1. science
2. chemistry

Available online at www.sciencedirect.com
Journal of Chromatography A, 1184 (2008) 191–219
Review
Sample preparation
Yi Chen a,∗ , Zhenpeng Guo a,b , Xiaoyu Wang a,b , Changgui Qiu a,b
a
Beijing National Laboratory of Molecular Science; Laboratory of Analytical Chemistry for Life Science, Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100080, China
b Graduate School, Chinese Academy of Sciences, Beijing 100039, China
Available online 16 October 2007
Abstract
A panorama of sample preparation methods has been composed from 481 references, with a highlight of some promising methods fast developed
during recent years and a somewhat brief introduction on most of the well-developed methods. All the samples were commonly referred to molecular
composition, being extendable to particles including cells but not to organs, tissues and larger bodies. Some criteria to evaluate or validate a sample
preparation method were proposed for reference. Strategy for integration of several methods to prepare complicated protein samples for proteomic
studies was illustrated and discussed.
© 2007 Elsevier B.V. All rights reserved.
Keywords: Sample preparation; Highlighted method; Method survey; Protein; Criteria for method evaluation
Contents
1.
2.
3.
4.
∗
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
A brief historical retrospect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
A survey of methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. Chemical processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2. Non-chemical processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.1. Liquid partition methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.2. Adsorptive methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.3. Filtration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.4. Speed-dependent methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Highlighted methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1. Environment friendly methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.1. Supercritical fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.2. Room temperature ionic liquids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2. Acceleration techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.1. Pressurized liquid extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.2. Microwave- or sonication-assisted extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3. Scale down . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3.1. Liquid-phase microextraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4. Adsorptive methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4.1. Multifunctional sorbents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4.2. Selective sorbents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4.3. Solid-phase microextraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4.4. Stir bar sorptive extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4.5. Matrix solid-phase dispersion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Corresponding author. Tel.: +86 10 62618240; fax: +86 10 62559373.
E-mail address: [email protected] (Y. Chen).
0021-9673/$ – see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.chroma.2007.10.026
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Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219
4.5.
4.6.
5.
6.
7.
Microdialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
On-line stacking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.6.1. Isotachophoresis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.6.2. Capillary isoelectric focusing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.6.3. Field amplification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.6.4. pH regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.6.5. Sweeping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.7. Derivatization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.8. Miniaturization and integration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Criteria for method validation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Integration of sample preparation methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.1. Preparation of proteomics-oriented proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
In this review, sample preparation is in most cases
meant to be the isolation and/or (on-line or off-line) concentration of some components of interest or target analytes from
various matrices, making the analytes more suitable for separation and detection. Chemical modification of the interested
analytes could be involved in the procedure of sample preparation for an easy isolation, facile later separation and/or detection,
group protection or molecular structure elucidation.
Sample preparation impacts nearly all the later assayed steps
and is hence critical for unequivocal identification, confirmation
and quantification of analytes. In common, a clean sample assists
to improve separation and detection, while a poorly treated
sample may invalidate the whole assay. Use of ideally cleaned
samples also reduces the time to maintain instruments and in
turn the cost of assay.
It is because of the importance of sample preparation that
some excellent reviews on this topic have appeared in 2002 in
books [1,2] and special journal issues [3,4]. In 2003, Pawliszyn
[3] summarized the fundamental aspects of sample extraction
(equilibrium and kinetics related to mass transfer), which were
necessary for the development of methods, with special considerations of on-site and in situ extractions. Smith [4] provided
many examples on extraction and concentration of analytes from
solid, liquid and gas matrices. Selective extraction methods with
molecularly imprinted polymers (MIPs) and affinity columns
have also been considered. In 2004 and 2006, Raynie [5,6]
reviewed the experimental and fundamental developments on
sample extraction, and related methodology appeared during
the calendar years of 2002–2005, with an exclusion of general application articles but an inclusion of some individual
steps.
This review thus aims at systemizing the sample preparation methods to have a panorama on this field, with a stress on
some promising methods appeared and/or fast developed during recent years. The matured methods towards such cell and
particle preparation are only briefly discussed, while tissues and
organs are commonly excluded. Some criteria to evaluate or
validate a method for better preparation of complicated samples
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210
211
212
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have been proposed for reference. The strategy on total preparation of complicated protein samples (used in proteomic study)
or polysaccharides from dried plant materials (for comparison
only) is illustrated.
2. A brief historical retrospect
Study of sample preparation might be traced back to the
very beginning of analytical chemistry when complex samples were first touched. Following the rapid development of
analytical techniques in the post-World War II era, increasing
demands were placed on sample quality because the samples
collected from natural environment, living body and many other
sources had very complex matrices, and their subsequent analysis was undoubtedly difficult or even impossible without any
pretreatment. As known, sample matrix remains a serious challenge in conducting liquid chromatography–mass spectrometry
(LC–MS), not only reducing the resolution of LC and the ionization efficiency of MS but also increasing the detection noise
and ultimately the limits of detection.
As analytical chemistry grows, sample preparation gradually
becomes a major part of analysis, capable of taking up to 80%
of the total time of a complete separation-based analytical process, which typically includes five steps, that is sampling, sample
preparation, separation, detection and data analysis. Since then,
sample preparation has developed increasingly during recent
years (Fig. 1).
Environmental application is a main cause driving the
development of many procedures of sample preparation due
to the increased public awareness that environmental contaminants are a health risk. The increased demands in
the analysis of foods and natural products have brought
another pressure to develop the technologies of sample
preparation. The appearance of more sensitive and reliable
methodology to monitor environment is also impelled by
governmental necessity to elevate public living standard and
quality.
During the past decade, active research on sample preparation has also been fueled by pressure to analyze combinatorial
chemistry and biological samples. The urge to analyze the
Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219
Fig. 1. Steady increase of publication in sample preparations during January
2002–December 2006, searched from the Science Citation Index Expanded
(SCIE) Database of the Institute for Scientific Inprocedureion (ISI) by keywords
of “subcritical water extraction”, “pressured liquid extraction”, “microwave
assisted extraction”, “supercritical fluid extraction”, “single drop” and “microextraction”, “hollow fiber” and “microextraction”, “ionic liquids extraction”,
“solid-phase extraction”, and “solid-phase microextraction” with restricting the
search to article titles.
unprecedented large-scale complex samples in various “-omics”
strongly pushes to sweep off the garbage-in garbage-out modus
operandi, strongly stimulating the exploration of sample preparation methods with lower organic solvent consumption, higher
selectivity, faster speed, and more suitable for high throughput quantification (i.e. with better recovery, reproducibility and
linearity) by high-level automation. New or advanced techniques have been developed for sample preparation based on
some novel concepts such as miniaturization, integration and
hyphenation. On-line coupling of sampling, sample preparation
(especially sample stacking) and/or chemical modification for a
separation method has been demonstrated to be very promising
to finish total analysis within a compact system or a ship.
3. A survey of methods
Numerous methods have appeared for sample preparation. It
looks helpful to have an overview on them but is hard since they
have been termed quite ambiguously. Various ways such as principle, configuration, scale or size, operation procedure, physical
state of samples and/or solvent, and the physical or chemical
nature of sampling process may be used to sort them. There
is no attempt to rename the methods in this paper but we aim
towards an easier understanding of them. We are trying to classify the methods based on the core principle used, providing 11
categories with more than 50 methods as shown in Table 1. Most
of the methods listed in the first seven categories are matured or
well developed, while those in the last four categories are mostly
new or undergoing development and innovation.
3.1. Chemical processing
Nearly all chemical reactions in theory are applicable to sample preparation but only limited reactions in practice match the
193
analytical standards. Table 1 shows some well-known examples
(nos. 6 and 7). The type of reactions most often used is addition or attachment of a group, a fragment or a whole molecule
onto a target analytic molecule. This is normally termed labeling
or derivatization and is most often used to increase detectability. Another famous type of chemical reactions used in sample
preparation is called degradation or decomposition, commonly
used to liberate target analytes from samples.
The analysis of intact polymeric materials, including natural and synthetic polymers, is rather a difficult task because
they are involatile with poor solubility and incertitude structure. A number of chemical decompositions such as hydrolysis
or solvolysis, pyrolysis and enzymatic cleavage are needed to
break the macromolecules into characteristic smaller fragments.
Analytical pyrolysis combined with gas chromatography (GC),
MS or GC–MS have routinely been used for the characterization
of synthetic polymers [7].
The well-known Edman degradation is the basic chemistry
in protein sequencing. Combining with electroblotting it now
becomes a microsequencing technique able to reach low pmol
range [8]. Recently, in-gel digestion of proteins, simultaneous
sample cleanup and concentration, and direct transfer of the prepared composition to matrix-assisted laser desorption/ionization
time-of-flight MS (MALDI-TOF-MS) were performed by solidphase extraction (SPE) microplate [9].
In DNA sequencing, the very large DNA molecule should
first be cleaved into specific fragments using restriction enzymes
and then it should undergo the famous Sanger reaction [10] in
combination with polymerase chain reaction [11] or MaxamGilbert cleavage [12].
Partial hydrolysis has also been used in the size separation
of such as polysaccharides by capillary electrophoresis (CE) in
combination with labeling of detection-sensitive reagents. Complete decomposition is a prerequisite to elucidate the monomer
composition of a macromolecule by separation methods, and
burning is a basic means for element analysis and is a useful
principle to detect gaseous composition by GC. Decompositionbased techniques look well matured so that their development is
fairly rare during recent years.
Differently, derivatization or labeling-based methods remain
very active in development, mainly due to the challenge often
encountered in the analysis of trace substances. For instance,
labeling is critical to conduct fluorescence or UV absorption
detection in CE of various biological samples and in probing or
tracing some intra- and inter-cellular bioactive compounds. In
principle, derivatization can be used for many purposes, e.g. to
increase detection sensitivity, to improve separating resolution,
to protect a target molecule or its group(s), to reveal molecular structure (such as the linking sites of polysaccharides), and
to introduce specific, affinity or functionalized group(s) onto
analytes. Although there are additional reaction steps, interferences (arising from excess reagents and byproducts) and extra
matrix effects, analytical derivatizations have been considered,
by many separation scientists, as the means of last resource
to get over detection and sometime separation problems, and
numerous applications continue to appear as new developments
in basic chemistry and innovations in instrumentation. As a part
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Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219
Table 1
Classification of sample preparation methods by principle
No.
Core principle
Method
Common usage
1
Mechanics
2
Gravity
Grinding
Blending
Sieving
Sedimentation
Centrifugation
Ultracentrifugation
Powdering, alloying
Alloying, mixing
Solid particle sieving
Solid material isolation
Phase/density separation
Macromolecule isolation/purification
3
4
5
Magnetic field
Size exclusion
Electrochemistry
Magnetic sedimentation
Size-exclusion chromatography
Electro-sedimentation or dissolution
Particle-based isolation
Molecular sieving
Electric active sample preparation
6
Derivatization or labeling
Methylation
Methoxylation
Silylation
...
