High Throughput Screening of Complex Biological Samples with Mass Spectrometry – From Bulk Measurements to Single Cell Analysis

High throughput screening (HTS) of molecular analytes is demanded by and implemented in many areas of chemistry, medicine and industrial biotechnology including the discovery of biomarkers and the development of new chemical entities. Despite its prevalence, technical challenges remain in many of the new application areas for HTS which require rapid results from complex mixtures for example in: screening biotransformations; targeted metabolomics; and in locating drugs and/or metabolites in biological matrices. Common to all of these are lengthy and costly sample preparation stages, involving recovery from cell cultures, extractions followed by low throughput LC-MS/MS methods or specific fluorescent measurements. In the latter the target molecules need to be inherently fluorescent, or to include a fluorescent label or tag which can adversely influence a cellular system. Direct infusion mass spectrometry coupled with robotic sample infusion is a viable contender for information rich HTS with sub second analysis times, and recent developments in ambient ionisation have heralded a new era where screening can be performed on crude cell lysates or even from live cells. As well as commercially available technologies such as RapidFire, Acoustic Mist Ionisation, and the TriVersa ChipMate there are promising new developments from academic groups. Novel applications using desorption electrospray ionisation, microfluidics, rapid LC-Separation and ‘one cell’ direct infusion methods offer much for increasing throughput from ‘messy’ complex samples and for significantly reducing the amount of material that needs to be analysed. Here we review recent advances in HTS coupled with MS, with an emphasis on methods that reduce or remove all sample preparation and will facilitate single cell screening approaches.