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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
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. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
2. A brief historical retrospect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
3. A survey of methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
3.1. Chemical processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
3.2. Non-chemical processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
3.2.1. Liquid partition methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
3.2.2. Adsorptive methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
3.2.3. Filtration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
3.2.4. Speed-dependent methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
4. Highlighted methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
4.1. Environment friendly methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
4.1.1. Supercritical fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
4.1.2. Room temperature ionic liquids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
4.2. Acceleration techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
4.2.1. Pressurized liquid extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
4.2.2. Microwave- or sonication-assisted extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
4.3. Scale down . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
4.3.1. Liquid-phase microextraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
4.4. Adsorptive methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
4.4.1. Multifunctional sorbents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
4.4.2. Selective sorbents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
4.4.3. Solid-phase microextraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
4.4.4. Stir bar sorptive extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
4.4.5. Matrix solid-phase dispersion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
0021-9673/$ – see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.chroma.2007.10.026
192 Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219
1. Introduction have been proposed for reference. The strategy on total prepara-
tion of complicated protein samples (used in proteomic study)
In this review, sample preparation is in most cases or polysaccharides from dried plant materials (for comparison
meant to be the isolation and/or (on-line or off-line) concen- only) is illustrated.
tration of some components of interest or target analytes from
various matrices, making the analytes more suitable for sepa- 2. A brief historical retrospect
ration and detection. Chemical modification of the interested
analytes could be involved in the procedure of sample prepara- Study of sample preparation might be traced back to the
tion for an easy isolation, facile later separation and/or detection, very beginning of analytical chemistry when complex sam-
group protection or molecular structure elucidation. ples were first touched. Following the rapid development of
Sample preparation impacts nearly all the later assayed steps analytical techniques in the post-World War II era, increasing
and is hence critical for unequivocal identification, confirmation demands were placed on sample quality because the samples
and quantification of analytes. In common, a clean sample assists collected from natural environment, living body and many other
to improve separation and detection, while a poorly treated sources had very complex matrices, and their subsequent anal-
sample may invalidate the whole assay. Use of ideally cleaned ysis was undoubtedly difficult or even impossible without any
samples also reduces the time to maintain instruments and in pretreatment. As known, sample matrix remains a serious chal-
turn the cost of assay. lenge in conducting liquid chromatography–mass spectrometry
It is because of the importance of sample preparation that (LC–MS), not only reducing the resolution of LC and the ion-
some excellent reviews on this topic have appeared in 2002 in ization efficiency of MS but also increasing the detection noise
books [1,2] and special journal issues [3,4]. In 2003, Pawliszyn and ultimately the limits of detection.
[3] summarized the fundamental aspects of sample extraction As analytical chemistry grows, sample preparation gradually
(equilibrium and kinetics related to mass transfer), which were becomes a major part of analysis, capable of taking up to 80%
necessary for the development of methods, with special con- of the total time of a complete separation-based analytical pro-
siderations of on-site and in situ extractions. Smith [4] provided cess, which typically includes five steps, that is sampling, sample
many examples on extraction and concentration of analytes from preparation, separation, detection and data analysis. Since then,
solid, liquid and gas matrices. Selective extraction methods with sample preparation has developed increasingly during recent
molecularly imprinted polymers (MIPs) and affinity columns years (Fig. 1).
have also been considered. In 2004 and 2006, Raynie [5,6] Environmental application is a main cause driving the
reviewed the experimental and fundamental developments on development of many procedures of sample preparation due
sample extraction, and related methodology appeared during to the increased public awareness that environmental con-
the calendar years of 2002–2005, with an exclusion of gen- taminants are a health risk. The increased demands in
eral application articles but an inclusion of some individual the analysis of foods and natural products have brought
steps. another pressure to develop the technologies of sample
This review thus aims at systemizing the sample prepara- preparation. The appearance of more sensitive and reliable
tion methods to have a panorama on this field, with a stress on methodology to monitor environment is also impelled by
some promising methods appeared and/or fast developed dur- governmental necessity to elevate public living standard and
ing recent years. The matured methods towards such cell and quality.
particle preparation are only briefly discussed, while tissues and During the past decade, active research on sample prepara-
organs are commonly excluded. Some criteria to evaluate or tion has also been fueled by pressure to analyze combinatorial
validate a method for better preparation of complicated samples chemistry and biological samples. The urge to analyze the
Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219 193
Table 1
Classification of sample preparation methods by principle
No. Core principle Method Common usage
1 Mechanics Grinding Powdering, alloying
Blending Alloying, mixing
Sieving Solid particle sieving
2 Gravity Sedimentation Solid material isolation
Centrifugation Phase/density separation
Ultracentrifugation Macromolecule isolation/purification
6 Derivatization or labeling Methylation Increasing volatility, identifying linking or branching sites, group protection
Methoxylation
Silylation
...
Stravidinylation, avidinylation, biotinylation, etc. Conjugation of protein, DNA, etc.
Aldehyde addition Immobilizing/fixing proteins
...
Chiral addition Chirality elimination
In situ labeling Selective probing or sensing
Pre-, off or after column labeling Detection by absorption, emission or radiation, etc.
On-column labeling
8 Filtration and membrane separation 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) Cleanup, particle isolation
Ultra-filtration, microfiltration Macromolecule isolation/purification
Gel filtration Sieving/purification
10 Sorption or equilibration Solid-phase extraction Collection or concentration of analytes from gaseous and liquid matrices
Solid-phase microextraction
Matrix solid-phase dispersion
Stir bar sorptive extraction
Polystyrene surface adsorption Immobilazation of antibody or antigen for such as enzyme-
linked immunosorbent assay (ELISA)
11 Speed variation Preparative chromatography Thin-layer chromatography General preparation
Ion-exchange chromatography Desalting, purification
Counter-current chromatography Productive preparation and purification
Column chromatography General preparation
Electrophoresis (EP) Isoelectric focusing For preparing zwitterions
Free flow electrophoresis Large scale preparation of proteins, DNA, Cells and other
charged particles
Gel EP (including disc electrophoresis) Preparing proteins and DNA
Field flow fraction For soluble species, it can better be sorted in chromatography
On-line stacking Field amplification For charged analytes
Isotachophoresis For charged analytes
Sweeping For chargeable substances
pH regulation For dissociable samples
At column capture Depends
Barrage Depends
Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219 195
of sample preparation, various derivatization protocols, deriva- 3.2.1. Liquid partition methods
tizing reagents and reaction conditions for many analytes have Liquid partitioning means the transfer and distribution of
been reported in several excellent books and reviews [1,13–15]. soluble analytes in a liquid-containing phase system. Various
In GC analysis, most of the derivatizations aim at increasing extraction methods have been created based on the liquid–liquid,
the volatility and stability of the analytes by following princi- liquid–solid or sometimes liquid–gas partitioning systems.
