present sequentially: polarized square patterns produced on a soft magnetic material, with a microfluidic channel above them; magnetic microparticles captured by the magnetic elements; the polarizing field is removed and the captured particles start to unpin; the system no longer holds magnetic particles. Separation by magnetic/non-magnetic character can be done using this technique, which is basically the one shown previously with bulk magnets (i.e. MACS) but integrated in a microfluidic device.
The capturing/releasing approach has been also used for biological studies [13]. Ino et al., for instance, developed a method of organizing magnetically labelled cells based on microstructured pillars produced on soft iron [14]. In certain conditions, a single cell can be trapped above each pillar and individually studied.
Ramadan et al. presented different arrangements of micro-wires which can be integrated in micro-devices, especially for biological manipulation [15, 16]. The figure shows some configurations developed by the group and the resulting particle capture.
Few works have been reported concerning permanent micro-magnets and microfluidics. Yellen et al. have reported the possibility of positioning non-magnetic particles above arrayed magnetic patterns with high precision [17]. Non-magnetic, fluorescent particles were arrayed in precise positions due to the action of magnetic fields created by both the micro-magnets and an external electromagnet on magnetic nanoparticles dispersed in the solution. In another work, the displacement of a magnetic particle above a similar magnetic pattern was reported, when varying the external applied field [18].
Issadore et al. used micrometre-sized NdFeB grains to create high magnetic field gradients close to a microfluidic channel [19]. The NdFeB grains are suspended in uncured PDMS and self-assembled in the presence of an external field. The PDMS is then cured and a microfluidic channel is built above the magnet array. The system was used to sort magnetic/non-magnetic particles and labelled/non-labelled cells with high purity.
Zanini et al. presented a device incorporating magnetically microstructured hard magnetic NdFeB films. A flat film was microstructured using thermomagnetic patterning, thus producing micromagnets with size in the range of 5 to 100 µm. Magnetic micro and nanoparticles were flown through microfluidic channels produced above the magnets. Capture occurred at specific zones above the magnets and release was obtained by increasing the flow rate in the channel. Sorting by magnetic character using magnetic and non-magnetic particles was obtained with high efficiency, up to 99.9% of purity.[20]
Particle capture and release can be performed with relative ease. Continuously guiding and, in particular, sorting particles with microfluidics, on the other hand, can be a much more difficult task. A good control of the attraction force, as well as a fine balance between magnetic and drag forces are required. Numerous successful attempts of continuous flow magnetic cell sorting have been reported using bulk permanent magnets, soft magnets and electromagnets, as shown below.
The group of Pamme designed a system combining microfluidics and a bulk permanent magnet, in which the goal is to guide objects towards different outlets according to the magnetic label. One channel inlet is used to pump in the liquid solution containing the objects of study while a buffer solution is pumped in the other inlets. It should be noticed that the position of the magnet is in the opposite side of the main inlet. The outlets are used to collect the solution containing the particles which are separated by labels. This system has been used to sort magnetic particles based on their susceptibilities [21]; cells labeled with magnetic particles based on magnetic moment and particle size [22]; magnetic particles based on the variation of magnetic response in temperature [23]; and different types of cells, based on their endocytotic capacity [24].
A system based on soft magnets for particle sorting was developed by Afshar et al. (Prof. Martin Gijs’ group). The system is composed of soft magnetic poles near a microfluidic channel, the magnetic element being polarized by a coil. Two distinct zones of magnetic actuation are present. The first zone has the same function of attracting and concentrating the magnetic particles which flow near the magnetized elements. The second active zone is situated further in the channel and attracts the particles to the other side of the channel. The attraction force acting on the particles depends on their dimension, thus, particles of different size can be separated, as shown in the second frame of the figure [25].
Han et al. used a ferromagnetic wire magnetized by an external field in order to separate red and white blood cells [26,27]. Since red blood cells (RBC) are attracted to the highest magnetic field gradients, while white blood cells (WBC) are repelled from it, these cells can be sorted using a simple device. In the figure, the solution containing both types of cells is pumped in the only inlet and exits the channel by three possible outlets. The ferromagnetic wire placed in the center of the channel concentrates the RBC, which are guided towards the central outlet, while the WBC are repelled from the wire and exit the channel by the two external outlets.
Still based on the continuous sorting of objects, many advances have been made using ferromagnetic stripes. A magnetically tagged object submitted to a drag force inside a microfluidic channel is also submitted to a magnetic force when passing near soft magnetic stripes. The angle between the magnetic and the drag force deviates the object from its initial path, thus, separation can be achieved. This binary separation (magnetic/non-magnetic) has been reported in several publications [28,29].
Other systems based on the deviation of particles for separation were reported by Derec et al. [30] and Shevkoplyas et al. [31]. The deviation of the particles, in this case, is obtained by a permanent magnetic field created by a wire in the vicinity of the microfluidic channel. In the system produced by the group of Shevkoplyas a microfluidic channel is seen in the center, with a conductive wires on each side. The magnetic particles inside the channel are randomly dispersed at first, since no magnetic field acts on them. Once a current passes through the top wire, the particles are attracted to it and are concentrated on one side of the channel. This method can be used to sort particles in a continuous fashion, since they are continuously guided, instead of captured/released.
Adams et al. developed a system based on the same principle, but in which three types of objects can be sorted [32]. The system has one inlet for the solution of objects to be sorted and one inlet for a buffer solution. The objects are concentrated in one side of the channel. A first set of magnetic stripes deviates a first group of magnetically labelled objects, while a second set deviates a second group. The third group is not labelled and follows the fluid flow without being deviated. The three groups are collected in different conveniently placed outlets. The separation of two different magnetically labelled objects results from a difference in both the drag force and the magnetic force, due to the use of different labels.
Another interesting system was developed by Fulcrand et al. (A.-M. Gué’s group), which allows dynamic particle manipulation[33]. Magnetic particles flow in a liquid solution through a microfluidic channel. A set of micro-coils disposed successively from one side of the channel to the other is placed below the channel. The first coil is activated in order to capture the magnetic beads. The following coil is activated and the precedent is deactivated, displacing the group of particles further in the channel and towards a different position in the channel section. This is repeated until the particles are conveniently placed as regards to the channel outlets, then the particles are released from the coils and collected.
A general review on magnetic fluids and microfluidics can be found here.
For more reviews about microfluidics, please have a look at: «Microfluidics reviews». The photos in this article come from the Elveflow® data bank, Wikipedia or elsewhere if precised. Article written by Luiz Zanini and Timothée Houssin.
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