Hyphenated sample preparation-electrospray and nano-electrospray ionization mass spectrometry for biofluid analysis

Stand-alone electrospray ionization mass spectrometry (ESI-MS) has been advancing through enhancements in throughput, selectivity and sensitivity of mass spectrometers. Unlike traditional MS techniques which usually require extensive offline sample preparation and chromatographic separation, many sample preparation techniques are now directly coupled with stand-alone MS to enable outstanding throughput for bioanalysis. In this review, we summarize the different sample clean-up and/or analyte enrichment strategies that can be directly coupled with ESI-MS and nano-ESI-MS for the analysis of biological fluids. The overview covers the hyphenation of different sample preparation techniques including solid phase extraction (SPE), solid phase micro-extraction (SPME), slug flow micro-extraction/nano-extraction (SFME/SFNE), liquid extraction surface analysis (LESA), extraction electrospray, extraction using digital microfluidics (DMF), and electrokinetic extraction (EkE) with ESI-MS and nano-ESI-MS.