pal reactions: (1) formation of trimethylsilyl ethers from sugars, Liquid–liquid extraction (LLE) transfers target analytes from
steroids and alkaloids, (2) methylation of fatty acids, (3) transes- a liquid matrix into another immiscible liquid-phase according
terification of lipids, and (4) acylation of amines. Derivatization to solubility difference. The most classical extraction is per-
has also been used for structure confirmation in MS, to obtain formed in separating funnels to extract analytes from an aqueous
the spectra of derivatives containing molecular ion signals [16]. biological or environmental solution into a non-polar or less
Some derivatizations are adapted in concentrating process or polar organic solvent. Classical LLE operates manually, requir-
sample cleanup. ing repetitive coalescence and phase separation, which can be
Much more frequently, the derivatization is adopted to very slow when emulsions form and in turn produces a large
change the analyte properties for sensitive detection or/and volume of organic waste. Some alternative techniques include
better separation (by GC, LC, CE, etc.). Derivatization for membrane-separated liquid extraction (MSLE) [22], counter-
CE is mainly conducted to enhance the detectability, partially current chromatography (CCC), single drop microextraction
to modify both the detectability and polarity (or charge-to- (SDME) [23], and laminar flow techniques [24], etc. The laminar
mass ratio) to increase resolution [17,18]. Pre-, on-, post- or flow methods are commonly performed in a miniaturized device
off-column labeling has extensively been explored for high- called microfluidic system, allowing extraction of analytes from
performance LC (HPLC) and especially for capillary-based a liquid into another miscible liquid-phase [25]. Based on mixing
separation techniques such as nano-LC and CE, thereinto the of two incompatible polymers or polymer-salt in water, extrac-
on- or in-column labeling is the most promising which con- tion of analytes can be performed using aqueous two-phase
sumes very limited (down to sub-nanoliter) reagents and samples extraction without the conditions of laminar flow [26]. In case of
[19]. This is highly favored in single cell analysis or other using aqueous micellar solutions, cloud point extraction can be
ultra-trace analysis. Derivatization is also used to introduce realized by adjusting temperature and pressure [27]. In addition
an energy exchanging structure into a fluorescent molecule, to water and common organic solvents, room temperature ionic
which is at present a novel technique to prepare molecular bea- liquids (RTILs) are drawing more and more attention as a new
cons [20] or measure fluorescence resonance energy transfer type of extraction solvents.
[21]. Liquid–solid extraction (LSE) is used to isolate analytes from
Other types of chemical reactions may also be considered a solid or semi-solid matrix into solvents by liquid–solid-phase
like electrochemistry-, heat-, sonication-, or microwave-assisted partitioning and/or desorption, which can simply be performed
reaction. Enzymatic reactions are gentle and favorable for the by stirring a solid sample in a hot or cold solvent, classically, in a
preparation of biomolecules. closed vessel like the well-known Soxhlet extraction. Sometimes
It should be noted that surface modification is inseverable microwave [28–30] or sonication [31–37] is used to accelerate
from many processes of sample preparation. To improve the the dissolution of analytes and the penetration of solvent(s) into
selectivity or to get off the non-specific adsorption of sam- the solid matrix, they are termed microwave-assisted extraction
ple preparation materials like cartridge, channel(s) or packings, (MAE) and sonication-assisted extraction (SAE) respectively.
surface modifications by chemical (and sometimes physical) Further development of the extraction strategies based on new
adsorption of some affinity or inert substances have to be con- instrumentation and new fluids have been achieved, allowing
ducted. to reduce the consumption of solvent, sample and extraction
time, and to enhance the selectivity of extraction. Two typi-
3.2. Non-chemical processing cal examples are the supercritical fluids and sub-critical fluids,
and the corresponding techniques are supercritical fluid extrac-
Most of the methods listed in nos. 1–4 and nos. 8–11 in tion (SFE), sub-critical water extraction (SWE), and pressurized
Table 1 can roughly be considered as non-chemical techniques. liquid extraction (PLE).
The mechanical processes such as grinding, blending and sieving Liquid–gas extraction is widely used to capture atmospheric
are mainly used to prepare sized particles. They are suitable for pollutants by dynamic or passive techniques. Sampling and
the preparation of solid samples. Gravity-based methods such preconcentration of analytes are often integrated in one step.
as centrifugation and sedimentation are often used for the isola- Recently, liquids have been used as a sorptive collecting phase
tion of heterogeneous samples and liquid layers in liquid–liquid in some headspace techniques.
extraction. Centrifugation is known as a robust technique for
sample preparation routinely used in chemical and especially 3.2.2. Adsorptive methods
biological laboratories. When filtration is incorporated, ultra- Adsorptive extraction methods first trap analytes onto immo-
filtration can be obtained. The methods based on filtration, phase bilized phases and the adsorbed analytes are eluted by an
partitioning, adsorption and equilibration or speed variation are appropriate solvent or desorbed thermally. These methods can
in most cases non-chemical approaches remaining in fast devel- also be considered as special solid–liquid or gas–liquid-phase
opment. extraction techniques but are considerably faster and consume
196 Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219
significantly smaller volumes of solvents and samples. They some plastic membrane filters are better alternations for their
have hence a wide use in a further treatment of the samples clean feature with pore size and scale selectable or variable.
prepared by other methods and can also be used for gaseous Syringe filters with different diameters and filter thicknesses
sampling/extraction via either dynamic (forced flow) or passive have been used for microfiltration. Filters incorporated into a
mode. sample vial or into a centrifuge tube are now often used for the
There is another type of adsorptive extraction humorously filtration of viscous samples at a very small volume [38].
called “poor man’s chromatography” or rigorously SPE. This
technique likely starts off with the conventional column chro- 3.2.4. Speed-dependent methods
matographic cleanup and fractionation, and later develops into Speed variation happens in nearly all the sample prepara-
an extraction mode with various formats. The desire for even tion methods but is the core of separation-based techniques
more selective phases is the current driving force in SPE such as electrophoresis, chromatography and on-line or in-
research, and restricted-access materials (RAMs) and MIPs have column stacking. Chromatography is frequently used for sample
hence been explored. Innovation of adsorptive extraction for- preparation in various laboratories and industrial processes.
mats is the most recent effort that has brought solid-phase Thin-layer chromatography is a very common technique used
microextraction (SPME) in this world. in organic synthetic laboratories, it prepares target analytes by
Magnetic separation may be included in solid–liquid-phase separating the sample dots printed on one side of a silica gel slab
extraction in combination with affinity techniques. Solution sub- through development using one or mixed solvents. The separated
stances can be extracted by affinity reagents immobilized on dots are cut-off from the silica gel slab and eluted by solvent(s)
magnetic particles and separated from the solution by attracting to collect the required analytes.