Stravidinylation, avidinylation, biotinylation, etc.
Aldehyde addition
...
Chiral addition
In situ labeling
Pre-, off or after column labeling
On-column labeling
Increasing volatility, identifying linking or branching sites, group protection
7
8
Degradation
Filtration and membrane separation
Conjugation of protein, DNA, etc.
Immobilizing/fixing proteins
Chirality elimination
Selective probing or sensing
Detection by absorption, emission or radiation, etc.
Edman degradation
Sanger reaction
Maxam-Gilbert cleavage
Partial hydrolysis
Total hydrolysis
Burning
Protein sequencing
DNA sequencing
Sequencing
Composition determination
Detection or Elements analysis
Dialysis
Special types of liquid–liquid extraction used for purification
of or cutting off macromolecules
Microdialysis
Membrane-separated liquid extraction
Electrodialysis
Filtration (frit, paper or membrane filter)
Ultra-filtration, microfiltration
Gel filtration
9
10
11
Phase partition
Sorption or equilibration
Speed variation
Cleanup, particle isolation
Macromolecule isolation/purification
Sieving/purification
Liquid-phase extraction
Liquid–liquid extraction
Liquid-phase microextraction
Aqueous two-phase extraction
Cloud point extraction
Liquid–solid extraction
Soxhlet extraction
Sub-critical water extraction
Pressurized liquid extraction
Supercritical fluid extraction
Microwave/sonication-assisted extraction
Solid matrix-supported liquid film extraction
Gas–liquid extraction
Liquid absorbing
Headspace liquid-phase microextraction
Membrane extraction with sorbent interface
Isolation of soluble analytes
Analyte isolation from solid matrices
Extracting analytes from solution or gases
Extraction of gaseous analytes
Solid-phase extraction
Solid-phase microextraction
Matrix solid-phase dispersion
Stir bar sorptive extraction
Polystyrene surface adsorption
Preparative chromatography
Electrophoresis (EP)
On-line stacking
Collection or concentration of analytes from gaseous and liquid matrices
Thin-layer chromatography
Ion-exchange chromatography
Counter-current chromatography
Column chromatography
Isoelectric focusing
Free flow electrophoresis
Gel EP (including disc electrophoresis)
Field flow fraction
Field amplification
Isotachophoresis
Sweeping
pH regulation
At column capture
Barrage
Immobilazation of antibody or antigen for such as enzymelinked immunosorbent assay (ELISA)
General preparation
Desalting, purification
Productive preparation and purification
General preparation
For preparing zwitterions
Large scale preparation of proteins, DNA, Cells and other
charged particles
Preparing proteins and DNA
For soluble species, it can better be sorted in chromatography
For charged analytes
For charged analytes
For chargeable substances
For dissociable samples
Depends
Depends
Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219
of sample preparation, various derivatization protocols, derivatizing reagents and reaction conditions for many analytes have
been reported in several excellent books and reviews [1,13–15].
In GC analysis, most of the derivatizations aim at increasing
the volatility and stability of the analytes by following principal reactions: (1) formation of trimethylsilyl ethers from sugars,
steroids and alkaloids, (2) methylation of fatty acids, (3) transesterification of lipids, and (4) acylation of amines. Derivatization
has also been used for structure confirmation in MS, to obtain
the spectra of derivatives containing molecular ion signals [16].
Some derivatizations are adapted in concentrating process or
sample cleanup.
Much more frequently, the derivatization is adopted to
change the analyte properties for sensitive detection or/and
better separation (by GC, LC, CE, etc.). Derivatization for
CE is mainly conducted to enhance the detectability, partially
to modify both the detectability and polarity (or charge-tomass ratio) to increase resolution [17,18]. Pre-, on-, post- or
off-column labeling has extensively been explored for highperformance LC (HPLC) and especially for capillary-based
separation techniques such as nano-LC and CE, thereinto the
on- or in-column labeling is the most promising which consumes very limited (down to sub-nanoliter) reagents and samples
[19]. This is highly favored in single cell analysis or other
ultra-trace analysis. Derivatization is also used to introduce
an energy exchanging structure into a fluorescent molecule,
which is at present a novel technique to prepare molecular beacons [20] or measure fluorescence resonance energy transfer
[21].
Other types of chemical reactions may also be considered
like electrochemistry-, heat-, sonication-, or microwave-assisted
reaction. Enzymatic reactions are gentle and favorable for the
preparation of biomolecules.
It should be noted that surface modification is inseverable
from many processes of sample preparation. To improve the
selectivity or to get off the non-specific adsorption of sample preparation materials like cartridge, channel(s) or packings,
surface modifications by chemical (and sometimes physical)
adsorption of some affinity or inert substances have to be conducted.
3.2. Non-chemical processing
Most of the methods listed in nos. 1–4 and nos. 8–11 in
Table 1 can roughly be considered as non-chemical techniques.
The mechanical processes such as grinding, blending and sieving
are mainly used to prepare sized particles. They are suitable for
the preparation of solid samples. Gravity-based methods such
as centrifugation and sedimentation are often used for the isolation of heterogeneous samples and liquid layers in liquid–liquid
extraction. Centrifugation is known as a robust technique for
sample preparation routinely used in chemical and especially
biological laboratories. When filtration is incorporated, ultrafiltration can be obtained. The methods based on filtration, phase
partitioning, adsorption and equilibration or speed variation are
in most cases non-chemical approaches remaining in fast development.
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3.2.1. Liquid partition methods
Liquid partitioning means the transfer and distribution of
soluble analytes in a liquid-containing phase system. Various
extraction methods have been created based on the liquid–liquid,
liquid–solid or sometimes liquid–gas partitioning systems.
Liquid–liquid extraction (LLE) transfers target analytes from
a liquid matrix into another immiscible liquid-phase according
to solubility difference. The most classical extraction is performed in separating funnels to extract analytes from an aqueous
biological or environmental solution into a non-polar or less
polar organic solvent. Classical LLE operates manually, requiring repetitive coalescence and phase separation, which can be
very slow when emulsions form and in turn produces a large
volume of organic waste. Some alternative techniques include
membrane-separated liquid extraction (MSLE) [22], countercurrent chromatography (CCC), single drop microextraction
(SDME) [23], and laminar flow techniques [24], etc. The laminar
flow methods are commonly performed in a miniaturized device
called microfluidic system, allowing extraction of analytes from
a liquid into another miscible liquid-phase [25]. Based on mixing
of two incompatible polymers or polymer-salt in water, extraction of analytes can be performed using aqueous two-phase
extraction without the conditions of laminar flow [26]. In case of
using aqueous micellar solutions, cloud point extraction can be
realized by adjusting temperature and pressure [27]. In addition
to water and common organic solvents, room temperature ionic
liquids (RTILs) are drawing more and more attention as a new
type of extraction solvents.
Liquid–solid extraction (LSE) is used to isolate analytes from
a solid or semi-solid matrix into solvents by liquid–solid-phase
partitioning and/or desorption, which can simply be performed
by stirring a solid sample in a hot or cold solvent, classically, in a
closed vessel like the well-known Soxhlet extraction. Sometimes
microwave [28–30] or sonication [31–37] is used to accelerate
the dissolution of analytes and the penetration of solvent(s) into
the solid matrix, they are termed microwave-assisted extraction
(MAE) and sonication-assisted extraction (SAE) respectively.
Further development of the extraction strategies based on new
instrumentation and new fluids have been achieved, allowing
to reduce the consumption of solvent, sample and extraction
time, and to enhance the selectivity of extraction. Two typical examples are the supercritical fluids and sub-critical fluids,
and the corresponding techniques are supercritical fluid extraction (SFE), sub-critical water extraction (SWE), and pressurized
liquid extraction (PLE).
Liquid–gas extraction is widely used to capture atmospheric
pollutants by dynamic or passive techniques. Sampling and
preconcentration of analytes are often integrated in one step.
Recently, liquids have been used as a sorptive collecting phase
in some headspace techniques.
3.2.2. Adsorptive methods
Adsorptive extraction methods first trap analytes onto immobilized phases and the adsorbed analytes are eluted by an
appropriate solvent or desorbed thermally. These methods can
also be considered as special solid–liquid or gas–liquid-phase
extraction techniques but are considerably faster and consume
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significantly smaller volumes of solvents and samples. They
have hence a wide use in a further treatment of the samples
prepared by other methods and can also be used for gaseous
sampling/extraction via either dynamic (forced flow) or passive
mode.
There is another type of adsorptive extraction humorously
called “poor man’s chromatography” or rigorously SPE. This
technique likely starts off with the conventional column chromatographic cleanup and fractionation, and later develops into
an extraction mode with various formats. The desire for even
more selective phases is the current driving force in SPE
research, and restricted-access materials (RAMs) and MIPs have
hence been explored. Innovation of adsorptive extraction formats is the most recent effort that has brought solid-phase
microextraction (SPME) in this world.
Magnetic separation may be included in solid–liquid-phase
extraction in combination with affinity techniques. Solution substances can be extracted by affinity reagents immobilized on
magnetic particles and separated from the solution by attracting
the particles with a magnetic field. Since strong magnets are now
available in a small sizes, magnet-assisted extraction is spaceand cost-effective and easy in operation.
3.2.3. Filtration
Nearly all filtration methods are membrane-based techniques
working with the size-exclusion mechanism via the throughmembrane pores which allow small molecules to pass through
freely but stop the flow of large molecules. More accurately, a
filter with a certain size of pores can “cut-off” the molecules
with a size larger than the pores, making them free from the
smaller molecules or reversely. The molecular size cut-off value
is thus a key factor to characterize a filter or a membrane. Since
macromolecules are often identified by their molecular weight,
the characterizing thus uses the value of molecular weight cut-off
which is the molecular mass of the smallest compound retained
by a membrane to an extent larger than 90%.
There are several different forces available to drive filtrations. The most common filtrations are operated under pressure
differences simply caused by gravity so that they can easily be
used in many common laboratories and even in industrial processes. The more advanced micro- and ultra-filtrations need the
assistance of vacuum or centrifugation. Dialysis, microdialysis and other MSLE are induced by concentration difference or
diffusion. Electrodialysis should be conducted under an electric potential difference coupled with a concentration gradient.
Gel filtration is achieved by retaining small molecules in gel
pores and eluting macromolecules from the gel body or packed
columns.
Filtration is frequently used to separate suspended particles
from dissolved substances, supposing the particles meet the size
requirement of a specific filter or membrane. Ultra-filtration and
gel filtration are often used for purifying, concentrating and
fractionating macromolecules or colloidal suspensions.
