Nanomechanical Gravimetric Analysis of Single Microdroplets for Liquid Biopsy

The gravimetric analysis of nanoliter-volume droplets could serve as a novel method for liquid biopsy of small-volume biofluids. However, direct mass quantification of a single microdroplet at the nanoliter scale remains challenging due to complex hydrodynamic effects. Here, we present a nanomechanical gravimetric method that enables accurate mass measurement of individual ∼100 μm droplets using a quartz tuning fork-based resonator. By generating nanometric longitudinal waves within the droplet and employing dynamic force spectroscopy, we isolate the added mass effect from various fluidic interactions, thereby determining the true mass of the droplet. For the first time, we demonstrate direct measurement of mass, density, and total dissolved solids in single microdroplets of human aqueous humor, revealing individual-specific physical properties. Our method significantly advances the gravimetric analysis of biofluids to sub-nanoliter volumes, providing a new approach for liquid biopsy.