In its current state, MALDI is primarily based on the laser desorption of solid matrix-analyte deposits. The technique suffers from some disadvantages such as low shot-to-shot reproducibility, short sample lifetime and strong dependence on the sample preparation method. The sample crystallization methodologies described above were developed to increase the homogeneity of the matrix-analyte deposits and avoid some of the problems just mentioned.
A few research groups have investigated the possibility of using “liquid matrices” as an alternative sample preparation approach. The main goal for the development of such matrices is to increase sample lifetime and eliminate the search for sweet-spots, by exploiting the self-healing properties of the sampling position through molecular diffusion.
The efforts in this area can be divided into three major groups:
- Chemical Liquid Matrices :  The liquid-matrix works in the same way as traditional solid matrix materials by absorbing energy from the laser and aiding the ionization of the analyte after desorption.
- Particle-doped liquid matrices : [22-24] Fine metal or graphite particles are suspended on a low volatility solvent that does not absorb at the frequency of the laser. The fine particles absorb most of the energy from the laser beam and promote the desorption. The liquid molecules provide the charge for ionization, usually through protonation or deprotonation.
- Chemical-doped liquid matrices : [25 ] An organic compound, highly absorbent at the frequency of the laser, is added to the liquid medium. Very often the compounds used are the traditional MALDI matrix materials. The additive absorbs the energy from the laser and provides the charge during ionization.
The current state of performance for the laser desorption of macromolecules out of liquid matrices can be summarized as follows:
- The accessible mass range is limited to 25 KDa ( with few exceptions reported). Most of the work is centered on small organic molecules, peptides and small proteins.
- The sensitivity is typically in the 1-10 picomole range. This contrasts to sensitivities down to the femtomole range for traditional MALDI.
- Sample preparation can still be tricky. Samples can easily detach from the vertically-held sample plates unless they are properly formulated based on viscosity and surface tension. Dissolved gases can also cause drops to explode in the vacuum of the mass spectrometer.
- Mass resolutions rarely exceed a few hundred. To be contrasted to resolutions in the thousands for traditional MALDI.
Liquid matrices remain the subject of interest of a few research groups, but are not part of the mainstream MALDI methodology. No step-by-step procedures for liquid-matrix sample preparation protocols will be included here. More detailed liquid-matrix MALDI information can be found in the references [22-26 ].