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.