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Su et al. J Cancer Metastasis Treat 2020;6:19 I http://dx.doi.org/10.20517/2394-4722.2020.48 Page 3 of 21

magnetic field. The migration velocity of a MNP under the application of a homogeneous magnetic field,
[18]
i.e. the magnetophoresis process, largely depends on the magnetic moments of the MNPs. Bruus et al.
theoretically calculated the magnetophoretic force acting on a spherical particle in non-homogeneous field.
It is given by equation:

3
2
F MAP = 2πμ ƒ a ∇[H (r ) ] (1)
0
0 cm
ext
where ∇H is the gradient of the external magnetic field, the diameter of the particle is represented by
ext
a, and f is the Clausius-Mossotti factor of magnetization (CM). f is represented as: (μ - μ )/(μ + 2μ ).
CM
0
CM
0
Here, μ and μ are the magnetic permeabilities of the spherical particle and vacuum, respectively.
0
Iron oxide MNPs, such as γ-Fe O and Fe O , are widely used in the biosensing area due to their good
3
2
3
4
stability and biocompatibility. However, the saturation magnetization of iron oxide MNPs is around three
times smaller than that of high-moment MNPs such as Fe, FeCo, Fe N , etc. [19,20] . These high-moment
16
2
MNPs can provide much higher magnetic forces and, as a result, enhance the capture efficiency and reduce
the dose of MNPs needed for liquid biopsy. Many research groups have reported the synthesis of high-
moment MNPs. Generally, two approaches are used to synthesis high-moment MNPs: the bottom-up
approach and the top-down approach. For the bottom-up approach, MNPs are formed from atoms that
nucleate and grow into nanoparticles. For example, a gas-phase condensation (GPC) method is used to
obtain these atoms either by thermal evaporation or sputtering. By cooling down these atoms, nucleation
starts and then the nuclei grow into nanoparticles of various shapes. High-moment MNPs such as Fe,
and FeCo have been successfully synthesized using this GPC method [21,22] . In addition, high-moment
MNPs with biocompatible shells such as SiO , Ag, and Au can also be synthesized by the GPC method.
2
[23]
FeCo MNPs are also reported by using a wet chemistry method , which also belongs to the bottom-up
approach. In contrast, for the top-down approach, MNPs are made from raw bulk materials that are broken
down to small nanoparticles, such as the ball milling method. Chakka et al. successfully prepared Fe,
[24]
Co, and FeCo MNPs by using a surfactant-assisted ball milling method, and the size of these MNPs can be
smaller than 10 nm. These high-moment MNPs are promising candidates for liquid biopsy.
Magnetic separation in liquid biopsy
Besides the search for novel materials and synthesis techniques to develop high-moment MNPs, surface
functionalization strategies also play an important role in the cell-particle interactions, which can greatly
impact the capture efficiency and specificity. The most commonly used technique to conjugate MNPs to
the target cells is by functionalizing antibodies on MNP surfaces that can bind specifically to the antigens
on the target cells [25,26] . However, extra surface coating is required to further enhance both the efficiency
and the specificity of the cell capture process. A good example would be the biomimetic cell-membrane-
[27]
camouflaged nanoparticles. Rao et al. coated platelet (PLT)-leukocyte (WBC) hybrid membranes
followed by the modification of antibodies [Figure 1]. They showed that the PLT membranes can recognize
and communicate with CTCs, thus enhancing the binding efficiency. On the other hand, the WBC coatings
can reduce the interactions between the MNPs and the white blood cells in the background. Combining
the characteristics of both coatings, the hybrid membrane-coated immunomagnetic beads exhibited an
improvement of capture efficiency from 66.68% (commercial product) to 91.77% with an increase in cell
purity, too.

In addition to the optimization of MNPs, much attention has been paid to developing novel cell separation
devices. In magnetic separation, the device performance largely depends on the strength and spatial
distribution of the magnetic field. Traditional magnetic separation utilizes permanent magnets that are
in the size range of several millimeters to centimeters, which suffers from small magnetic field gradient,
low density of magnetic traps, and poor control over the magnetic field profile. To increase the capture