the particles with a magnetic field. Since strong magnets are now Ion-exchange chromatography is commonly used to isolate,
available in a small sizes, magnet-assisted extraction is space- desalt or purify neutral molecules and the analytes charged
and cost-effective and easy in operation. the same sign as the exchanger. They are not retained as the
counter-ionic impurity does. Reverse operation is also possible
3.2.3. Filtration and adoptable.
Nearly all filtration methods are membrane-based techniques CCC pioneered by Ito et al. [39] can also be included in
working with the size-exclusion mechanism via the through- LLE since it is an all-liquid method without solid-phases. CCC
membrane pores which allow small molecules to pass through relies on the partition of a sample of two immiscible solvents
freely but stop the flow of large molecules. More accurately, a to achieve separation, and has been the subject of numerous
filter with a certain size of pores can “cut-off” the molecules research papers, review articles [40–43] and books [44–50].
with a size larger than the pores, making them free from the This technique is now developing rapidly from its time con-
smaller molecules or reversely. The molecular size cut-off value suming formats into droplet CCC and rotation locular CCC and
is thus a key factor to characterize a filter or a membrane. Since new generations of CCC instruments called high-speed CCC
macromolecules are often identified by their molecular weight, or high-performance CCC have also appeared, of which high-
the characterizing thus uses the value of molecular weight cut-off speed CCC has been widely used in preparative separation of
which is the molecular mass of the smallest compound retained natural products [51–54]. Although CCC is not as efficient as
by a membrane to an extent larger than 90%. HPLC, it is an excellent alternative for other large-scaled sample
There are several different forces available to drive filtra- pretreating approaches able to preserve the chemical integrity of
tions. The most common filtrations are operated under pressure mixtures. With these advantages, CCC is a preferred purifica-
differences simply caused by gravity so that they can easily be tion tool for natural products, especially for the bioassay-guided
used in many common laboratories and even in industrial pro- fractionation of plant-derived compounds.
cesses. The more advanced micro- and ultra-filtrations need the In addition, all column chromatographic methods more or
assistance of vacuum or centrifugation. Dialysis, microdialy- less suit for sample isolation (by exploring their separation func-
sis and other MSLE are induced by concentration difference or tion), of which analytically reversed phase HPLC is often used as
diffusion. Electrodialysis should be conducted under an elec- a semi-preparative tool in various laboratories for it is a common
tric potential difference coupled with a concentration gradient. tool at hand.
Gel filtration is achieved by retaining small molecules in gel Field flow fraction (FFF) proposed by Giddings [63–65] can
pores and eluting macromolecules from the gel body or packed also be considered a special class of chromatographic methods
columns. particularly suitable for the purification and characterization of
Filtration is frequently used to separate suspended particles macromolecules, colloids and particles [66,67]. In FFF, samples
from dissolved substances, supposing the particles meet the size with different molar mass, size and/or other physical properties
requirement of a specific filter or membrane. Ultra-filtration and are separated, under some fields, into different velocity regions
gel filtration are often used for purifying, concentrating and in a parabolic flow of mobile phase across the channel, and
fractionating macromolecules or colloidal suspensions. then exit the channel at different retention times. Different FFF
Filters are essential in filtration. They can be a membrane approaches can be available by varying the applied fields, for
of fibers (paper), glass, celluloses or other plastic substances instance, electrical field flow fraction is obtained when using
with various porosities, of which paper and glass frit filters are electric field as the driving force and has been shown useful
classical and remain in use in various laboratories. Cellulose and in the separation of proteins [63], DNA [68] and polystyrene
Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219 197
sulfonates [69] but is hindered by the unavailability of commer- Possibly enlightened by IEF, in-column sample stacking
cial instruments. Crossflow or flow FFF is the most universal (ICSS) techniques have been explored in CE since 1990s. Orig-
technique in FFF family, applicable to macromolecules with inally ICSS was developed to improve the detection sensitivity
molecular weight of 103 –109 Da and particles with diameter up by increasing sample load. However, an on-line sample prepa-
to 50 m [70]. Sedimentation FFF uses a centrifugal field and ration way is able to integrate sampling, purifying, desalting
is a high-resolution separation technique for submicrometer- to and concentrating into one step and is thus especially useful for
micrometer-sized particles [71]. Thermal or temperature gradi- pretreating samples with a limited volume. There are various
ent FFF has been used mainly for separating the organosoluble ICSS methods developed during the last 20 years. The methods
polymers [72] and to a lesser extent the particles. The most are distinguishable according to their principle including field
recent appealing applications of FFF include: (1) sorting and amplification (FA), isotachophoresis (ITP), sweeping, pH regu-
fingerprinting of bacteria for whole-cell vaccine production; (2) lation at column capture and barrage. For more discussion please
non-invasive and tagless sorting of immature and stem cells; refer to Section 4.6.
(3) separation of intact proteins and enzymes in top-down pro-
teomics; and (4) the development of flow-assisted, multianalyte 4. Highlighted methods
immunoassays using nano- and micrometer-sized particles with
immobilized biomolecules [73,74]. During recent years, many modified, innovated and even
Similar to chromatography, electrophoresis can be used for novel sample preparation methods have been proposed and
the preparation of various charged samples especially biologic underwent various evaluations or validations to meet the chal-
macromolecules such as proteins, glycoconjugates and nucleic lenges constantly appearing in life sciences. This section
acids. It has hence been adopted more often in biological studies collects some advanced and promising methods to hit and high-
than chromatography. The powerful methods of electrophoresis light the new trends in developing the methods for sample
used for sample preparation include isoelectric focusing (IEF), preparation.
free flow electrophoresis (FFE), and gel electrophoresis.
IEF is a known format of electrophoresis. It achieves sample 4.1. Environment friendly methods
isolation and concentration by forcing analytes to migrate in a
pH gradient medium (either free solutions or gels) and stop at 4.1.1. Supercritical fluids
the isoelectric points (pI), and is commonly adopted to focus An environment friendly method of sample preparation
proteins at their pI. mainly means the use of environment friendly solvents such
FFE, introduced more than 40 years ago [55], allows a con- as water, supercritical fluids, RTILs, etc. SFE and SWE are two
tinuous injection of samples into a carrier solution flowing as a typical environment friendly methods.
