What’s the opportunity of next-generation liquid biopsy
instrument?
Until today, the accuracy of liquid biopsy is not comparable with that
of tissue biopsy in cancer confirmation, as well as their clinical
utility is not well demonstrated, thus current liquid biopsy only serves
as a complementary method to tissue biopsy [38]. To fully benefit
from the many advantages of LB, next-generation LB instruments must
become a priority.
First, enhanced detection accuracy and sensitivity are warranted; most
existing LB instruments for cancer diagnosis are only based on a single
biomarker, thereby significantly limiting their output. Comprehensive
detection using multiple biomarkers might address this issue and is
crucial for the advancement of next-generation LB instruments [39].
For example, CTC and ctDNA detection are believed to be complementary,
with ctDNA being more suitable for detecting mutations and CTCs for
studying drug sensitivity and tumor heterogeneity [40]. Notably,
achieving multiple biomarker-based detections should first address key
issues, such as integrating different biomarker isolation components in
a single instrument.
Second, most LB instruments still require several
manual operation steps, such as cell
incubation and immunofluorescence labeling, resulting in multiple
variables that can cause substantial errors in their clinical utility.
Additionally, regarding some comprehensive sample-to-result workflows,
the isolation and detection of biomarkers must be performed across
platforms. For example, in the
LiquidBiopsy platform workflow
[31,41], cfDNA is purified and analyzed on the LiquidBiopsy, and Ion
Chef and Ion S5 XL platforms, respectively. Integrating the preparation,
isolation, detection, and other components into a single LB instrument
can improve its automation level and simplify the operation steps,
facilitating the standardization of crucial procedures, thereby
improving detection reliability. Therefore, ideal next-generation
instruments should meet the requirement that even non-professionals can
readily obtain reliable results using highly automated LB instruments.
Multiple analytical components are
hard to integrate with other LB instruments, especially multigene assays
that require considerable sample processing time, as well as expensive
and bulky equipment [42]. To reduce the complexity of LB
instruments, complex biochemical assays can be performed in a superior
laboratory. Therefore, the next-generation LB instrument may be designed
to isolate and then primarily detect biomarkers, and a
sophisticated follow-up analysis
may be conducted through off-site centralized testing. Furthermore, a
database should be established to share extensive analytical data in
real-time, which may accelerate the investigation of cancers. In the
future, integrating label-free based cell separation and detection
components in the LB instrument would make it possible to achieve this
goal. With such LB instruments, CTCs may be isolated based on their
physical properties using inertial microfluidic, acoustofluidics, or
other technologies [43,44]. Then, isolated CTCs may be detected by
label-free interrogation technologies, including impedance cytometry and
image flow cytometry [45,46]. The obtained CTCs with high activeness
will be suitable for further investigation of tumor composition,
invasiveness, drug susceptibility, and resistance to therapy in a
central laboratory [47]. Moreover, a label-based biomarker
separation method that obtains active target biomarkers by labeling
non-target biomarkers, as well as impedance cytometry for detecting
submicron bioparticles (such as exosomes), also holds promise for rapid
and primarily detection of biomarkers [48,49].
Assessment of multiple biomarkers and parameters for the comprehensive
detection of cancer, which will generate a large amount of analytical
data, may be the future of LB instruments. Hospital personnel who obtain
these data should receive adequate training to interpret such results
and act accordingly. However, such training typically requires
considerable time and effort. Moreover, with the increase in detection
parameters, the corresponding analytical data also become complex,
causing obstacles for physicians to make accurate diagnoses and
treatment decisions. In next-generation LB instruments, artificial
intelligence may help comprehensively analyze the clinicogenomic,
metabolomic, immunomic, microbiomic, and homeostatic data obtained from
LB instruments to assist diagnosis and treatment decisions [50].
Apart
from making next-generation LB instruments more
multifunctional, downscaling the
size of instruments may also be a significant future development
[51,52]. In general, patients experience a recovery period of months
to years after cancer surgery, and daily monitoring is essential for
preventing cancer recurrence. However, LB-based total-analysis
instruments may not be easily accessible to patients in health
resource-limited locations. Therefore, the development of portable or
wearable LB instruments for real-time monitoring of cancer is of great
significance, as critical detection data can be obtained and shared with
physicians in real-time to evaluate the recovery of patients with
cancer. Label-free cfDNA and CTC
detection methods or membrane filtration methods, such as
electrochemical sensing technology for label-free cfDNA detection and
thin membrane with special micro-pores or structures for tumor cell line
capture [53,54], are promising approaches to achieve this
requirement, as no expensive reagents or bulky external platforms are
required. Portable or wearable LB instruments are expected to be
developed to isolate and detect tumor biomarkers from patients.
Several points need to be considered
to make next-generation LB instruments commercially available. First,
the basic requirement of the LB instrument is to ensure analytical and
clinical validity, and achieve clinical utility. Additionally,
cost-effectiveness analyses are
essential, as an LB instrument can be highly expensive and inaccessible
to certain clinical settings. Lastly, the analytical results must be
incorporated into the clinical workflow to guide cancer diagnosis and
treatment. Before being widely adopted in clinical applications, a large
number of on-site validations should be performed in clinical trials by
comparing and evaluating the results of the newly developed LB
instruments and routine assays [55].
In all, with the improvement of highly sensitive techniques for accuracy
disease detection, the next-generation liquid biopsy instruments are a
promising tool for the early diagnosis, real-time monitor, prognosis,
and prediction of the response to treatment in various types of cancers.