Filters are essential in filtration. They can be a membrane
of fibers (paper), glass, celluloses or other plastic substances
with various porosities, of which paper and glass frit filters are
classical and remain in use in various laboratories. Cellulose and
some plastic membrane filters are better alternations for their
clean feature with pore size and scale selectable or variable.
Syringe filters with different diameters and filter thicknesses
have been used for microfiltration. Filters incorporated into a
sample vial or into a centrifuge tube are now often used for the
filtration of viscous samples at a very small volume [38].
3.2.4. Speed-dependent methods
Speed variation happens in nearly all the sample preparation methods but is the core of separation-based techniques
such as electrophoresis, chromatography and on-line or incolumn stacking. Chromatography is frequently used for sample
preparation in various laboratories and industrial processes.
Thin-layer chromatography is a very common technique used
in organic synthetic laboratories, it prepares target analytes by
separating the sample dots printed on one side of a silica gel slab
through development using one or mixed solvents. The separated
dots are cut-off from the silica gel slab and eluted by solvent(s)
to collect the required analytes.
Ion-exchange chromatography is commonly used to isolate,
desalt or purify neutral molecules and the analytes charged
the same sign as the exchanger. They are not retained as the
counter-ionic impurity does. Reverse operation is also possible
and adoptable.
CCC pioneered by Ito et al. [39] can also be included in
LLE since it is an all-liquid method without solid-phases. CCC
relies on the partition of a sample of two immiscible solvents
to achieve separation, and has been the subject of numerous
research papers, review articles [40–43] and books [44–50].
This technique is now developing rapidly from its time consuming formats into droplet CCC and rotation locular CCC and
new generations of CCC instruments called high-speed CCC
or high-performance CCC have also appeared, of which highspeed CCC has been widely used in preparative separation of
natural products [51–54]. Although CCC is not as efficient as
HPLC, it is an excellent alternative for other large-scaled sample
pretreating approaches able to preserve the chemical integrity of
mixtures. With these advantages, CCC is a preferred purification tool for natural products, especially for the bioassay-guided
fractionation of plant-derived compounds.
In addition, all column chromatographic methods more or
less suit for sample isolation (by exploring their separation function), of which analytically reversed phase HPLC is often used as
a semi-preparative tool in various laboratories for it is a common
tool at hand.
Field flow fraction (FFF) proposed by Giddings [63–65] can
also be considered a special class of chromatographic methods
particularly suitable for the purification and characterization of
macromolecules, colloids and particles [66,67]. In FFF, samples
with different molar mass, size and/or other physical properties
are separated, under some fields, into different velocity regions
in a parabolic flow of mobile phase across the channel, and
then exit the channel at different retention times. Different FFF
approaches can be available by varying the applied fields, for
instance, electrical field flow fraction is obtained when using
electric field as the driving force and has been shown useful
in the separation of proteins [63], DNA [68] and polystyrene
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sulfonates [69] but is hindered by the unavailability of commercial instruments. Crossflow or flow FFF is the most universal
technique in FFF family, applicable to macromolecules with
molecular weight of 103 –109 Da and particles with diameter up
to 50 ␮m [70]. Sedimentation FFF uses a centrifugal field and
is a high-resolution separation technique for submicrometer- to
micrometer-sized particles [71]. Thermal or temperature gradient FFF has been used mainly for separating the organosoluble
polymers [72] and to a lesser extent the particles. The most
recent appealing applications of FFF include: (1) sorting and
fingerprinting of bacteria for whole-cell vaccine production; (2)
non-invasive and tagless sorting of immature and stem cells;
(3) separation of intact proteins and enzymes in top-down proteomics; and (4) the development of flow-assisted, multianalyte
immunoassays using nano- and micrometer-sized particles with
immobilized biomolecules [73,74].
Similar to chromatography, electrophoresis can be used for
the preparation of various charged samples especially biologic
macromolecules such as proteins, glycoconjugates and nucleic
acids. It has hence been adopted more often in biological studies
than chromatography. The powerful methods of electrophoresis
used for sample preparation include isoelectric focusing (IEF),
free flow electrophoresis (FFE), and gel electrophoresis.
IEF is a known format of electrophoresis. It achieves sample
isolation and concentration by forcing analytes to migrate in a
pH gradient medium (either free solutions or gels) and stop at
the isoelectric points (pI), and is commonly adopted to focus
proteins at their pI.
FFE, introduced more than 40 years ago [55], allows a continuous injection of samples into a carrier solution flowing as a
thin laminar film (0.3–1.0 mm wide) between two plates, and the
samples are separated while flowing down with the carrier solution and colleted at the bottom outlets for subsequent analysis by
applying an electric field along the liquid film perpendicular to
the direction of flow. Either IEF or zone electrophoretic mechanism can be adopted for the preparation of proteins, organelles,
etc. In 2004, Mortiz et al. [56,57] described a two-dimensional
separation system that used FFE to fractionate protein mixtures
by IEF into 96 well pools. A recent development of FFE is
miniaturization to improve its performance and heat dissipation
[58–61].
Gel electrophoresis is termed not according to principle but to
the medium. For sample preparation the most often used methods are (1) sodium dodecyl sulfate or sulfonate-polyacrylamide
gel electrophoresis (SDS-PAGE) which is a zone electrophoresis
retarded by gel pores, and (2) disc electrophoresis which is a type
of isotachophoresis performed on gel column with leading and
terminating electrolytes (or discontinuous buffers). Samples prepared by gel media are collected by cutting off sample dots from
the gel and eluted or dissolved in solvents. Electroblotting protein onto chemically inert membranes is probably a better way
for micro-sample preparation. In the case of two-dimensional
electrophoresis (2-DE) which is currently the workhorse for
proteomics when combing with MS [62], the first dimension
of separation can actually be considered as a means of sample
preparation and the prepared samples were “on-line” transferred
into the second analytical dimension by electric field.
197
Possibly enlightened by IEF, in-column sample stacking
(ICSS) techniques have been explored in CE since 1990s. Originally ICSS was developed to improve the detection sensitivity
by increasing sample load. However, an on-line sample preparation way is able to integrate sampling, purifying, desalting
and concentrating into one step and is thus especially useful for
pretreating samples with a limited volume. There are various
ICSS methods developed during the last 20 years. The methods
are distinguishable according to their principle including field
amplification (FA), isotachophoresis (ITP), sweeping, pH regulation at column capture and barrage. For more discussion please
refer to Section 4.6.
4. Highlighted methods
During recent years, many modified, innovated and even
novel sample preparation methods have been proposed and
underwent various evaluations or validations to meet the challenges constantly appearing in life sciences. This section
collects some advanced and promising methods to hit and highlight the new trends in developing the methods for sample
preparation.
4.1. Environment friendly methods
4.1.1. Supercritical fluids
An environment friendly method of sample preparation
mainly means the use of environment friendly solvents such
as water, supercritical fluids, RTILs, etc. SFE and SWE are two
typical environment friendly methods.
Supercritical fluids, the intervening physical state between
gas and liquids, possess unique properties. In particular, their
viscosity is lower than that of liquids, allowing faster diffusion and more efficient extractions. By such fluids, SFE obtains
ability to perform selective extractions through adjusting the
fluid properties by regulating pressure, temperature and the content of modifiers. Carbon dioxide is currently the solvent of
choice. Non-polar supercritical CO2 produces high extraction
efficiency for compounds from non-polar to low polarity. Cosolvent systems combining CO2 with one or more small amounts
of modifiers (≤15%) extend the utility of CO2 to polar and
even ionic compounds. The numerous adjustable parameters
have not only made SFE flexible but also tedious in optimization and difficult in use. Important points in favor of SFE are
its relatively short extraction time, mild pressures and temperatures used, which minimize the risks of losing activity to
preserve the integrity of functional compounds of food and
natural products, and to extract labile compounds from environmental samples [75–79]. SFE works the best for finely powdered
solids with good permeability, such as soils and dried plant materials. Extraction of wet or liquid samples and solutions can be
achieved by SFE but with somewhat difficulty [80,81].
SFE can be accomplished in a static mode in which sample and solvent are mixed and kept for a user-specified time
at a constant pressure and temperature, or in a dynamic mode
where the solvent flows through the sample in a continuous
manner. The extracted analytes can be collected into an off-line
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link the extraction system directly to LC or it is even better to
link it to a superheated water chromatography through a solidphase trapping interface [105–108]. SWE has also been coupled
to GC using a membrane or a solid-phase trap as an interface
[109,110].
Nevertheless, SWE suffers from two disadvantages of low
extraction efficiency and impassability for thermal instable composition. A way to kill two birds with one stone is modifying
the water with organic solvents or surfactants to reduce the
extraction temperature and improve extraction efficiencies. In
conclusion, SWE is waiting for further investigation before it
becomes widely adaptable.
Fig. 2. Schematic configuration of SFE–LC–GC–MS system. C, position of
back pressure regulator operated during elution; CR, capillary restrictor; EV,
extraction vessel; R, pressure restrictor; V1–V7, multi-port valves (all at the
loading position) [93]. From ref. [93], with permission.
device or transferred to a on-line chromatographic system for
direct analysis. The off-line trapping is performed by depressurizing the supercritical fluid and absorbing analytes into a
solvent or onto a solid sorbent. For on-line coupling, supercritical fluid chromatography, GC or LC can be chosen but with
different interfaces. With SFE–GC the analytes can be trapped
directly in the GC injector with a restrictor, or first on a solid
material and then transferred to GC column [82]. SFE–LC is
most commonly conducted through solid-phase trapping techniques [83–85]. Fig. 2 shows an example of on-line coupled
SFE–LC–GC–MS [86,87].
Although various advancements have been achieved including techniques, instrumentation and applications [88–91], SFE
has turned more or less to analytical aspects [92]. Although SFE
is inherently superior to many other techniques, it is not a facile
means that can be used widely. How to facilitate the use of SFE
remains a challenge.
Water is much too polar to be used for extracting nonand moderate-polar organic compounds at a room temperature. However, when water is brought to its sub-critical state
by increasing temperature up to 100–374 ◦ C at a sufficiently
high pressure, its polarity, viscosity and surface tension decrease
markedly [94,95]. Water is thus able to extract low-polar compounds at a higher temperature and polar compounds at a
suitably lower temperature (Fig. 3). SWE has been shown
applicable to the extraction of organic pollutants such as
polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), pesticides, herbicides, phenolic compounds
and others from soils and plant materials [96,97]. The extraction
of volatile components such as essential oils in plant materials has also been reported [98,99]. The application of SWE
to the extraction of bioactive compounds or biomarkers from
botanicals and medicinal plant materials has been well reviewed
recently [100].