thin laminar film (0.3–1.0 mm wide) between two plates, and the Supercritical fluids, the intervening physical state between
samples are separated while flowing down with the carrier solu- gas and liquids, possess unique properties. In particular, their
tion and colleted at the bottom outlets for subsequent analysis by viscosity is lower than that of liquids, allowing faster diffu-
applying an electric field along the liquid film perpendicular to sion and more efficient extractions. By such fluids, SFE obtains
the direction of flow. Either IEF or zone electrophoretic mecha- ability to perform selective extractions through adjusting the
nism can be adopted for the preparation of proteins, organelles, fluid properties by regulating pressure, temperature and the con-
etc. In 2004, Mortiz et al. [56,57] described a two-dimensional tent of modifiers. Carbon dioxide is currently the solvent of
separation system that used FFE to fractionate protein mixtures choice. Non-polar supercritical CO2 produces high extraction
by IEF into 96 well pools. A recent development of FFE is efficiency for compounds from non-polar to low polarity. Cosol-
miniaturization to improve its performance and heat dissipation vent systems combining CO2 with one or more small amounts
[58–61]. of modifiers (≤15%) extend the utility of CO2 to polar and
Gel electrophoresis is termed not according to principle but to even ionic compounds. The numerous adjustable parameters
the medium. For sample preparation the most often used meth- have not only made SFE flexible but also tedious in optimiza-
ods are (1) sodium dodecyl sulfate or sulfonate-polyacrylamide tion and difficult in use. Important points in favor of SFE are
gel electrophoresis (SDS-PAGE) which is a zone electrophoresis its relatively short extraction time, mild pressures and tem-
retarded by gel pores, and (2) disc electrophoresis which is a type peratures used, which minimize the risks of losing activity to
of isotachophoresis performed on gel column with leading and preserve the integrity of functional compounds of food and
terminating electrolytes (or discontinuous buffers). Samples pre- natural products, and to extract labile compounds from environ-
pared by gel media are collected by cutting off sample dots from mental samples [75–79]. SFE works the best for finely powdered
the gel and eluted or dissolved in solvents. Electroblotting pro- solids with good permeability, such as soils and dried plant mate-
tein onto chemically inert membranes is probably a better way rials. Extraction of wet or liquid samples and solutions can be
for micro-sample preparation. In the case of two-dimensional achieved by SFE but with somewhat difficulty [80,81].
electrophoresis (2-DE) which is currently the workhorse for SFE can be accomplished in a static mode in which sam-
proteomics when combing with MS [62], the first dimension ple and solvent are mixed and kept for a user-specified time
of separation can actually be considered as a means of sample at a constant pressure and temperature, or in a dynamic mode
preparation and the prepared samples were “on-line” transferred where the solvent flows through the sample in a continuous
into the second analytical dimension by electric field. manner. The extracted analytes can be collected into an off-line
198 Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219
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 extraction treatments are especially required in the extraction
compounds from solid or semi-solid matrices. The utilization of of fatty samples from such as biological matrices and food
elevated pressures allows solvents to be used above their atmo- because the selectivity of the organic solvents is now not enough.
spheric boiling points to increase solvation power and extraction There are three types of post-extraction cleanup approaches:
kinetics. Increased temperatures can also disrupt the strong (1) common column chromatography with packings of florisil,
solute–matrix interactions. These increase the extraction effi- neutral alumina, silica gel and/or sulfuric acid-impregnated sil-
ciency and rate, and reduce the consumptions of organic solvents ica; (2) gel-permeation chromatography, and (3) SPE. Fig. 4
and operation time. shows a comparison of the cleanup approaches in the removal
PLE is mostly carried out in static mode followed by a of unwanted fat and other co-extracted interferences [133–139].
post-extraction cleanup and an enrichment procedure. The post- A better way is to integrate the cleanup step into the extraction
200 Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219
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 4.2.2. Microwave- or sonication-assisted extraction
in situ approach prevents the unwanted lipids and other inter- Microwave radiation can greatly speed up the extraction
fering materials from being extracted into solvent [140–142]. and the so-called microwave-assisted extraction [28–30] is thus
References [143–146] provide quite some detailed information established. In principle, only samples or solvents containing
including basic principle, equipment, some practical considera- dipolar materials or microwave absorbents can be affected by
tions and applications. microwaves which heat the extraction body from inside to out-
PLE is much similar to SWE except for the solvents. They side in a very short time, much different from the common
both should have thus similar disadvantages related to the ther- heating methods. The acceleration is resulted from the fast and
mal stability and extraction selectivity. However, PLE has more uniform heating feature.
possibility to get over the problems for instance using differ- MAE can be conducted with an open or closed microwave
ent solvents. It looks to be a key to further develop the PLE by system or even with a kitchen microwave heater. A closed-vessel
finding new solvents. offers a special way to regulate the extracting temperature by
Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219 201
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 somewhat difficult [179]. HF-LPME has recently been focused
solution and is back-extracted by the other aqueous phase. Such on in-vial format either in a rod-like or U-shaped configura-
a three-phase system can suit the extraction of polar and even tion (Fig. 6C and D) [192], and the moving phase, normally
ionic compounds like organic acids, bases and metal ions. If the the acceptor, can be automated (Fig. 6E) [193–196], which
two aqueous phases at the both sides of membrane have different improves the extraction speed with higher enrichment factor
pH, higher selectivity and enrichment factors can be obtained. [194].
The separating membrane can be made of silicone rubber or
polyethylene that provides a mechanically stable system but at 4.4. Adsorptive methods
the cost of losing extraction speed [179].
These two systems can both be performed in a flow-through 4.4.1. Multifunctional sorbents
format, suitable for on-line combination with chromatographic The principal goals of SPE should be trace enrichment,
techniques [22,179] such as LC [182,183] and GC [184–188]. matrix simplification (sample cleanup) and medium exchange.
The flow-through cells are formed by intercalating a flat micro- Although SPE disks have been developed, since 1990s, to scale
porous membrane in between donor and acceptor solvents with up the sample preparation, miniaturized techniques and devices
different designs (Fig. 6A and B). Hollow fibers (HF) are also have been causing more and more concerns to handle small vol-
used in flow-through format to largely reduce the channel vol- ume of samples. Thin disk and small column have enabled SPE
umes [189–191], but the handing of the hollow fibers tends to be to largely increase its throughput by automation in combina-
Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219 203
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 sampling period [277–280]. Recently PDMS-rod and membrane
near-equilibrium [257]), the loaded extraction phase is trans- were used as the passive samplers of SPME to improve extraction
ferred to the injection port of chromatographic or other analytical efficiency and sensitivity [281–283].
instrument in use. The small dimension and nearly solvent-free feature of
However, fiber SPME has the drawbacks of limited capac- SPME enable in vivo sampling without severe damage to
ity and complexity in coupling with LC. The in-tube SPME the live organisms. The reported in vivo methods include
was thus explored which uses an open tubular fused-silica cap- monitoring the biogenic volatile organic compounds emitted
illary instead of the fiber [259] to suit on-line hyphenation. from plants, isolating the insect semiochemicals and other
The column length and the thickness of extractant coating are microbiological inspections [284,285]. Direct extraction from
tunable. flowing blood [286] and sampling of volatiles emitted by
The study of stationary phases for SPME assists the develop- humans [287–289] and insects [290,291] have also been
ment of applications [260–262]. Several coatings from non-polar achieved.
