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Page 2 of 21 Su et al. J Cancer Metastasis Treat 2020;6:19 I http://dx.doi.org/10.20517/2394-4722.2020.48
[2-4]
and RNA (ctRNA), and exosomes . To date, liquid biopsy has been performed in various biological fluids
including peripheral blood, urine, ascites, pleural effusion, etc. for early diagnosis, screening, prognosis
assessment, detection of minimal residual disease, and the design of personalized treatment for cancer
[3,5]
therapy . The target biomarkers are firstly separated and enriched via a variety of separation technologies,
followed by the determination of the biomarker concentration using different biosensor platforms.
[6]
Many novel nanotechnologies have been developed in the liquid biopsy field. Loeian et al. fabricated a
nanotube-CTC chip with the ability to selectively capture CTCs in the blood sample. It was shown that
this nanotube-based device can successfully capture CTCs from the peripheral blood of breast cancer
[6]
[7]
patients with a range of 0.5-28 CTCs per mL . Yu et al. developed a fluorescent probe that can release
the outmost antibodies after binding with CTCs, making it possible to release and recycle CTCs in future
[7]
liquid biopsy processes . Besides the separation and detection of CTCs, a polymerase chain reaction (PCR)
approach was proposed for the detection of ctDNA by using a quencher-free fluorescent probe DNA and
graphene oxides. This method can detect as low as 49 pg of epidermal growth factor receptor (EGFR) exon
[8]
19 detection DNA with a detection limit of 0.1% . A comprehensive review on the current liquid biopsy
[9]
technologies is contributed by Tang et al. .

Of all the proposed technologies for liquid biopsy, magnetic nanotechnologies stand out for the ease in
cell manipulation under magnetic field during biomarker separation [10-12] , as well as low background noise
and high theoretical sensitivity during biomarker detection due to the fact that most of the biological
environment is non-magnetic. However, as with other types of biosensors, the sensitivity of the magnetic
biosensors also depends on the system setup, the surface biofunctionalization processes, and the intrinsic
sensitivity of the sensing segment. In this review, magnetic separation technologies using high-moment
magnetic nanoparticles (MNPs) as tags are introduced. Microfluidic channels are reviewed in the following
section regarding their crucial role in both magnetic separation and magnetic sensing. Finally, two types of
magnetic nanotechnologies for liquid biopsy are introduced: magnetoresistance (MR) sensors as a surface-
based liquid biopsy technology and nuclear magnetic resonance (NMR) as a volume-based liquid biopsy
technology.

MAGNETIC SEPARATION
The majority of cell-based liquid biopsy research has been focused on the detection of CTCs since it is
the major cause of death and can be detected by non-invasive techniques from patients’ blood samples .
[13]
However, due to the low abundance of CTCs, cell sorting or cell separation is required prior to the
detection process. To date, various devices have been developed to separate the CTCs from other undesired
background substances. Cell size-based separation is a label-free technique that sorts the target cells out
according to their unique properties such as size and stiffness [14,15] . Alternatively, specific binding-based
separation captures the target cells on patterned surfaces through chemical/immunoassays. While cell size-
based devices exhibit high throughput and label-free characteristics, the specificity of the capture is often
sacrificed due to the variation of the size and stiffness of the CTCs. On the other hand, techniques based
on binding cells to certain surfaces show higher specificity, but suffer from low throughput and difficulties
in cell recycling [12,16-18] . Magnetic separation falls into the category of specific binding-based technologies.
However, instead of binding the target cells to surfaces, MNPs are employed to mark the target cells, which
are captured onto magnetized surfaces subsequently. Unlike the aforementioned techniques, the captured
cells can be released easily by removing the magnetic field. In this section, high-moment MNPs are
introduced first as an important approach to increase the capture efficiency. Optimization of the capture
process from both surface functionalization and device configuration aspects is also summarized.

High-moment magnetic nanoparticles
MNPs have been widely used as biomarkers for biosensing and could also be used to mark the CTCs
for liquid biopsy. By labeling CTCs using MNPs, these CTCs can be separated by applying an external