SWE is generally performed in a flowing mode, giving fairly
diluted aqueous extracts which has to be further extracted and
concentrated with a small volume of organic solvents, SPE or
SPME [101,102]. Alternatively, the analytes can be trapped in
situ by addition of a SPE sorbent disk or cartridge into the SWE
extraction vessel [103,104]. Another interesting alternative is to
4.1.2. Room temperature ionic liquids
RTILs are absorbing new type of liquids having at least
one organic cation or anion, integrating both of the advantages
of water and organic solvents into one molecule. Because of
extremely low vapor pressure, they are safe to use and possibly
friendly to environment, and have since been considered to be
environment friendly solvents as an alternative to the conventional solvents.
RTILs can be hydrophilic or hydrophobic depending on
the structures of their skeletal cations and anions. Consequently, their extraction selectivity and efficiency are somewhat
adjustable with the assistance of other additives or extractants [112,113]. For instance, in the extraction of special metal
ions from aqueous solutions, RTILs are used together with 18crown-6 family crown ethers and some synthesized extractants
[114–116]. For better extraction of metal ions from aqueous solutions, some task-specific RTILs have been synthesized
[117,118], combining both functions of hydrophobic solvent
and extractant in one molecule. RTILs extraction has also been
applied to the removal of organic environmental contaminants
from water [119,120] and to the deep desulfurization of diesel
fuels [121].
Importantly, extraction of biomolecules using RTILs has
significantly increased during recent years [122]. The extraction of proteins or double-stranded DNA from an aqueous
phase into RTILs has been reported quite recently [123–125].
In SPME 1-octyl-3-methylimidazolium (OMIM) PF6 was
used as a disposable liquid absorbent [126] and in liquidphase microextraction (LPME) as an extraction solvent
[127,128].
Some reviews emphasizing the use of RTILs in analytical chemistry can be found in references [129–131]. Although
RTILs themselves are not a new type of chemicals, they are
indeed a novel and promising extraction solvents worth of trying
and exploring with great efforts.
4.2. Acceleration techniques
4.2.1. Pressurized liquid extraction
PLE is also known as pressurized fluid extraction, pressurized
solvent extraction, accelerated solvent extraction, pressurized
hot solvent extraction, high-pressure solvent extraction, highpressure and high-temperature solve extraction or sub-critical
solvent extraction [132], possibly rooting in SWE. Clearly PLE
Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219
199
Fig. 3. Chromatogram obtained through sequential extraction of antioxidant compounds from rosemary leaves with sub-critical water at different temperatures.
HPLC-DAD conditions: column, Nova-Pak C18 column (150 mm × 3.9 mm I.D., 4 ␮m, Waters); mobile phase, a mixture of solvent A (1% acetic acid in water) and
solvent B (1% acetic acid in acetonitrile) according to a step gradient, lasting 40 min, changing from 50% B at 5 min to 70% B at 15 min and to 100% B at 40 min;
flow rate, 0.7 mL/min; diode array detector detection, 230 nm. From ref. [111], with permission.
relies on the use of temperature and pressure to extract organic
compounds from solid or semi-solid matrices. The utilization of
elevated pressures allows solvents to be used above their atmospheric boiling points to increase solvation power and extraction
kinetics. Increased temperatures can also disrupt the strong
solute–matrix interactions. These increase the extraction efficiency and rate, and reduce the consumptions of organic solvents
and operation time.
PLE is mostly carried out in static mode followed by a
post-extraction cleanup and an enrichment procedure. The post-
extraction treatments are especially required in the extraction
of fatty samples from such as biological matrices and food
because the selectivity of the organic solvents is now not enough.
There are three types of post-extraction cleanup approaches:
(1) common column chromatography with packings of florisil,
neutral alumina, silica gel and/or sulfuric acid-impregnated silica; (2) gel-permeation chromatography, and (3) SPE. Fig. 4
shows a comparison of the cleanup approaches in the removal
of unwanted fat and other co-extracted interferences [133–139].
A better way is to integrate the cleanup step into the extraction
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Fig. 4. GC–electron-capture detection (ECD) chromatograms of organochlorine pesticides extracted from soils by PLE for comparison of different cleanup approaches.
(A) Without cleanup; (B) silica + alumina/glass column/1 g + 1 g; (C) florisil/Sep-Pak/1 g + alumina/cartridge/1 g; (D) florisil/cartridge/1 g; (E) silica in cell/3 g; (F)
carbon 100 m2 g−1 /cartridge/1 g. From ref. [134], with permission.
by addition of fat-retaining adsorbents in the PLE cells. This
in situ approach prevents the unwanted lipids and other interfering materials from being extracted into solvent [140–142].
References [143–146] provide quite some detailed information
including basic principle, equipment, some practical considerations and applications.
PLE is much similar to SWE except for the solvents. They
both should have thus similar disadvantages related to the thermal stability and extraction selectivity. However, PLE has more
possibility to get over the problems for instance using different solvents. It looks to be a key to further develop the PLE by
finding new solvents.
4.2.2. Microwave- or sonication-assisted extraction
Microwave radiation can greatly speed up the extraction
and the so-called microwave-assisted extraction [28–30] is thus
established. In principle, only samples or solvents containing
dipolar materials or microwave absorbents can be affected by
microwaves which heat the extraction body from inside to outside in a very short time, much different from the common
heating methods. The acceleration is resulted from the fast and
uniform heating feature.
MAE can be conducted with an open or closed microwave
system or even with a kitchen microwave heater. A closed-vessel
offers a special way to regulate the extracting temperature by
Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219
201
simply adjusting the vessel pressure in a way somewhat similar to PLE technology [147]. The use of open-vessel mainly
focused on Soxhlet extraction has been reported and reviewed
recently [148]. Although almost all reported MAE methods were
conducted off-line, on-line approaches have been shown to be
possible [149–151].
The main advantage of MAE is its wide applicability for
fast extractions of analytes including some thermal instable substances. Its main disadvantage is less incorporable into a flow
system. It should be noted that MAE is better conducted with
a thermostatic microwave oven. Microwave can also accelerate
labeling reaction [152].
Sonication is an alternative means to enhance the extraction
through induced cavitations which creates microenvironments
with high temperatures and high pressures, and in turn speed up
the removal of analytes from sample matrices. SAE [33,36] are
performed mostly in static modes, some in dynamic or on-line
combinations with analytical systems [31–35,37]. Sonication is
an expeditious, inexpensive and efficient means to innovate some
conventional extraction techniques such as SFE, PLE, Soxhlet
extraction and LLE [153–157].
4.3. Scale down
4.3.1. Liquid-phase microextraction
For analytical purposes, scaling down the size of sample
preparation is more applicable than scaling-up which is critical
for productive preparation. There are two important scale-down
liquid-phase extraction approaches, i.e. SDME [23,158] and
MSLE pioneered by Audunsson [159].
SDME normally extracts analytes into a (1–10 ␮L) droplet
of water immiscible extracting solvent attached at a syringe
needle. The droplet can either be immersed into a stirred
aqueous solution or hung over a sample (Fig. 5A and B).
In common, the liquid drop varies its volume regularly or
dynamically (Fig. 5C) to improve the extraction efficiency
[160] by simulating the traditional separatory funnel working manner. Further improvement of the performance can be
achieved by automation [161–163]. Since 2000, a new format of SDME appeared which captures analytes by inserting
the droplet in a flowing sample stream and hence termed
continuous-flow microextraction [164,165]. Due to the continuous contact with the flowing fresh sample solution, the extraction
efficiency and concentration factor are higher than the static
extraction.
The hanging-over or headspace SDME allows the use of both
organic and aqueous [166,167] solvents as receiving phase to
extract volatile or semivolatile compounds since the droplet does
not contact with the sample solution directly. This type of extraction is mostly preferred by GC [168–171] and somewhat by LC
[172], CE [167,173]) and MS [174,175].
Clearly SDME features simplicity, cost-effectiveness and
negligible solvent consumption. However, it inherits some
drawbacks from LLE such as the formation of emulsion and dissolution of the liquid droplet in dealing with some dirty samples.
In most cases the micro liquid drop is not as stable as desired,
and dedicated operators may be a prerequisite to conduct an ele-
Fig. 5. Schematic diagram of (A and B) direct immersion and headspace singledrop microextraction [23] and (C) automatic dynamic LPME. From ref. [160],
with permission.
gant extraction. To improve the stability of the droplet is thus a
challenging topic needed to get over.
MSLE uses a porous membrane to separate the sample phase
(donor) from liquid extractant (acceptor) and microextraction
can be achieved by using hollow fibers. Its most absorbing advantages include (1) very low consumption of solvent,
(2) remarkable cleanup efficiency, (3) high enrichment factors
(>100-fold) for inorganic and organic analytes in a wide range
of polarity, and (4) capability of on-line coupling to chromatography and other instrumental systems [22,176–180].
MSLE may work across more than two phases. In most of
two-phase systems, the donor and acceptor contact each other
through the membrane pores [181] and the mass transfer is driven
by the concentration gradient or diffusion. When the pores are
pre-filled with an organic solvent, the two-phase system changes
to a three-phase system, where the donor and acceptor (both are
aqueous phase) are separated by the organic filled hydrophobic
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Fig. 6. Liquid-phase microextraction systems using (A and B) flat-membrane [197], and (C [198] and E [196]) rod-shaped and (D) U-shaped [199] hollow fiber with
(E) and without automatic flow (reprinted with permission).
membrane which extracts analytes from one aqueous sample
solution and is back-extracted by the other aqueous phase. Such
a three-phase system can suit the extraction of polar and even
ionic compounds like organic acids, bases and metal ions. If the
two aqueous phases at the both sides of membrane have different
pH, higher selectivity and enrichment factors can be obtained.
The separating membrane can be made of silicone rubber or
polyethylene that provides a mechanically stable system but at
the cost of losing extraction speed [179].
These two systems can both be performed in a flow-through
format, suitable for on-line combination with chromatographic
techniques [22,179] such as LC [182,183] and GC [184–188].
The flow-through cells are formed by intercalating a flat microporous membrane in between donor and acceptor solvents with
different designs (Fig. 6A and B). Hollow fibers (HF) are also
used in flow-through format to largely reduce the channel volumes [189–191], but the handing of the hollow fibers tends to be
somewhat difficult [179]. HF-LPME has recently been focused
on in-vial format either in a rod-like or U-shaped configuration (Fig. 6C and D) [192], and the moving phase, normally
the acceptor, can be automated (Fig. 6E) [193–196], which
improves the extraction speed with higher enrichment factor
[194].
4.4. Adsorptive methods
4.4.1. Multifunctional sorbents
The principal goals of SPE should be trace enrichment,
matrix simplification (sample cleanup) and medium exchange.