to polar are commercially available, including polydimethyl- Most fiber SPME methods have been used in combination
siloxane (PDMS), polyacrylate, divinylbenzene, Carboxen (a with GC and LC (Fig. 9) [292–294]. A fiber SPME is incor-
carbon molecular sieve) and Carbowax (polyethylene glycol). porated with HPLC through a desorption chamber as a part of
For coating, sol–gel technique provides an efficient incorpora- injection loop (Fig. 9D) [295–298]. In-tube SPME can be fully
tion of organic components into inorganic polymeric structures automated [259,299], its capillary column is generally placed in
under extraordinarily mild thermal conditions [263], and has between the HPLC autosampler needle and the injection valve
been applied to the preparation of coated fibers [264–267] and or inserted in the injection loop [300].
capillary columns [268–270]. On-line coupling of SPE with GC is similar to those used for
Fibers are available in different film thicknesses with single large volume injection and on-line LC–GC. On-column, inter-
coatings, combined coatings or co-polymers but remain very calated loop and programmable temperature vaporiser (PTV)
limited, which restricts the wide application of SPME [260]. interfaces are the basic choice (Fig. 10) [302,303]. SPE-HPLC
Besides coatings, monolithic sorbents with different kinds of can be built by “column switching” that is inserting a piece
functional groups [271–275], including MIPs [276], have shown of SPE material as a small pre-column into the injection loop
to be a promising alternative. (Fig. 11) [304]. By setting robust and reliable chromatographic
SPME may integrate sampling with sample preparation, methods and cartridge exchangeable modules, large increase
making it suitable for on-site sampling and analysis. Corre- of the sample throughput is possible with a saving of the total
sponding passive sampling devices have been reported for the analysis time [305–307].
time-weighted average air/water sampling in which the fiber is Micro SPE can be on-line coupled to CE through a Tee-
retracted a known distance into its needle housing during the shaped 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 niques are no doubt powerful, but have some drawbacks: the
of approaches have been reported including: (1) an open-tubular required SPE part is usually manually constructed and not
capillary coated with a sorbent [310,311], (2) a small sec- widely propagable. “Memory” effect may appear due to the
tion of capillary packed with microsphere beads [312–314], adsorption of analytes onto the sorbents. In order to over-
or (3) monolithic materials in situ formed in the desired come this adsorption problem, open capillary should be used
region of capillary [315–323]. These SPE-CE coupling tech- [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.
206 Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219
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.
remove the co-eluted interferent or to cleanup the analytes by lapping each other, and all migrate at the same speed as the
further fractionation [336,337]. leading ion. Their concentration should be adjusted to a bit less
MSPD can eliminate many complicated steps in classical LSE than that of the leading ion by largely reducing their zone length
and/or SPE [338–340] and is useful for the isolation of a wide since they are generally at a trace level. The enrichment factor
range of drugs, pesticides, naturally occurring constituents and thus depends on the content of the leading ion which can be up
other compounds from a wide variety of complex biological to more than 0.1 M. High stacking factor is expected by ITP in
matrices. This method is however fairly labour intensive. theory and has been achieved in practice.
There are two distinguishable approaches to conduct an ITP
4.5. Microdialysis stacking, i.e. two dimensional coupling and in-capillary com-
bination called transient-ITP (t-ITP) [349,350]. The former
Microdialysis is inherently an in vivo sampling technique conducts first a step of sample clean-up and concentration by
extensively used in clinical research, medicine development and ITP with a wide bore capillary and second a step of separating
life sciences. A microdialysis system is essentially composed ITP (ITP-ITP) [351,352] or CE (ITP-CE) [352,353] in a narrow
of a micropump, a microdialytic probe with a semipermeable bore capillary. Samples in urea can directly be analyzed by either
membrane at the tip and liquid delivery and collection devices. the ITP-ITP or ITP-CE.
During sampling, the probe is implanted into a living being and t-ITP allows sample stacking at the beginning of CE separa-
perfused with buffered solutions, and the flowing-out dialysate tion. The stacking is achieved by introducing a plug of leading
is collected into microvials or directly transferred into a LC or electrolytes followed by a section of sample solution with ter-
CE separation system. minating ions, or reversely, by introducing a plug of sample
Initially, microdialysis sampling is used to collect small solution with leading ion followed by a section of terminating
molecules such as pharmaceuticals and neurotransmitters. electrolyte. As early as in 1993, Shihabi [354] suggested an easy
Recently, its application has extended to macromolecules. way to perform the t-ITP by introducing a plug of sample pre-
Schutte et al. [341] used polyethersulfone microdialysis probe to pared in acetonitrile and NaCl. The acetonitrile largely reduces
collect proteins and dextrans ranging from 3000 to 150,000 and the viscosity of sample solution to accelerate Cl− or Na+ moving
Ao et al. [342] obtained inflammatory cytokines with relatively to the right leading position to fast build up an ITP environment
high recovery using a similar method. in a short sample plug [355]. This type of t-ITP has been suc-
In order to increase the recovery of microdialysis, an cessfully applied to the analysis of physiological samples, able
enhanced technique has been developed by chemically con- to stack analytes by factors of 10- to 30-fold [356–358]. t-ITP
verting the target species to other forms once they diffuse have been shown to be useful for the preconcentration of trace
into the receiving solution. This conversion can maintain the analytes in the matrices containing surplus ionic components
highest driving force of diffusion required for analyte trans- [359–362].
portation. For example, metal ions can efficiently be collected
by converting them into complexes with chelating agents and/or 4.6.2. Capillary isoelectric focusing
biopolymers added in the receiving solutions [343]. Similarly, - Capillary isoelectric focusing (cIEF) works the same way
cyclodextrins are used to extract some drugs through host–guest as IEF but in a capillary filled with free solution ampholytes
complexation [344]. By introducing affinity solid particles into [363]. Proteins can be separated and focused or stacked at their
the receiving solution, Pettersson et al. [345] has developed a pI position. cIEF is suitable for large volume (one column)
solid-support-enhanced microdialysis method. concentration of zwitterions and can be coupled with other cap-
Compared with others, microdialytic system is ready to cou- illary or column separation techniques such as capillary zone
ple with column separation systems such as CE [346], HPLC electrophoresis (CZE) [364], ITP [365], capillary electrochro-
[347] and microchip electrophoresis [348]. This creates a broad matography [366], capillary gel electrophoresis (CGE) [367],
bridge to link an analytic system to a living body. capillary non-gel sieving electrophoresis [368] and reversed-
phase liquid chromatography [369,370]. Compared with other
4.6. On-line stacking techniques, cIEF is in theory an interesting candidate for on-line
sample preparation but requires further intensive exploration.
