Femtoliter-Droplet Mass Spectrometry Interface Utilizing Nanofluidics for Ultrasmall and High-Sensitivity Analysis

In the fields of biology and medicine, comprehensive protein analysis at the single-cell level utilizing mass spectrometry (MS) with pL sample volumes and zmol to amol sensitivity is required. Our group has developed nanofluidic analytical pretreatment methods that exploit nanochannels for downsizing chemical unit operations to fL-pL volumes. In the field of analytical instruments, mass spectrometers have advanced to achieve ultrahigh sensitivity. However, a method to interface between fL-pL pretreatments and mass spectrometers without sample loss and dispersion is still challenging. In this study, we developed an MS interface utilizing nanofluidics to achieve high-sensitivity detection. After charging analyte molecules by an applied voltage through an electrode, the liquid sample was converted to fL droplets by a nanofluidic device. Considering the inertial force that acts on the droplets, the droplets were carried with a controlled trajectory, even in turbulent air flow, and injected into a mass spectrometer with 100% efficiency. A module for heat transfer was designed and constructed, by which all of the injected droplets were vaporized to produce gas-phase ions. The detection of caffeine ions was achieved at a limit of detection of 1.52 amol, which was 290 times higher than a conventional MS interface by electrospray ionization with sample dispersion combined with a similar mass spectrometer. Therefore, sensitivity that was 2 orders of magnitude higher could be realized due to the 100% sample injection rate. The present study provides a new methodology for the analysis of ultrasmall samples with high-sensitivity, such as protein molecules produced from a single cell.