Although SPE disks have been developed, since 1990s, to scale
up the sample preparation, miniaturized techniques and devices
have been causing more and more concerns to handle small volume of samples. Thin disk and small column have enabled SPE
to largely increase its throughput by automation in combina-
Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219
tion with the multiwell extraction plates [200–202]. SPE-based
micropipette tips are now essential in the purification, concentration and selective isolation of proteins and peptides for
MALDI-TOF-MS and other advanced analytical techniques
[203–205].
Various sorbents have been developed to facilitate the convenient processing of different types of samples. While traditional
reversed-phase, normal-phase, gel filtration and ion-exchange
SPE sorbents are well-established and widely used, multifunctionalized and selective sorbents are also being developed
together with such as miniaturized fiber-in-tube solid-phase
[206].
The multifunctionalized sorbents emerged to have combined
the ion-exchange and reversed-phase functional moieties on one
resin, being able to produce a mixed mechanism of hydrophobic
and ionic interaction. The introduction of ion-exchange moieties
enables the chargeability of analytes, interferent or adsorbent (in
the case of weak ion-exchanger) to be adjustable by pH in any
extraction step, for example to eliminate interference in washing
step and to elute analytes more selectively in each eluting step.
The strong retention of analytes by ion-exchanger and the use
of efficient rinse solvents will naturally result in cleaner extracts
compared with the single-mode sorbents. These types of sorbents can thus be applied mainly to the extraction of acidic,
neutral and basic pharmaceuticals, of pollutants, and of many
other types of compounds such as from food [207–209], biological fluids [210–213], animal tissue [214,215] and wastewaters
[216–218].
4.4.2. Selective sorbents
Immunosorbents with covalent immobilized antibodies or
antigens have high affinity to the corresponding antigens, or
antibodies, allowing the extraction (immunoaffinity extraction,
IAE), concentration and clean-up of target analytes from complex matrices in a single step once their compound-selective
[219,220] or structure- or group-selective [221–223] feature is
well explored. Nevertheless, the sorbents with too high selectivity like monoclonal antibodies may not be ideal to capture a
class or a family of substances compared with polyclonal ones
[224,225].
Although the immunosorbents have high selectivity [226],
they are instable in most cases and can be obtained at high
cost [227]. MIPs extractants look to be a favorable alternative and have been explored extensively during recent years,
leading to the establishment of molecularly imprinted SPE
(MISPE) [228–230]. An MIP with specific cavities formed from
a template molecule possesses specific molecular recognition
mechanism (Fig. 7). As a consequence, the MIP selectively
extracts the template molecule, offering the advantages of
an easy, low cost and rapid preparation, and high thermal and chemical stability. MIP has recently been proven
to have high chemical robustness, providing the opportunity to clean and reactivate them for multiple uses in SPE
[231].
One MIP is normally not synthesized for a class of analytes,
but it is possible to prepare the class-selective MIP on the condition that the template is carefully selected [232–236]. For this
203
Fig. 7. HPLC chromatograms of mycophenolic acid (MPA) in human plasma
after treated by ODS C18 SPE, MISPE and non-imprinted polymer (NIP) SPE,
respectively. MPAG: mycophenolic acid glucuronide; I.S.: suprofen, 10 ␮g/ml.
HPLC conditions: column, Apollo C18 column (150 mm × 4.6 mm I.D., 5 ␮m,
Alltech); mobile phase, methanol–20 mM phosphate buffer (pH 3.3) (55:45,
v/v); flow rate, 1.0 ml/min; UV detection, 254 nm, ambient temperature. From
ref. [231], with permission.
purpose “dummy” template is used to decrease the synthetic cost
of template or to avoid the template bleeding risk [237–245].
Another important issue in preparing MIPs is the selection
of monomers. Computational methods have been developed to
screen a virtual library of monomers that interact strongly with
the target analytes [246–249]. A few recent studies revealed an
interesting hint for the design of MIPs usable in polar and protic
solvents such as methanol, ethanol and even water. The key is
the introduction of strong electrostatic interaction by using basic
monomers for acidic templates or reversely [250–252].
In addition to MIPs, various RAMs have been used as a
special type of extraction sorbents. A RAM prevents the macromolecules from accessing the retention regions of target analytes
by a pore size limitation and/or diffusion barrier (a macromolecular network formed outside the particle surface). It can serve as
a pre-column to preliminarily cleanup the biological fluids and to
preseparate and preconcentrate the target analytes from the biological matrices. With RAM-based on-line SPE, direct injection
of untreated biological fluids into LC is possible [253,254].
MIPs and RAMs are absorbing but the desired properties do
not necessarily be obtained from original designs. It remains a
great challenge to design and synthesis of aqueous MIPs. Both
of these difficulties form high barriers in the exploration of MIPand RAM-based extraction methods.
4.4.3. Solid-phase microextraction
SPME was introduced in the early 1990s as a simple and
effective adsorption/absorption (based on the used solid/liquid
coating) and desorption technique which eliminates the need
for solvents, and the first commercial SPME was declared by
Supelco (Fig. 8). SPME can combine sampling, isolation and
enrichment in one step [255,256], by two conformations: fiber
SPME and in-tube SPME. Fiber SPME is the initially developed
and most widely used form where the extraction phase, usually
a polymer coated onto the fiber, is exposed in the headspace
of a sample or to a sample solution to capture and accumulate
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Fig. 8. Design of the first commercial SPME device made by Supelco. From ref. [258], with permission.
analytes. After a certain time to reach equilibration (sometimes
near-equilibrium [257]), the loaded extraction phase is transferred to the injection port of chromatographic or other analytical
instrument in use.
However, fiber SPME has the drawbacks of limited capacity and complexity in coupling with LC. The in-tube SPME
was thus explored which uses an open tubular fused-silica capillary instead of the fiber [259] to suit on-line hyphenation.
The column length and the thickness of extractant coating are
tunable.
The study of stationary phases for SPME assists the development of applications [260–262]. Several coatings from non-polar
to polar are commercially available, including polydimethylsiloxane (PDMS), polyacrylate, divinylbenzene, Carboxen (a
carbon molecular sieve) and Carbowax (polyethylene glycol).
For coating, sol–gel technique provides an efficient incorporation of organic components into inorganic polymeric structures
under extraordinarily mild thermal conditions [263], and has
been applied to the preparation of coated fibers [264–267] and
capillary columns [268–270].
Fibers are available in different film thicknesses with single
coatings, combined coatings or co-polymers but remain very
limited, which restricts the wide application of SPME [260].
Besides coatings, monolithic sorbents with different kinds of
functional groups [271–275], including MIPs [276], have shown
to be a promising alternative.
SPME may integrate sampling with sample preparation,
making it suitable for on-site sampling and analysis. Corresponding passive sampling devices have been reported for the
time-weighted average air/water sampling in which the fiber is
retracted a known distance into its needle housing during the
sampling period [277–280]. Recently PDMS-rod and membrane
were used as the passive samplers of SPME to improve extraction
efficiency and sensitivity [281–283].
The small dimension and nearly solvent-free feature of
SPME enable in vivo sampling without severe damage to
the live organisms. The reported in vivo methods include
monitoring the biogenic volatile organic compounds emitted
from plants, isolating the insect semiochemicals and other
microbiological inspections [284,285]. Direct extraction from
flowing blood [286] and sampling of volatiles emitted by
humans [287–289] and insects [290,291] have also been
achieved.
Most fiber SPME methods have been used in combination
with GC and LC (Fig. 9) [292–294]. A fiber SPME is incorporated with HPLC through a desorption chamber as a part of
injection loop (Fig. 9D) [295–298]. In-tube SPME can be fully
automated [259,299], its capillary column is generally placed in
between the HPLC autosampler needle and the injection valve
or inserted in the injection loop [300].
On-line coupling of SPE with GC is similar to those used for
large volume injection and on-line LC–GC. On-column, intercalated loop and programmable temperature vaporiser (PTV)
interfaces are the basic choice (Fig. 10) [302,303]. SPE-HPLC
can be built by “column switching” that is inserting a piece
of SPE material as a small pre-column into the injection loop
(Fig. 11) [304]. By setting robust and reliable chromatographic
methods and cartridge exchangeable modules, large increase
of the sample throughput is possible with a saving of the total
analysis time [305–307].
Micro SPE can be on-line coupled to CE through a Teeshaped interface [308,309] or in-line coupled by placing
Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219
205
Fig. 9. Schematics of headspace and immersion fiber SPME procedures, and thermal and solvent desorption systems for GC and HPLC analyses. From ref. [301],
with permission.
adsorptive materials directly in capillary. To this end, a variety
of approaches have been reported including: (1) an open-tubular
capillary coated with a sorbent [310,311], (2) a small section of capillary packed with microsphere beads [312–314],
or (3) monolithic materials in situ formed in the desired
region of capillary [315–323]. These SPE-CE coupling tech-
niques are no doubt powerful, but have some drawbacks: the
required SPE part is usually manually constructed and not
widely propagable. “Memory” effect may appear due to the
adsorption of analytes onto the sorbents. In order to overcome this adsorption problem, open capillary should be used
[325].
Fig. 10. Scheme of an on-line SPE–GC system consisting of three switching valves (V1–V3), two pumps (SDU pump and syringe pump) and a GC system equipped
with an SVE, and a mass-selective detector. From ref. [324], with permission.
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Fig. 11. Schematic diagram of an on-line SPE–LC–MS system with Prospekt-2 device (Emmen, The Netherlands) which is composed of an autosampler (Triathlon),
a dual syringe high-pressure dispenser (HPD) and an automatic cartridge exchange (ACE) module. From ref. [307], with permission.
4.4.4. Stir bar sorptive extraction
In contrast with the coated fiber SPME, stir bar sorptive
extraction (SBSE) uses a coated magnetic stir bar to capture
analytes during stirring [326,327]. The coated phase is mostly
PDMS to have 50–250 times larger extraction volume than
PDMS-coated fiber SPME. Consequently SBSE has higher
recoveries and higher sample capacity than the fiber SPME
(Fig. 12). Besides PDMS, other phases such as RAMs and
carbon adsorbent material have been tried [328,329].
Normally, SBSE is applied to the extraction of volatile and
semi-volatile organic compounds at a low content in aqueous matrices from environment, food and biomedicines. The
stir bar is simply added and rotated in the aqueous samples to perform extraction. After a certain time, the captured
molecules on the bars can be desorbed either thermally for GC
or into a solvent for LC. In situ derivatization of relatively
polar analytes may reach better recoveries than off-site. The
main disadvantage SBSE is that the operation is in most cases
manual.