Stacking is originally explored to increase the detection sen-
sitivity of CE by increasing sample loading, but it is actually 4.6.3. Field amplification
a new type of sample preparation route waiting for exploration FA stacking technique first introduced by Mikkers et al. [371]
since it can tremendously concentrate analytes into a tiny zone. works under a discontinuous electric field distribution to have a
charged analyte migrate from high to low electric fields to lose
4.6.1. Isotachophoresis its speed suddenly, causing an accumulation of the analyte at the
When an analyte plug is sandwiched in between a leading speed dropping edge. FA can simply be realized in CE by diluting
electrolyte having the fastest ion and a terminating electrolyte the sample zone with a pure solvent or by placing a section of
with a slowest co-ion, the analyte co-ions can only migrate and pure solvent in front of the sample in capillary. The solvent or
separate in between the leading and terminating ions. The sep- the low ionic strength sample zone draws higher electric field
arated analyte zones will line up one after another according across it than other parts in the capillary once the voltage is
to their apparent mobility or speed, neither isolating nor over- switched on. However, the solvent plug can only persist in a
208 Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219
short time because the ions outside will soon fill in under the the biological samples are not strong electrolytes, pH regulation
high electric field. As the ionic strength increases, the electric is especially preferred. “Dynamic pH junction”, first mentioned
field strength decreases and so does the FA efficiency. To prolong by Britz-Mckibbin and Chen [388], makes analytes focus at the
the stacking time, the conductivity difference between sample moving boundary of H+ /OH− . Two electrolytes are required
zone and background should be as greater as possible (normally at different pH values to form a sharp pH junction boundary,
>10). This can be achieved by using the running buffers of high for example, to stack weak acidic analytes, the sample solution
conductivity in addition to the use of pure solvent plug [372]. should be acidified while the running buffer should be basified.
The injected sample volume should also be optimized at about Monton et al. [392] used this method to concentrate peptides by a
10–30% of capillary length. After optimization, FA can obtain factor of 124-fold. Hsieh and Chang [398] employed it to deter-
10- to 10,000-fold enrichments in the analysis of opioids [373], mine biologically active amines and acids with 5200- and 14
alkaloids [374], heroin metabolites [375] and arsenic species 000-fold improvements of detection sensitivity. Over 1000-fold
[376]. enrichment has been obtained in the preconcentration of proteins
Large-volume sample stacking (LVSS) is possible by FA at their pI [399], and about 100-fold enrichment in the separa-
principle and was first tried by Chien and Burgi [377]. A sample tion of a group of steroids (including androgens, corticosteroids
of 90% capillary volume can be concentrated by a voltage with and estrogens) under alkaline conditions [400].
polarity reversing to separation. It is very important that, dur- Importantly, dynamic pH junction is a selective stacking
ing stacking, the background electrolyte for building up a low method because its stacking efficiency depends on the pKa value
electric field is pumped into the capillary against the analytes. of analytes and the pH values of background electrolytes and
This can be achieved by making an electroosmotic flow opposite sample matrix. Dynamic pH junction is tolerant of ionic strength.
to the direction of analyte migration or by completely sup- However, since the sample is introduced by pressure, the capil-
pressing the electroosmosis at a low pH condition [378]. More lary volume restricts the increase of total sample volume.
simply, LVSS can be conducted under normal voltage polarity “pH-mediated stacking” was first introduced by Lunte
with a back pressure [379]. This method has been applied to [401–403] to preconcentrate samples in highly conductive solu-
the analysis of various substances such as 3-nitrotyrosine [380], tions. To form a zone of low conductivity to stack the ionic
mercaptopurine and its metabolites [381], modified aromatic analytes, the weak counter-ions in the sample zone are titrated
amino acids [382] and non-steroidal anti-inflammatory drugs by a plug of OH− or H+ electrokinetically injected following the
[383], with 20- to 100-fold enhancements. sample. Hoque et al. [404] used this pH-mediated technique to
Feng reported a modified approach called constant pressure- preconcentrate glutathione and glutathione disulfide in the anal-
assisted electrokinetic injection [384] for the analysis of ysis of microdialysis samples with about 26-fold enrichment.
negatively charged nucleotides. The pressure is used to counter- Gillogly and Lunte (Fig. 13) [394] used the same technique to
balance the reverse electroosmotic flow in the capillary column stack acidic composition with reverse pressure to push out the
during sample injection under FA conditions. At balance, the titrated neutral zone, increasing the sample loading for six times.
running buffer in capillary is stationary and the injection time pH-mediated sample stacking has also been used in microchip
can extend up to 1200 s in CZE/MS and 3600 s in CZE/UV. A CGE to achieve high sensitive DNA fragment analysis [405].
bit complicated method is in combination with LPME [385]. This pH-mediated method is adaptable to samples containing
A water-immiscible sample solution was covered by a layer of high salt due the creation of a low conductive zone during titra-
water and electrokinetically injected into CE system. When the tion.
low conductive water is modified with a moderate content of Our group has developed another type of pH-mediated
organic solvent and a small amount of H+ , it provides the high- method named acid barrage stacking (ABS) [406]. This method
est sensitivity for analyzing positively chargeable compounds, was validated by determining either standard amino acids
such as cocaine and thebaine. (Fig. 14) in Ringer’s solution or trace Glu and Asp in real sam-
Erny and Cifuentes [386] introduced a type of field amplified ples of rat brain microdialysate, rat serum and human saliva.
separation in CE. A capillary was coated to provide near-zero Different from the mentioned approaches, ABS is performed on
electroosmotic flow at the required pH and the separation was normal polar CE by sucking in a plug of acid following a sample
allowed to happen in the high field zone before stacking, lead- zone. The acid plug serves as a barrage to block the backward
ing to 7-fold reduction of the total analysis time (40 s). This migration of the weak anionic analytes due to a sudden mobility
might open an avenue to create novel analytical methods from reduction via acid–base reaction. It has been proven that this
the existed sample preparation methods. method can stand up to 500 mM NaCl and stack analytes by
103 -fold increase of UV detection limits.
