Here we report a continuous flow-based ionization method, capillary Vibrating Sharp-edge Spray Ionization (cVSSI), that nebulizes liquid sample directly at the outlet of a capillary without using high-speed nebulization gas or a high electrical field. cVSSI is built upon the recently reported VSSI principle which nebulizes bulk liquid using vibrating sharp-edges. By attaching a short piece of fused silica capillary on top of the vibrating glass slide in VSSI, liquid is nebulized at the outlet of the capillary as the result of the vibration. Utilizing standard 360 μm OD/100 μm ID capillary, cVSSI works with a wide range of flow rates from 1 μL/min to 1 mL/min. The power consumption is as low as 130 mW. ESI-like MS spectra are obtained for small molecules, peptides and proteins. 5 orders of magnitude linear response for acetaminophen solution is achieved with a limit of detection (LOD) of 3 nM. cVSSI is also demonstrated to be compatible with LC-MS analysis. Two LC-MS applications are demonstrated with cVSSI: 1) separation and detection of a mixture of small molecules; 2) bottom-up proteomics using a protein digest. A mixture of 9 common metabolites was appropriately separated and detected using LC-cVSSI-MS. In the bottom-up experiment, 78 peptides were detected using LC-cVSSI-MS/MS with a protein coverage of 100% for cytochrome c, which is comparable with the coverage obtained using LC-ESI-MS. cVSSI offers a means of interfacing LC or other continuous flow-based applications to mass spectrometers with the salient features of voltage-free, flexibility, small footprint and low power consumption.

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Nanomedicines are engineered nanoscale structures that have an extensive range of application in the diagnosis and therapy of many diseases. Despite the rapid progress in and tremendous potential of nanomedicines, their clinical translational process is still slow, owing to the difficulty in understanding, evaluating, and predicting their behavior in complex living organisms. Microfluidic techniques offer a promising way to resolve these challenges. Carefully designed microfluidic chips enable in vivo microenvironment simulation and high-throughput analysis, thus providing robust platforms for nanomedicine evaluation. Here, we summarize the recent developments and achievements in microfluidic methods for nanomedicine evaluation, categorized into four sections based on their target systems: single cell, multicellular system, organ, and organism levels. Finally, we provide our perspectives on the challenges and future directions of microfluidics-based nanomedicine evaluation.

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