4.4.5. Matrix solid-phase dispersion
Matrix solid-phase dispersion (MSPD) is capable of preparing, extracting and fractionating solid, semi-solid and viscous
samples. It operates by blending a sample with a solid support
to simultaneously disrupt and disperse the desired components
on the solid support which is commonly a silica-based material such as derivatized silica, silica gel, sand and florisil, and
sometimes graphitic fibers [331] and alumina [332]. The blended
mixture should then be packed into a column and a sequential
elution is conducted with solvents to collect the analytes by
fractionation. Hot water was shown to be a fast and efficient
eluting solvent for various biological matrices [333–335]. The
eluate may be directly used for further instrumental analysis, but
additional (co-column or external column) SPE is suggested to
Fig. 12. (a) SBSE–LC–MS chromatograms in selected-ion monitoring mode
of (A) untreated honey sample spiked at 10 times the LOQ, (B) untreated
honey sample, and (C) contaminated honey sample with 2.2 ± 0.22 mg kg−1 of
chlorpyriphos methyl. (b) SPME–LC–MS chromatograms in SIM mode of (A)
untreated honey sample spiked at twice the LOQ, (B) untreated honey sample,
and (C) sample containing 2.0 ± 0.28 mg kg−1 of chlorpyriphos methyl. Peaks:
1: phenthoate, 2: fonofos, 3: diazinon, 4: phosalone, 5: chlorpyriphos methyl,
and 6: pirimiphos ethyl. From [330] with permission.
Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219
remove the co-eluted interferent or to cleanup the analytes by
further fractionation [336,337].
MSPD can eliminate many complicated steps in classical LSE
and/or SPE [338–340] and is useful for the isolation of a wide
range of drugs, pesticides, naturally occurring constituents and
other compounds from a wide variety of complex biological
matrices. This method is however fairly labour intensive.
4.5. Microdialysis
Microdialysis is inherently an in vivo sampling technique
extensively used in clinical research, medicine development and
life sciences. A microdialysis system is essentially composed
of a micropump, a microdialytic probe with a semipermeable
membrane at the tip and liquid delivery and collection devices.
During sampling, the probe is implanted into a living being and
perfused with buffered solutions, and the flowing-out dialysate
is collected into microvials or directly transferred into a LC or
CE separation system.
Initially, microdialysis sampling is used to collect small
molecules such as pharmaceuticals and neurotransmitters.
Recently, its application has extended to macromolecules.
Schutte et al. [341] used polyethersulfone microdialysis probe to
collect proteins and dextrans ranging from 3000 to 150,000 and
Ao et al. [342] obtained inflammatory cytokines with relatively
high recovery using a similar method.
In order to increase the recovery of microdialysis, an
enhanced technique has been developed by chemically converting the target species to other forms once they diffuse
into the receiving solution. This conversion can maintain the
highest driving force of diffusion required for analyte transportation. For example, metal ions can efficiently be collected
by converting them into complexes with chelating agents and/or
biopolymers added in the receiving solutions [343]. Similarly, ␤cyclodextrins are used to extract some drugs through host–guest
complexation [344]. By introducing affinity solid particles into
the receiving solution, Pettersson et al. [345] has developed a
solid-support-enhanced microdialysis method.
Compared with others, microdialytic system is ready to couple with column separation systems such as CE [346], HPLC
[347] and microchip electrophoresis [348]. This creates a broad
bridge to link an analytic system to a living body.
4.6. On-line stacking
Stacking is originally explored to increase the detection sensitivity of CE by increasing sample loading, but it is actually
a new type of sample preparation route waiting for exploration
since it can tremendously concentrate analytes into a tiny zone.
4.6.1. Isotachophoresis
When an analyte plug is sandwiched in between a leading
electrolyte having the fastest ion and a terminating electrolyte
with a slowest co-ion, the analyte co-ions can only migrate and
separate in between the leading and terminating ions. The separated analyte zones will line up one after another according
to their apparent mobility or speed, neither isolating nor over-
207
lapping each other, and all migrate at the same speed as the
leading ion. Their concentration should be adjusted to a bit less
than that of the leading ion by largely reducing their zone length
since they are generally at a trace level. The enrichment factor
thus depends on the content of the leading ion which can be up
to more than 0.1 M. High stacking factor is expected by ITP in
theory and has been achieved in practice.
There are two distinguishable approaches to conduct an ITP
stacking, i.e. two dimensional coupling and in-capillary combination called transient-ITP (t-ITP) [349,350]. The former
conducts first a step of sample clean-up and concentration by
ITP with a wide bore capillary and second a step of separating
ITP (ITP-ITP) [351,352] or CE (ITP-CE) [352,353] in a narrow
bore capillary. Samples in urea can directly be analyzed by either
the ITP-ITP or ITP-CE.
t-ITP allows sample stacking at the beginning of CE separation. The stacking is achieved by introducing a plug of leading
electrolytes followed by a section of sample solution with terminating ions, or reversely, by introducing a plug of sample
solution with leading ion followed by a section of terminating
electrolyte. As early as in 1993, Shihabi [354] suggested an easy
way to perform the t-ITP by introducing a plug of sample prepared in acetonitrile and NaCl. The acetonitrile largely reduces
the viscosity of sample solution to accelerate Cl− or Na+ moving
to the right leading position to fast build up an ITP environment
in a short sample plug [355]. This type of t-ITP has been successfully applied to the analysis of physiological samples, able
to stack analytes by factors of 10- to 30-fold [356–358]. t-ITP
have been shown to be useful for the preconcentration of trace
analytes in the matrices containing surplus ionic components
[359–362].
4.6.2. Capillary isoelectric focusing
Capillary isoelectric focusing (cIEF) works the same way
as IEF but in a capillary filled with free solution ampholytes
[363]. Proteins can be separated and focused or stacked at their
pI position. cIEF is suitable for large volume (one column)
concentration of zwitterions and can be coupled with other capillary or column separation techniques such as capillary zone
electrophoresis (CZE) [364], ITP [365], capillary electrochromatography [366], capillary gel electrophoresis (CGE) [367],
capillary non-gel sieving electrophoresis [368] and reversedphase liquid chromatography [369,370]. Compared with other
techniques, cIEF is in theory an interesting candidate for on-line
sample preparation but requires further intensive exploration.
4.6.3. Field amplification
FA stacking technique first introduced by Mikkers et al. [371]
works under a discontinuous electric field distribution to have a
charged analyte migrate from high to low electric fields to lose
its speed suddenly, causing an accumulation of the analyte at the
speed dropping edge. FA can simply be realized in CE by diluting
the sample zone with a pure solvent or by placing a section of
pure solvent in front of the sample in capillary. The solvent or
the low ionic strength sample zone draws higher electric field
across it than other parts in the capillary once the voltage is
switched on. However, the solvent plug can only persist in a
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short time because the ions outside will soon fill in under the
high electric field. As the ionic strength increases, the electric
field strength decreases and so does the FA efficiency. To prolong
the stacking time, the conductivity difference between sample
zone and background should be as greater as possible (normally
>10). This can be achieved by using the running buffers of high
conductivity in addition to the use of pure solvent plug [372].
The injected sample volume should also be optimized at about
10–30% of capillary length. After optimization, FA can obtain
10- to 10,000-fold enrichments in the analysis of opioids [373],
alkaloids [374], heroin metabolites [375] and arsenic species
[376].
Large-volume sample stacking (LVSS) is possible by FA
principle and was first tried by Chien and Burgi [377]. A sample
of 90% capillary volume can be concentrated by a voltage with
polarity reversing to separation. It is very important that, during stacking, the background electrolyte for building up a low
electric field is pumped into the capillary against the analytes.
This can be achieved by making an electroosmotic flow opposite
to the direction of analyte migration or by completely suppressing the electroosmosis at a low pH condition [378]. More
simply, LVSS can be conducted under normal voltage polarity
with a back pressure [379]. This method has been applied to
the analysis of various substances such as 3-nitrotyrosine [380],
mercaptopurine and its metabolites [381], modified aromatic
amino acids [382] and non-steroidal anti-inflammatory drugs
[383], with 20- to 100-fold enhancements.
Feng reported a modified approach called constant pressureassisted electrokinetic injection [384] for the analysis of
negatively charged nucleotides. The pressure is used to counterbalance the reverse electroosmotic flow in the capillary column
during sample injection under FA conditions. At balance, the
running buffer in capillary is stationary and the injection time
can extend up to 1200 s in CZE/MS and 3600 s in CZE/UV. A
bit complicated method is in combination with LPME [385].
A water-immiscible sample solution was covered by a layer of
water and electrokinetically injected into CE system. When the
low conductive water is modified with a moderate content of
organic solvent and a small amount of H+ , it provides the highest sensitivity for analyzing positively chargeable compounds,
such as cocaine and thebaine.
Erny and Cifuentes [386] introduced a type of field amplified
separation in CE. A capillary was coated to provide near-zero
electroosmotic flow at the required pH and the separation was
allowed to happen in the high field zone before stacking, leading to 7-fold reduction of the total analysis time (40 s). This
might open an avenue to create novel analytical methods from
the existed sample preparation methods.
4.6.4. pH regulation
For weak electrolytic analytes, pH can be a very excellent
means to adjust their effective mobility and various stacking approaches have been explored by this principle, such as
dynamic pH junction [387–393] and pH-mediated field amplified sample stacking [394–397]. The same as FA, pH regulation
creates a discontinuous acidic–basic boundary to make weak
analytes lose their speed suddenly during stacking. Since most of
the biological samples are not strong electrolytes, pH regulation
is especially preferred. “Dynamic pH junction”, first mentioned
by Britz-Mckibbin and Chen [388], makes analytes focus at the
moving boundary of H+ /OH− . Two electrolytes are required
at different pH values to form a sharp pH junction boundary,
for example, to stack weak acidic analytes, the sample solution
should be acidified while the running buffer should be basified.
Monton et al. [392] used this method to concentrate peptides by a
factor of 124-fold. Hsieh and Chang [398] employed it to determine biologically active amines and acids with 5200- and 14
000-fold improvements of detection sensitivity. Over 1000-fold
enrichment has been obtained in the preconcentration of proteins
at their pI [399], and about 100-fold enrichment in the separation of a group of steroids (including androgens, corticosteroids
and estrogens) under alkaline conditions [400].
Importantly, dynamic pH junction is a selective stacking
method because its stacking efficiency depends on the pKa value
of analytes and the pH values of background electrolytes and
sample matrix. Dynamic pH junction is tolerant of ionic strength.
However, since the sample is introduced by pressure, the capillary volume restricts the increase of total sample volume.