4.6.4. pH regulation
For weak electrolytic analytes, pH can be a very excellent 4.6.5. Sweeping
means to adjust their effective mobility and various stack- Sweeping is a technique for in-column sample concentration
ing approaches have been explored by this principle, such as of non-polar molecules with an 80- to 5000-fold enhancement
dynamic pH junction [387–393] and pH-mediated field ampli- based on the partitioning capacity of analytes between the water
fied sample stacking [394–397]. The same as FA, pH regulation and pseudo-stationary phase in micellar electrokinetic chro-
creates a discontinuous acidic–basic boundary to make weak matography. Similar to FA, the stacking happens at the boundary
analytes lose their speed suddenly during stacking. Since most of having a sudden slowdown of sample ions. A zone of a sam-
Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219 209
zone produced an excellent CE resolution of chiral amino acids, for integration into microfluidic devices for cleaning of unde-
comparable with that of pre-column labeling [19]. sired compounds and preconcentration of desired analytes. SPE
Derivatization can also be carried out in sample matrix before has been performed on microchannels using packed particles
or simultaneously with extraction. This is a simple approach (usually coated silica beads) or integrated monolithic porous
used widely but is susceptible due to side reactions and interfer- polymers for DNA purification [447–451]. On-chip preconcen-
ences. An improved approach is implementing the derivization tration of peptides and proteins followed by separation has also
in the receiving or collection phase, mostly on the SPME been reported [452,453]. Broyles et al. showed that it was pos-
fiber. It can be performed by preloading the labeling agent sible to integrate on-chip filtration (by an array of thin channels
on SPE cartridges [419,420], SPME fibers [260,418,421] or to exclude particulates), sample concentration (employing C18
in the SDME micro liquid drops [422,423]. In this case, the as a stationary phase) and electrochromatographic separation
derivatization occurs only when analytes are extracted into the on a microfabricated device [454]. On-chip filtration and dialy-
collection phase, without any interference of sample matrices. sis can be achieved with the aid of porous membrane materials
Such sequential operation can be enlarged or stepped by first col- [455–459].
lecting and concentrating the analytes and then exposing them
to the labeling reagent [424,425]. 5. Criteria for method validation
4.8. Miniaturization and integration It is necessary to have some criteria to estimate a sample
preparation method for selection over the numerous exist-
Micro total analysis system (TAS) enables effective cou- ing techniques or to develop or innovate on a new approach.
pling of separation/detection processes with sample preparation Although numerous requirements may be encountered or need
approaches. Although the capability for handling real samples to be considered, a sample preparation method should measure
on microfluidic or lab-on-a-chip devices is a challenging hur- up first to the analytical purpose (for qualitative or quantitative
dle which is currently restricting the advancement of TAS, analysis, or a bit in detail, such as separation, detection, sensing,
many techniques have been tried for on-line purification and/or selective assaying, group protection, or structural elucidation,
preconcentration of analytes, and some of them were shown etc.), then to the regulation of safety, and to the cost-effectiveness
to be useful for coupling with separation approaches. The and simplicity. Of course, one has to consider what is at hand
on-line preconcentration in TAS can be achieved by using and potentially available in determining the importance of
solid sorbents, membranes, solvent microextraction, and elec- criteria.
tromigration focusing mechanisms, or sometimes by a unique In other words, if there are no special limitations, a sample
structural design of the TAS hardware. preparation method to be adopted or to be developed should
Electrokinetic concentration of charged biomolecules such be effective enough selectivity and throughput to produce high
as proteins and DNA has been conducted by allowing the pas- extraction efficiency and concentration factor in extracting a tar-
sage of buffer ions but excluded larger migrating molecules get analyte from any matrix of interest, the manageable sample
from semipermeable interfaces [426–430]. LPME has been inte- size and cleanness, which will depend on the sample matrix, the
grated into microchips utilizing co-current or counter-current properties and level of the analyte to be determined, should meet
microflow systems [25,431,432], producing microchip-based the demands of separation and detection, and it must be tailored
LPME. Wilson and Konermann [433] introduced an approach to the final analysis, considering the instrumentation to be used
for on-line desalting of macromolecule solutions in tens of and the degree of accuracy (or recovery), precision and linearity
milliseconds by utilizing a two-layered laminar flow geome- required. Especially, the method should be safe for operators and
try that exploits the differential diffusion of macromolecular environment, producing and discarding no pollutants. For most
analytes and low molecular weight contaminants between the of the users, the method should be cost-effective, consuming as
two flow layers. In addition, droplet LPME can be achieved minimum reagents and chemicals as possible and with as low
by trapping organic solvent droplets in recesses fabricated in expenses as possible on instrumentation and facility. A method
the channel walls, and delivering aqueous samples through the is always preferred which is very easy to use, has the minimum
channel [434]. Miniaturized MSLE has also been designed and steps and uses only simple devices or systems capable of full
fabricated for sample enrichment [435]. automation. Table 2 collects most of the items that need to be
Several sample preparation methods via electric field applica- considered in sample preparation.
tion including IEF [436–438], FA [439,440], and ITP [441–445] It is highly significant to minimize sample preparation steps
have been reported. Ross and Locascio described a new tech- to reduce the sources of error. A sample preparation method can
nique, temperature gradient focusing, for the concentration and have more than one step, such as homogenization, extraction,
separation of ionic species within microchannels or capillaries. cleanup, preconcentration and/or derivatization. The more the
Concentration was achieved by balancing the electrophoretic number of steps are involved, the more will be uncertainty will
velocity of analyte against the bulk flow of solution in the pres- be introduced into the assaying. Minimizing the sample prepa-
ence of a temperature gradient, with an enrichment factor up to ration steps is also an effective way to save time and operation
104 -fold [446]. cost. Using the minimum sample preparation step(s) is particu-
In addition to miniaturization, integration of different meth- larly favored in measuring the trace and ultra-trace analytes in
ods into one microfluidic device is a new trend. SPE well suited complex matrices.
Y. Chen et al. / J. Chromatogr. A 1184 (2008) 191–219 211
Table 2 Table 3
Some reference criteria for evaluating a sample preparation method Sample-state-based selection of a sample preparation method
Sort Item Preference Sample state Trapping Techniques
medium
Effectiveness Selectivity The higher the better
Efficiency Soxhlet extraction
Concentrating factor Supercritical fluid extraction
Throughput Liquid-phase Sub-critical water extraction
Sample size Depending on latter analysis Solid/semi- Pressurized liquid extraction
Quantitation solid Microwave/Sonication assisted extraction
Recovery Around 100% Solid-phase Matrix solid-phase dispersion
Linearity >2 orders, the wider the better Headspace Static headspace
Precision CV < 5%, the smaller the better related Dynamic headspace (Purge and Trap)
Accuracy Normally with >95% confidence limit
Liquid–liquid extraction
Separation demand As clean as possible
Liquid-phase Liquid-phase microextraction
Detection limitations Clean background or detector-dependent
Membrane-separated liquid extraction
Safety Chemical hazard Solid-phase extraction
Toxicity No or negligible Liquid Solid-phase microextraction
Solid-phase
Explosivity No or Stir bar sorptive extraction
Flammability avoidable Membrane extraction with sorbent interface
Volatility As low as possible or depends Static headspace
Headspace
Radiation Excluded whenever possible Dynamic headspace (Purge and Trap)
Pollution Measuring up legal regulations
Dynamic sampling/extraction
Device security Safe in use, little garbage or free Liquid-phase
Passive sampling/extraction
Operation risk Naught or preventable Gas-phase
Dynamic sampling/extraction
Solid-phase
Cost Materials consumption Passive sampling/extraction
Device or system price Low
Running cost
Maintenance Scarcely
Simplicity Steps Minimum
solubility, polarity and particular recognition forces. A gaseous
Convenience High
Integrating degree High sample or aerosol is better concentrated by some absorptive
Automation High or full methods, while liquid or solid samples are better extracted by
Preparation Free or rare 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
Increasing selectivity is a useful means to reduce the number the case of preparation of “-omics”-oriented samples, there will
of sample preparation steps. Extraction with selective sorbents not be too much space for rotation. But the four sorting criteria
(e.g. immunosorbents, MIPs, etc.) may eliminate or reduce many remain effective.
