Microfluidic chips for mass spectrometry
Aalto University, Department of Materials Science and Engineering, FI-00076 Aalto, Finland
Miniaturization of chemical analysis, known as MicroTAS or Lab-on-a-Chip, has been a major trend for the past two decades. Separation systems, especially capillary electrophoresis, was the initial driver, but the field has expanded rapidly [1,2]. Separation time can in theory be greatly reduced because sample transit time through a small sized system is faster, but total analysis time is often not reduced in same proportion because sample transfer between microchips and macroscopic world is often done manually. Integrated systems which have sample introduction, separation and detection components, have, however, been more difficult to realize than initially perceived [3].
Detection in microfluidic systems is often not miniaturized. Fluorescence and mass spectrometry (MS), the most sensitive and selective detection methods, remain mainstay, and have to be coupled to microchips. Optofluidic designs [4] can be used to improve optical detection, but the light sources themselves have remained macroscopic. Interfacing a mass spectrometer to a microfluidic chip has centered on ionization: separation can be either on chip or in a classical system, and the new microfabricated ionization techniques can often be applied to both. Miniaturization of mass spectrometers themselves has not reached level where they would be serious competitors for general purpose use. These developments have recently been reviewed in [5]. We have developed a universal miniaturized atmospheric ionization (API) microchip for MS analysis based on a heated nebulizer microchip. The chip consists of fluidic mixer, nozzle and microheater to create a hot gas jet, Fig. 1. The vapor jet is highly collimated, and therefore sample loss is minimized. Contrary to conventional wisdom, this flow rate sensitive detector in fact has 100-fold improvement in sensitivity despite 100-fold decrease in flow rate. This shows that scaling into microscale involves surprises. This chip has potential to replace a macroscopic system, Fig. 2.
Fig. 1. Heated nebulizer chip Fig. 2: Macroscopic ionization system vs. microchip
This chip can be used in many different ionization modes: in atmospheric pressure chemical ionization (APCI), atmospheric pressure photoionization (APPI), atmospheric thermospray ionization (APTSI), supersonic ionization (SSI), ion spray (IS) and electrospray ionization (ESI). It shows very good sensitivity for large range of compounds from nonpolar to polar and from small to large molecules. Applications have included analysis of sports doping, pharmaceuticals, confiscated street drugs and crude oil composition. Further developments are taking place in integrating separation systems with the heated nebulizer, for example liquid chromatography on-chip, Fig.3. The same chip is also an integral part in a new ambient MS method, desorption APPI/MS (DAPPI). In DAPPI solid surfaces can be analyzed directly, and liquid samples can be dried on a PMMA sample plate before analysis. The hot jet from a heated nebulizer chip then desorbs the sample, and molecules are ionized by an UV-lamp, and analyzed by MS, Fig. 4. DAPPI provides extremly fast analysis, a few seconds per sample. It has been applied to analysis of flame retardants in PC boards, pesticides in orange feels and polyaromatic hydrocarbons in soil samples.
Fig. 3: Liquid chromatograph column integrated with the Fig. 4: DAPPI surface analysis heated nebulizer chip Desorption ionization (DAPPI) We have also been working on electrospray ionization (ESI). An integrated system made in SU-8 polymer consists of separation channel and an ESI tip, Fig. 5. The SU-8 CE-ESI/MS chip provides fast separations with excellent resolution and extremely high sensitivity.Measured limit of detection (S/N=3) was found to be approximately 100 nM corresponding to a total amount of only 4.5 attomoles verapamil in the injected volume of 45 pL. The applications include proteins, peptides, amino acids, and drug metabolites. Another ESI design is the µPESI (micro pillar ESI), where a microfabricated pillar array facilitates capillary flow, and no external actuation is needed. If the sample spot is coated by TiO2 (by ALD), it can be used as a photocatalytic reactor. The reaction products can be eluted into capillary channel by solvent change, and analysed by ESI. This has been successfully to mimic phase I metabolism reactions of drug molecules [6].
Fig. 5: SU-8 CE-ESI-MS Fig. 6: Silicon µPESI chip
References: 1. G.B. Salieb-Beugelaar, G. Simone, A. Arora, A. Philippi, A. Manz: Latest Developments in Microfluidic Cell Biology and Analysis Systems, Anal. Chem.2010, 82,4848–4864 2. D. Mark, S Haeberle, G Roth, F von Stetten, R Zengerle, Microfluidic lab-on-a-chip platforms, Chem.Soc.Revs. 2010, p. 1153 3. P Abgrall and A-M Gue: Lab-on-chip technologies: making a microfluidic network and coupling it into a complete microsystem—a review, J. Micromech. Microeng. 17 (2007) R15–R49 4. D. Psaltis, S.R. Quake, C. Yang: Developing optofluidic technology through the fusion of microfluidics and optics, Nature 442 (2006) p. 381 5. T. Sikanen, S. Franssila, T. Kauppila, R. Kostiainen, T. Kotiaho, R. Ketola: Microchips for mass spectrometry, Mass Spectrometry Reviews, 2010, pp.351-391 6. T. Nissilä, L. Sainiemi, S. Franssila, R. Kostiainen, R. Ketola: accepted in LabChip, 2011
LEGISLATURE OF NEBRASKA NINETY-SIXTH LEGISLATURE SECOND SESSION LEGISLATIVE BILL 1079 Introduced by Schrock, 38; Chambers, 11; Dierks, 40 Read first time January 7, 2000 Committee: Agriculture FOR AN ACT relating to agriculture; to amend sections 2-954, 16-230, and 17-563, Reissue Revised Statutes of Nebraska, section 81-2,147.06, Revised Statutes Supplement, sect