“pH-mediated stacking” was first introduced by Lunte
[401–403] to preconcentrate samples in highly conductive solutions. To form a zone of low conductivity to stack the ionic
analytes, the weak counter-ions in the sample zone are titrated
by a plug of OH− or H+ electrokinetically injected following the
sample. Hoque et al. [404] used this pH-mediated technique to
preconcentrate glutathione and glutathione disulfide in the analysis of microdialysis samples with about 26-fold enrichment.
Gillogly and Lunte (Fig. 13) [394] used the same technique to
stack acidic composition with reverse pressure to push out the
titrated neutral zone, increasing the sample loading for six times.
pH-mediated sample stacking has also been used in microchip
CGE to achieve high sensitive DNA fragment analysis [405].
This pH-mediated method is adaptable to samples containing
high salt due the creation of a low conductive zone during titration.
Our group has developed another type of pH-mediated
method named acid barrage stacking (ABS) [406]. This method
was validated by determining either standard amino acids
(Fig. 14) in Ringer’s solution or trace Glu and Asp in real samples of rat brain microdialysate, rat serum and human saliva.
Different from the mentioned approaches, ABS is performed on
normal polar CE by sucking in a plug of acid following a sample
zone. The acid plug serves as a barrage to block the backward
migration of the weak anionic analytes due to a sudden mobility
reduction via acid–base reaction. It has been proven that this
method can stand up to 500 mM NaCl and stack analytes by
103 -fold increase of UV detection limits.
4.6.5. Sweeping
Sweeping is a technique for in-column sample concentration
of non-polar molecules with an 80- to 5000-fold enhancement
based on the partitioning capacity of analytes between the water
and pseudo-stationary phase in micellar electrokinetic chromatography. Similar to FA, the stacking happens at the boundary
having a sudden slowdown of sample ions. A zone of a sam-
Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219
209
Fig. 14. Comparison of (A and B) normal pressure injection with (C and D)
ABS by CE-UV of mixed FMOC-labeled amino acids (10 ␮M for A, B, D and
0.01 ␮M for C) prepared in 107 mM borate buffer (pH 9.4) containing 5.5 mM
KCl, 2.3 mM CaCl2 and (B) 0 or (A, C, D) 150 mM NaCl. The CE was performed
with 60 mM borate (pH 10.5) at +15 kV (normal polarity). (A) Sample injected at
0.2 psi for 3 s; (B) sample injected at 0.5 psi for 30 s (corresponding to 3.75 cm in
length); (C, D) ABS, sample injected at 0.5 psi for 30 s followed by 15 s injection
(1.88 cm in length) of 100 mM tartaric acid at pH 2.4.
Fig. 13. Separation of three cationic pharmaceuticals eletriptan, dofetilide, and
doxazosin in Ringer’s solution: (A) without acid, (B) acid-stacked, and (C)
acid-stacked with reverse pressure. Analytes were each 50 ␮M. Injection was
performed electrokinetically at 5 kV, and separation was performed at 20 kV.
The background electrolyte (BGE) was 100 mM lithium acetate buffer, pH 4.75.
From ref. [394], with permission.
ple having the same conductivity as that of the background but
without micelles is injected into a capillary filled with a micellecontaining background. Upon applying a high voltage, these two
zones are forced to move against each other and analytes are
“swept” towards and extracted into the micellar phase, forming
a narrow front at the micellar zone.
Sweeping was first proposed by Quirino and Terabe [407]
and has attracted a wide attention and application. In 2001,
Quirino and Terabe [408] proved that the sweeping could also be
successfully used in CZE in the absence of micelles. The innovation of sweeping techniques seemingly lies in the exploration
of new pseudo-stationary phases including polymers to improve
the extraction capacity. In 2002, Shi and Palmer [409] used polymeric pseudo-stationary phase to sweep analytes, resulting in
more than 1000-fold increase in signal for quinine, heptanophenone and progesterone. In 2007, Kirschner et al. [410] used
sulfated ␤-cyclodextrin to sweep chiral cyanobenz isoindoleamino acids. Chang and co-workers [411–413] have suggested
a method to stack analytes by a polymer solution with a higher
viscosity than that of the sample solution. By using a cationic surfactant, unlimited volume sweeping is possible by electrokinetic
injection [414].
Interestingly, when sweeping is combined with more than one
of the above discussed modes, its selectivity and concentration
ability increases greatly. Isoo and Terabe [415] have achieved up
to 140,000-fold enrichment in the analysis of trace divalent and
trivalent metal ions by combination of sweeping technique with
dynamic complexation and cation-selective exhaustive injection. By combining the sweeping method with dynamic pH
junction, Yu et al. [416] have obtained a successful analysis
of trace toxic pyrrolizidine in Chinese herbal medicine.
Sweeping is a very strong on-line preconcentration method
and more applications are expected in CE field.
4.7. Derivatization
As has been mentioned, the most common use of derivatization has been mainly focused on the enhancement of detection
sensitivity and the treatment of polar compounds to convert them
into more easily extractable, thermally stable, more volatile
analytes or with better chromatographic behavior [417,418].
The new exploration includes the study of novel configuration
for better derivatization and less consumption of sample and
solutes.
On-column derivatization is an absorbing mode in the analysis of samples with limited volume and of precious analytes
with such as CE and capillary LC. It is clearly a challenge to
conduct derivatization in a tiny capillary. However, in-capillary
labeling of amino acids with 9-fluorenylmethyl chloroformate
(FMOC) has been shown to be successful, mixed by electric
force, the reaction was finished within 2 min and the resulted
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Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219
zone produced an excellent CE resolution of chiral amino acids,
comparable with that of pre-column labeling [19].
Derivatization can also be carried out in sample matrix before
or simultaneously with extraction. This is a simple approach
used widely but is susceptible due to side reactions and interferences. An improved approach is implementing the derivization
in the receiving or collection phase, mostly on the SPME
fiber. It can be performed by preloading the labeling agent
on SPE cartridges [419,420], SPME fibers [260,418,421] or
in the SDME micro liquid drops [422,423]. In this case, the
derivatization occurs only when analytes are extracted into the
collection phase, without any interference of sample matrices.
Such sequential operation can be enlarged or stepped by first collecting and concentrating the analytes and then exposing them
to the labeling reagent [424,425].
for integration into microfluidic devices for cleaning of undesired compounds and preconcentration of desired analytes. SPE
has been performed on microchannels using packed particles
(usually coated silica beads) or integrated monolithic porous
polymers for DNA purification [447–451]. On-chip preconcentration of peptides and proteins followed by separation has also
been reported [452,453]. Broyles et al. showed that it was possible to integrate on-chip filtration (by an array of thin channels
to exclude particulates), sample concentration (employing C18
as a stationary phase) and electrochromatographic separation
on a microfabricated device [454]. On-chip filtration and dialysis can be achieved with the aid of porous membrane materials
[455–459].
4.8. Miniaturization and integration
It is necessary to have some criteria to estimate a sample
preparation method for selection over the numerous existing techniques or to develop or innovate on a new approach.
Although numerous requirements may be encountered or need
to be considered, a sample preparation method should measure
up first to the analytical purpose (for qualitative or quantitative
analysis, or a bit in detail, such as separation, detection, sensing,
selective assaying, group protection, or structural elucidation,
etc.), then to the regulation of safety, and to the cost-effectiveness
and simplicity. Of course, one has to consider what is at hand
and potentially available in determining the importance of
criteria.
In other words, if there are no special limitations, a sample
preparation method to be adopted or to be developed should
be effective enough selectivity and throughput to produce high
extraction efficiency and concentration factor in extracting a target analyte from any matrix of interest, the manageable sample
size and cleanness, which will depend on the sample matrix, the
properties and level of the analyte to be determined, should meet
the demands of separation and detection, and it must be tailored
to the final analysis, considering the instrumentation to be used
and the degree of accuracy (or recovery), precision and linearity
required. Especially, the method should be safe for operators and
environment, producing and discarding no pollutants. For most
of the users, the method should be cost-effective, consuming as
minimum reagents and chemicals as possible and with as low
expenses as possible on instrumentation and facility. A method
is always preferred which is very easy to use, has the minimum
steps and uses only simple devices or systems capable of full
automation. Table 2 collects most of the items that need to be
considered in sample preparation.
It is highly significant to minimize sample preparation steps
to reduce the sources of error. A sample preparation method can
have more than one step, such as homogenization, extraction,
cleanup, preconcentration and/or derivatization. The more the
number of steps are involved, the more will be uncertainty will
be introduced into the assaying. Minimizing the sample preparation steps is also an effective way to save time and operation
cost. Using the minimum sample preparation step(s) is particularly favored in measuring the trace and ultra-trace analytes in
complex matrices.
Micro total analysis system (␮TAS) enables effective coupling of separation/detection processes with sample preparation
approaches. Although the capability for handling real samples
on microfluidic or lab-on-a-chip devices is a challenging hurdle which is currently restricting the advancement of ␮TAS,
many techniques have been tried for on-line purification and/or
preconcentration of analytes, and some of them were shown
to be useful for coupling with separation approaches. The
on-line preconcentration in ␮TAS can be achieved by using
solid sorbents, membranes, solvent microextraction, and electromigration focusing mechanisms, or sometimes by a unique
structural design of the ␮TAS hardware.
Electrokinetic concentration of charged biomolecules such
as proteins and DNA has been conducted by allowing the passage of buffer ions but excluded larger migrating molecules
from semipermeable interfaces [426–430]. LPME has been integrated into microchips utilizing co-current or counter-current
microflow systems [25,431,432], producing microchip-based
LPME. Wilson and Konermann [433] introduced an approach
for on-line desalting of macromolecule solutions in tens of
milliseconds by utilizing a two-layered laminar flow geometry that exploits the differential diffusion of macromolecular
analytes and low molecular weight contaminants between the
two flow layers. In addition, droplet LPME can be achieved
by trapping organic solvent droplets in recesses fabricated in
the channel walls, and delivering aqueous samples through the
channel [434]. Miniaturized MSLE has also been designed and
fabricated for sample enrichment [435].
Several sample preparation methods via electric field application including IEF [436–438], FA [439,440], and ITP [441–445]
have been reported. Ross and Locascio described a new technique, temperature gradient focusing, for the concentration and
separation of ionic species within microchannels or capillaries.
Concentration was achieved by balancing the electrophoretic
velocity of analyte against the bulk flow of solution in the presence of a temperature gradient, with an enrichment factor up to
104 -fold [446].
