Multi-Modal Microfluidics (M 3 ) for Sample Preparation of Liquid Biopsy: Bridging the Gap between Proof-of-Concept Demonstrations and Practical Applications

Liquid biopsy, the technique used to shed light on diseases via liquid samples, has displayed various advantages, including minimal invasiveness, low risk, and ease of multiple sampling for dynamic monitoring, and has drawn extensive attention from multidisciplinary fields in the past decade. With the rapid development of microfluidics, it has been possible to manipulate targets of interest including cells, microorganisms, and exosomes at a single number level, which dramatically promotes the characterization and analysis of disease-related markers, and thus improves the capability of liquid biopsy. However, when lab-ready techniques transfer into hospital-applicable tools, they still face a big challenge in processing raw clinical specimens, which are usually of a large volume and consist of rare targets drowned in complex backgrounds. Efforts toward the sample preparation of clinical specimens (i.e., recovering/concentrating the rare targets among complex backgrounds from large-volume liquids) are required to bridge the gap between the proof-of-concept demonstrations and practical applications. The throughput, sensitivity, and purity (TSP performance criteria) in sample preparation, i.e., the volume speed in processing liquid samples and the efficiencies of recovering rare targets and depleting the backgrounds, are three key factors requiring careful consideration when implementing microfluidic-based liquid biopsy for clinical practices. Platforms based on a single microfluidic module (single-modal microfluidics) can hardly fulfill all the aforementioned TSP performance criteria in clinical practices, which puts forward an urgent need to combine/couple multiple microfluidic modules into one working system (i.e., multi-modal microfluidics, M ) to realize practically applicable techniques for the sample preparation of liquid biopsy. This perspective briefly summarizes the typical microfluidic-based liquid biopsy techniques and discusses potential strategies to develop M systems for clinical practices of liquid biopsy from the aspect of sample preparation.