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Matrix Effects are the suppressing or enhancing properties of a co-eluting compound from a biological matrix on the primary signal response of the target analyte. In several liquid chromatography-tandem mass spectrometry (LC-MS) biological studies, Matrix Effects can suppress the ion intensity by interfering with target analyte ionization. Compounds with high mass, polarity, and basicity are typical candidates to trigger matrix effects.

Matrix components can deprotonate and neutralize the analyte ions produced in the liquid phase, causing ion suppression. Matrix Effects may also be caused by co-precipitation of the analytes with less-volatile and heavy compounds. Under these circumstances, the efficiency of droplet formation in liquid phase gets affected. High viscosity interfering compounds in a biological matrix could increase the surface tension of the charged droplets and further prevent evaporation. Additionally, matrix compounds can reduce the stability of the analyte ions produced in the gas phase. Also, the accumulation of charged matrix components in front of a quadrupole mass analyzer entrance could lead to charging issues, thus preventing the analyte ions from moving into the mass analyzer.

Figure 1 below summarizes the proposed mechanisms of matrix effects in Electrospray Ionization (ESI).

mechanisms of matrix effects in Electrospray Ionization (ESI)

P. Panuwet, R. Hunter, et al. Biological Matrix Effects in Quantitative Tandem Mass Spectrometry-Based Analytical Methods: Advancing Biomonitoring. Anal Chem. 2016;46 (2):93-105.


Scientists have investigated many methods to limit matrix effects and obtain reliable LC-MS data. Generally, the phospholipids in plasma are one of the significant sources of matrix effects. Therefore, cleaner sample preparation by using liquid and solid phase extraction could be helpful. Moreover, adjustments of HPLC chromatographic condition to avoid the co-eluting problem is time-consuming, especially when interfering compounds have very similar molecular properties as the analyte. It is hard to eliminate Matrix Effects, and one viable option is the use of isotopically labeled internal standards for quantitative compensation. Theoretically, the same degree of ion suppression or enhancement would occur for the target analyte and its isotopically labeled analog.

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