steps like repeating separation and cleanup. Miniaturization and
integration open a novel way to shorten the sample extract-
ing route. Two prominent examples are the SPME and SBSE, 6. Integration of sample preparation methods
they both may integrate sampling, isolation and enrichment into
only a single step. Introducing automatic techniques into sam- Nearly all the molecular related analysis concerns the sam-
ple preparation is also highly effective in saving time and in ple preparation. By surveying most of the complicated research
improving reproducibility compared with the manual methods fields such as environment, food and life sciences, we have found
but involves some cost. that there are two types of samples that may serve as the rep-
For quantitative analysis, consideration must also be given resentative to guide the establishment of a total or integrated
to the most appropriate preparation of calibration standards. In method for the preparation of samples from very complicated
some cases matrix-matched standards or the method of standard matrices. The first case is the preparation of protein samples
additions is necessary. The use of a suitable internal standard is from tissues or cells for proteomic studies and the second is the
widely adopted to eliminate some effects of matrices. extraction of polysaccharides from the raw materials of dried
The choice of an appropriate sample preparation technique plants.
can be based on the chemical and physical properties of analytes, There is no attempt in this review to go into a detailed dis-
such as molecular weight, charge, solubility (hydrophobicity), cussion on the preparation of such a colligated method, but for
polarity and volatility. Some selective methods utilize the selec- an integrality of this review, route maps as to how to prepare
tivity for specific structural groupings, like IAE, or mimic a these two types of samples are illustrated in Figs. 15 and 16,
biological selectivity such as MIP-based extraction. Volatile respectively. As the preparation of polysaccharides is not at this
analytes are often determined through headspace techniques. moment an urgent topic, it will not be further discussed. Instead,
In general, a sample preparation method is better selected by the preparation of proteins is discussed, to some extent, in
first considering the physical state of the sample and then the 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.
acid (TCA) or TCA/acetone [463]. Dialysis is another alter- bility to preconcentrate 10 L samples makes the separation
native frequently used but it is time consuming. consume only 1/10 of the concentrated sample [477]. With this
(3) The relative abundance of the protein(s) of interest must chip a throughput of 12 samples per hour was obtained, with a
be considered when choosing the solubilization approach sensitivity of 25 fmol peptides on-chip digested. Paterson et al.
[464]. The presence of high abundant proteins causes enor- have introduced an integrated device which has a 40-nL micro-
mous problems for the detection and analysis of the less column with immobilized trypsin for protein digestion and a
abundant proteins. Multi-component immuno-precipitation SPE micro cartridge for desalting/concentration of the digested
and affinity chromatography are now the methods of choice peptides [478]. Ramsey et al. presented a two-dimensional sep-
for the removal of abundant proteins. When dealing with low aration chip in which micellar electrokinetic chromatography is
abundant proteins like transcription factors, crude extracts combined with CE [479]. A peak capacity of 4200 was demon-
must be enriched to recover enough amounts of proteins strated. However, the microfluidic technology is still under
for visualization in the electrophoretic gels [465]. The development and is not presently adoptable to the proteomic
main enrichment strategies are (1) subcellular organelle studies [480,481].
fractionation using density-gradient centrifugation and
FFE, and (2) the selective fractionation and enrichment 7. Conclusions
of proteins by sequential solubilization, selective precip-
itation, affinity- and immunocapture-based purification, In conclusion, sample preparation is an inseverable step in
electrophoretic techniques or various chromatographic pro- analytical chemistry but it has not been fueled until environmen-
cedures. tal and life sciences became hot research topics which urgently
(4) Protein digestion is performed using either specific require automatic sample preparation methods of high sensitiv-
enzymes, or chemically, using peptide bond specific ity, high throughput and high selectivity (H3 method) to treat the
reagents, such as cyanogen bromide [466]. Chemical and very complicated samples. Although many other techniques (for
enzymatic digestions may be sequentially applied [467] instance, probing or sensor) may be used to analyze some target
through in-gel, in-solution or in-column format. The in- composition of interest, sample preparation is at present an uni-
column digestion reduces the reaction time from hours to versal, cost-effective and facile way to conquer the difficulties
minutes due to the high concentration of enzyme able to encountered in many scientific researches, allowing various lab-
reach inside the column. By this in-column approach, the oratories able to manipulate their complicated samples in situ.
protein digestion, peptide separation and MS identifica- Sample preparation is hence expected to further develop at a high
tion can be on-line coupled, making possible whole-line speed or to open a vast research field. High recovery and envi-
automation. There is hence a growing interest in the use of ronment friendly sample preparation methods for finding and
immobilized enzymes to perform digestions for proteomics concentrating the trace analytes enshrouded by abundant com-
studies [468,469]. It is also widely used to digest proteins position will be the focus of research for 10 years. Chip-based
on nitrocellulose [470] or polyvinylidene fluoride [471] sample preparation methods which can easily be integrated into
membranes after electroblotting. Electroelution [472] is an various analytical systems will be highlighted. Flexible and on-
instrumental approach to isolate intact proteins separated by line-integrable sample preparation methods and devices tend to
PAGE. be the center of research and commercialization from now on.
(5) MS has driven a significant improvement in sam-
ple preparation. For MALDI-MS home-made disposable Acknowledgements
micro-columns are available as a fast cleanup and con-
centrating step prior to MS [473]. More recently, it has We gratefully acknowledge the financial support from NSFC
been further simplified by using commercial prepacked (No. 20435030 & No. 20628507), Chinese Academy of Sci-
ZipTips (Millipore, Bedford, MA, USA). Apart from ences (KJCX2-YW-H11), Ministry of Science and Technology
stainless-steel MALDI target plates, the use of matrix- of China (No. 2006BAK03A09, No. 2007CB714504 & No.
precoated targets [474] for the MALDI-TOF-MS analysis 2002CB713803).
of peptides and proteins have been investigated fairly
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