In addition to miniaturization, integration of different methods into one microfluidic device is a new trend. SPE well suited
5. Criteria for method validation
Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219
211
Table 2
Some reference criteria for evaluating a sample preparation method
Table 3
Sample-state-based selection of a sample preparation method
Sort
Sample state
Item
Effectiveness Selectivity
Efficiency
Concentrating factor
Throughput
Sample size
Quantitation
Recovery
Linearity
Precision
Accuracy
Separation demand
Detection limitations
Safety
Chemical hazard
Toxicity
Explosivity
Flammability
Volatility
Radiation
Pollution
Device security
Operation risk
Preference
The higher the better
Trapping
medium
Liquid-phase
Depending on latter analysis
Solid/semisolid
Around 100%
>2 orders, the wider the better
CV < 5%, the smaller the better
Normally with >95% confidence limit
As clean as possible
Clean background or detector-dependent
No or negligible
No or
avoidable
As low as possible or depends
Excluded whenever possible
Measuring up legal regulations
Safe in use, little garbage or free
Naught or preventable
Cost
Materials consumption
Device or system price Low
Running cost
Maintenance
Scarcely
Simplicity
Steps
Convenience
Integrating degree
Automation
Preparation
Minimum
High
High
High or full
Free or rare
Increasing selectivity is a useful means to reduce the number
of sample preparation steps. Extraction with selective sorbents
(e.g. immunosorbents, MIPs, etc.) may eliminate or reduce many
steps like repeating separation and cleanup. Miniaturization and
integration open a novel way to shorten the sample extracting route. Two prominent examples are the SPME and SBSE,
they both may integrate sampling, isolation and enrichment into
only a single step. Introducing automatic techniques into sample preparation is also highly effective in saving time and in
improving reproducibility compared with the manual methods
but involves some cost.
For quantitative analysis, consideration must also be given
to the most appropriate preparation of calibration standards. In
some cases matrix-matched standards or the method of standard
additions is necessary. The use of a suitable internal standard is
widely adopted to eliminate some effects of matrices.
The choice of an appropriate sample preparation technique
can be based on the chemical and physical properties of analytes,
such as molecular weight, charge, solubility (hydrophobicity),
polarity and volatility. Some selective methods utilize the selectivity for specific structural groupings, like IAE, or mimic a
biological selectivity such as MIP-based extraction. Volatile
analytes are often determined through headspace techniques.
In general, a sample preparation method is better selected by
first considering the physical state of the sample and then the
Solid-phase
Headspace
related
Liquid-phase
Liquid
Solid-phase
Headspace
Liquid-phase
Gas-phase
Solid-phase
Techniques
Soxhlet extraction
Supercritical fluid extraction
Sub-critical water extraction
Pressurized liquid extraction
Microwave/Sonication assisted extraction
Matrix solid-phase dispersion
Static headspace
Dynamic headspace (Purge and Trap)
Liquid–liquid extraction
Liquid-phase microextraction
Membrane-separated liquid extraction
Solid-phase extraction
Solid-phase microextraction
Stir bar sorptive extraction
Membrane extraction with sorbent interface
Static headspace
Dynamic headspace (Purge and Trap)
Dynamic sampling/extraction
Passive sampling/extraction
Dynamic sampling/extraction
Passive sampling/extraction
solubility, polarity and particular recognition forces. A gaseous
sample or aerosol is better concentrated by some absorptive
methods, while liquid or solid samples are better extracted by
solvents or similar techniques. Tables 2 and 3 show two strategies
for the selection or evaluation of a sample preparation method.
Particularly, when a strong goal has been assigned such as in
the case of preparation of “-omics”-oriented samples, there will
not be too much space for rotation. But the four sorting criteria
remain effective.
6. Integration of sample preparation methods
Nearly all the molecular related analysis concerns the sample preparation. By surveying most of the complicated research
fields such as environment, food and life sciences, we have found
that there are two types of samples that may serve as the representative to guide the establishment of a total or integrated
method for the preparation of samples from very complicated
matrices. The first case is the preparation of protein samples
from tissues or cells for proteomic studies and the second is the
extraction of polysaccharides from the raw materials of dried
plants.
There is no attempt in this review to go into a detailed discussion on the preparation of such a colligated method, but for
an integrality of this review, route maps as to how to prepare
these two types of samples are illustrated in Figs. 15 and 16,
respectively. As the preparation of polysaccharides is not at this
moment an urgent topic, it will not be further discussed. Instead,
the preparation of proteins is discussed, to some extent, in
detail.
212
Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219
Fig. 15. A strategy for the preparation of proteomic oriented protein samples.
6.1. Preparation of proteomics-oriented proteins
There are different purposes to prepare proteins but at present
the most urgent task is to prepare better protein samples for
proteomic investigations. Considering that the most possible
resource to prepare this type of protein samples is tissues (or
organs) and cells, the preparation method design should never
turn away the sight from these tender materials. Since such
raw materials contain various types of biochemicals, the complete extraction of all the target proteins may not be possible
or necessary. Actually in proteomic studies, the key at present
is to uncover all the “hidden” protein fractions which are normally the low-abundance and membrane proteins. In addition,
the availability of separation and identification methodology
should seriously be taken into consideration in protein preparation. Over all, the consistency and standardization in proteomics
protocols for sample preparation are essential and under the auspices of the Human Proteome Organization, the laboratories of
the Sample Processing Working Group are working out research
initiatives to develop new procedures. However, at present, the
most powerful tools remain to be the 2-DE and multidimensional chromatography in combination with the biological MS
(bio-MS). Under these considerations, a route map to prepare
the complex protein samples should be more or less like the one
shown in Fig. 15, where some specifications should be further
addressed as follows:
(1) The preliminary steps should include tissue disruption, cell
lysis, protein extraction and pre-fractionation. Many techniques are available for tissue disruption and cell lysis
Fig. 16. A reference route for the preparation of polysaccharides from raw plant.
such as by detergents and mechanical methodologies. Prefractionation procedures constitute a valuable tool to find
the “hidden” protein fraction [460]. Although many potential methods can be found, the centrifugation, affinityand immune-based methods, chromatography and electrophoresis are at present the most often used tools for
the pre-fractionation purpose [461]. The selection of the
techniques strongly depends on the nature of samples and
the objects of study. Protein micro arrays are a good
alternative for pre-fractionation, but they remain very expensive [462]. Over all, the 2-DE should be considered and
optimized.
(2) Sample cleanup for electrophoresis should carefully be considered. 2-DE is the first step in the classical proteomics
strategy to resolve the inherently complex nature of cellular
proteomes but the samples should be as clean as possible so
that the interfering compounds, such as salts, nucleic acids,
polysaccharides, lipids and particulate materials and some
detergents can be removed prior to analysis. The salts can
be removed by precipitating the proteins with trichloroacetic
Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219
acid (TCA) or TCA/acetone [463]. Dialysis is another alternative frequently used but it is time consuming.
(3) The relative abundance of the protein(s) of interest must
be considered when choosing the solubilization approach
[464]. The presence of high abundant proteins causes enormous problems for the detection and analysis of the less
abundant proteins. Multi-component immuno-precipitation
and affinity chromatography are now the methods of choice
for the removal of abundant proteins. When dealing with low
abundant proteins like transcription factors, crude extracts
must be enriched to recover enough amounts of proteins
for visualization in the electrophoretic gels [465]. The
main enrichment strategies are (1) subcellular organelle
fractionation using density-gradient centrifugation and
FFE, and (2) the selective fractionation and enrichment
of proteins by sequential solubilization, selective precipitation, affinity- and immunocapture-based purification,
electrophoretic techniques or various chromatographic procedures.
(4) Protein digestion is performed using either specific
enzymes, or chemically, using peptide bond specific
reagents, such as cyanogen bromide [466]. Chemical and
enzymatic digestions may be sequentially applied [467]
through in-gel, in-solution or in-column format. The incolumn digestion reduces the reaction time from hours to
minutes due to the high concentration of enzyme able to
reach inside the column. By this in-column approach, the
protein digestion, peptide separation and MS identification can be on-line coupled, making possible whole-line
automation. There is hence a growing interest in the use of
immobilized enzymes to perform digestions for proteomics
studies [468,469]. It is also widely used to digest proteins
on nitrocellulose [470] or polyvinylidene fluoride [471]
membranes after electroblotting. Electroelution [472] is an
instrumental approach to isolate intact proteins separated by
PAGE.
(5) MS has driven a significant improvement in sample preparation. For MALDI-MS home-made disposable
micro-columns are available as a fast cleanup and concentrating step prior to MS [473]. More recently, it has
been further simplified by using commercial prepacked
ZipTips (Millipore, Bedford, MA, USA). Apart from
stainless-steel MALDI target plates, the use of matrixprecoated targets [474] for the MALDI-TOF-MS analysis
of peptides and proteins have been investigated fairly
widely. Many publications during the last 10 years refer to
either on-line procedures (coupling capillary reversed phase
HPLC separation with electrospray ionization MS [475]) or
off-line procedures using home-made or commercial microcolumns in which samples can be concentrated and eluted
in few microliters [476].
Recent advances in protein preparation feature the use
of miniaturized devices that have an integration of protein
digestion, one- or two-dimensional LC or CE separation with
nano-electrospray ionization tandem MS. Li et al. designed a
micro device with nanospray interface to MS and the possi-
213
bility to preconcentrate 10 ␮L samples makes the separation
consume only 1/10 of the concentrated sample [477]. With this
chip a throughput of 12 samples per hour was obtained, with a
sensitivity of 25 fmol peptides on-chip digested. Paterson et al.
have introduced an integrated device which has a 40-nL microcolumn with immobilized trypsin for protein digestion and a
SPE micro cartridge for desalting/concentration of the digested
peptides [478]. Ramsey et al. presented a two-dimensional separation chip in which micellar electrokinetic chromatography is
combined with CE [479]. A peak capacity of 4200 was demonstrated. However, the microfluidic technology is still under
development and is not presently adoptable to the proteomic
studies [480,481].
7. Conclusions
In conclusion, sample preparation is an inseverable step in
analytical chemistry but it has not been fueled until environmental and life sciences became hot research topics which urgently
require automatic sample preparation methods of high sensitivity, high throughput and high selectivity (H3 method) to treat the
very complicated samples. Although many other techniques (for
instance, probing or sensor) may be used to analyze some target
composition of interest, sample preparation is at present an universal, cost-effective and facile way to conquer the difficulties
encountered in many scientific researches, allowing various laboratories able to manipulate their complicated samples in situ.
Sample preparation is hence expected to further develop at a high
speed or to open a vast research field. High recovery and environment friendly sample preparation methods for finding and
concentrating the trace analytes enshrouded by abundant composition will be the focus of research for 10 years. Chip-based
sample preparation methods which can easily be integrated into
various analytical systems will be highlighted. Flexible and online-integrable sample preparation methods and devices tend to
be the center of research and commercialization from now on.
Acknowledgements
We gratefully acknowledge the financial support from NSFC
(No. 20435030 & No. 20628507), Chinese Academy of Sciences (KJCX2-YW-H11), Ministry of Science and Technology
of China (No. 2006BAK03A09, No. 2007CB714504 & No.
2002CB713803).
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