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Page 8 of 21 Su et al. J Cancer Metastasis Treat 2020;6:19 I http://dx.doi.org/10.20517/2394-4722.2020.48

This facilitated high throughput and gradient magnetic separation by simple pipetting procedure, thereby
leading to high rate of separation of bacteria from whole blood in addition to successful bacterial culture
[47]
and analysis of the sorted bacteria without off-tip processing. Gao et al. reported a novel wash-free
magnetic immunoassay technique for prostate specific antigen (PSA) that employs a surface enhanced
Raman scattering-based microdroplet sensor (SERS) for readout [Figure 3C]. A wash-free approach was
demonstrated to detect PSA antigens with a reported LOD of 0.1 ng/mL.

MR SENSORS
MR biosensors have been studied for the past 30 years as a sensitive surface-based detection approach.
During the detection process, the target analytes are captured by MNPs, which can subsequently bind
to the sensor surface through the corresponding antibodies or complementary DNAs functionalized on
the surface, resulting in a capture antibody-antigen-detection antibody-MNP complex or a probe DNA-
target DNA-MNP complex. The surface functionalization technologies for both antibody-antigen as well
[48]
as DNA-based magnetic assays are comprehensively . Under an external magnetic field, the MNP tags
can generate stray fields, which will result in the resistance change of the MR sensors. Since the sensor
signal is proportional to the number of MNPs in proximity to its surface, higher analyte concentrations will
result in higher sensor signals. MR sensors possess multiple advantages as compared to other biosensing
techniques. Detection based on magnetic field results in low background noise as most biological samples
are paramagnetic, diamagnetic, or nonmagnetic. The sensor signals are also less affected by the chemical
[49]
environment of the sample, such as pH and temperature . With the development of nanofabrication
technologies, MR sensors can also be integrated into high-density chips, which makes it possible to realize
multiplexed detection as well as the development of point-of-care (POC) detection with minimized device
size [50,51] . In this section, magnetoresistance effect are firstly introduced from a fundamental viewpoint,
followed by the surface functionalization strategies and some examples of MR sensors’ application in liquid
biopsy. The integration of MR sensors with POC devices is also reviewed.

Magnetoresistance
Three different MR effects have been applied to the field of biosensors. Anisotropic magnetoresistance
(AMR) refers to the phenomenon where the electrical conductivity of a spontaneously magnetized
materials depends on the relative orientation of the electrical current and the magnetization. Since it was
first discovered in Ni and Fe in 1857, the physical origin of the AMR effect has been extensively studied
[52]
and was found to originate from the anisotropic scattering of electrons due to the spin-orbital coupling ,
[53]
which was firstly described in the two-current model . Although AMR is one of the earliest discoveries in
the family of MR effects, the AMR ratio in most material systems are relatively low, which limited the signal
from AMR devices until the discovery of the giant magnetoresistance (GMR)effect [54,55] . Nevertheless, AMR
sensors still possess many advantages such as high sensitivity to the angle between magnetic field and the
current direction (application in angular sensors), lower cost, and simple material system.

As opposed to the simple ferromagnetic films in AMR devices, GMR and tunneling magnetoresistance
(TMR) exist in multilayer stacks [56,57] . In a stack with alternating ferromagnetic layers and spacers, the
magnetization orientation in the ferromagnetic layers can be altered by an external magnetic field.
The electrical resistance of the structure increases when the magnetizations are parallel in adjacent
ferromagnetic layers and decreases when the magnetizations are antiparallel. GMR and TMR occur when
the spacer is a conductive metal layer and an insulating layer, respectively. TMR and GMR stacks possess
much higher MR ratio than AMR sensors, which makes them better candidates for the sensing applications
where the sensor signal and sensitivity are the top priorities [58,59] . Compared to GMR sensors, TMR sensors
generally exhibit higher MR ratio, which results in higher sensor signals as well as sensitivity. However,
TMR sensors also suffer from poor linearity and larger noise. Furthermore, the complexity in TMR device
fabrication as well as the need of top electrodes also induces difficulties in the design of TMR biosensors.
Both GMR and TMR sensors’ application in liquid biopsies are reviewed in Section 4.2.