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Miniaturized liquid chromatography focusing on analytical columns and mass spectrometry: A review
Journal Pre-proof Miniaturized Liquid Chromatography Focusing on Analytical Columns and Mass Spectrometry: A review Edvaldo Vasconcelos Soares Maciel, Ana Lúcia de Toffoli, Eduardo Sobieski, Carlos Eduardo Domingues Nazário, Fernando Mauro Lanças PII:
S0003-2670(19)31534-X
DOI:
https://doi.org/10.1016/j.aca.2019.12.064
Reference:
ACA 237347
To appear in:
Analytica Chimica Acta
Received Date: 12 June 2019 Revised Date:
19 December 2019
Accepted Date: 20 December 2019
Please cite this article as: E.V. Soares Maciel, A. Lúcia de Toffoli, E. Sobieski, C.E. Domingues Nazário, F.M. Lanças, Miniaturized Liquid Chromatography Focusing on Analytical Columns and Mass Spectrometry: A review, Analytica Chimica Acta, https://doi.org/10.1016/j.aca.2019.12.064. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier B.V. All rights reserved.
1
Miniaturized Liquid Chromatography Focusing on
2
Analytical Columns and Mass Spectrometry: A review
3 4
Edvaldo Vasconcelos Soares Maciela, Ana Lúcia de Toffolia, Eduardo Sobieskib Neto,
5
Carlos Eduardo Domingues Nazáriob and Fernando Mauro Lançasa*
6 7
a
University of São Paulo, São Carlos, Institute of Chemistry of São Carlos, SP, Brazil
8
b
Federal University of Mato Grosso do Sul, Institute of Chemistry, Campo Grande,
9
MS, Brazil
10 11
*Corresponding author. Tel: +(55) 16 3373 9983; Fax: +(55) 16 3373 9984
12
E-mail address: [email protected] (F. M. Lanças)
13 14
Abstract
15
The technological advances achieved over the last decades boosted the
16
development of suitable benchtop platforms to work at miniaturized liquid
17
chromatography scale (capillary and nano-LC). Under the right conditions,
18
miniaturized LC can offer higher analysis efficiency resulting in superior
19
chromatographic resolution and overall sensitivity than conventional LC. Among the
20
main advantages are the reduced reagents and sample requirement, the decreasing on
21
analytical column dimensions, and consequently flow rates and the easer coupling to
22
mass spectrometry. This review describes fundamental aspects and advances over
23
miniaturized LC technology with a focus on the last decade. Therefore, relevant
24
characteristics of the most common analytical column, covering both filled (packed
25
and monolithic) and open tubular (PLOT and WCOT) columns, are herein discussed.
26
Alternatively, other modern approaches based on microchip separations or 2D 1
27
configurations aiming for the sample preparation on the first dimension, are also
28
introduced. Likewise, some positive and negative aspects of these systems over HPLC
29
are underscored. Besides, considering the necessity to developed components to work
30
at capillary or nanoscale, without significant dead-volumes, the most critical features
31
of specially designed instrumentation for benchtop instruments are briefly discussed
32
highlighting connectors, pumping, injections, oven and detection systems. Also, a
33
more detailed section is presented focused on mass spectrometry efforts towards its
34
miniaturization and how this trend can be useful working together with miniaturized
35
LC. Finally, applications of capillary and nano-LC involving bioanalytical,
36
environmental, and food methods are discussed to support the miniaturized LC as a
37
powerful and emergent separation technique for the years ahead.
38 39 40
Keywords: miniaturized; capillary liquid chromatography; instrumentation; mass
41
spectrometry, nano liquid chromatography; open tubular liquid chromatography.
42 43
Abbreviations
44
cLC - Capillary liquid chromatography; EOPs - Electroosmotic pumps; FLD -
45
Fluorescence detection; GSH - Glutathione; GSSG - Glutathione disulfide; IT-SPME
46
- In-tube solid-phase microextraction; LLE - Liquid-liquid extraction; MRM -
47
Multiple reaction monitoring; nano-LC - Nano liquid chromatography; OT-GC -
48
Open tubular gas chromatography; PLOT - Porous layer open tubular; RBCs - Red
49
blood cells; TFC - Turbo flow chromatography; WCOT - Wall coated open tubular.
50 51 2
52
Summary
53
1. INTRODUCTION
4
54
2. MINIATURIZED COLUMN TECHNOLOGY AND COUPLING TO MS
7
55
2.1 Miniaturized analytical columns
7
56
2.2 Chip-based liquid chromatography
13
57
2.3 Miniaturized systems integrating sample preparation
14
58
2.4 Coupling to mass spectrometry
16
59
2. MINIATURIZED INSTRUMENTATION
20
60
2.1 Pumps
20
61
2.2 Injector and connectors
22
62
2.3 Oven
24
63
2.4 Detectors
24
64
3. MINIATURIZED LC APPLICATIONS
28
65
3.1 Biological samples
28
66
3.2 Food research and quality
33
67
3.3 Environmental analysis
35
68
3.4 Other analytical applications
39
69
4. CONCLUDING REMARKS AND FUTURE TRENDS
41
70
ACKNOWLEDGMENTS
43
71
REFERENCES
43
72 73
FIGURE CAPTIONS
79
74 75 76 3
77
1. Introduction
78
Liquid chromatography is in constant development since its beginning in the
79
year of 1906, proposed by Mikhail Tswett [1]. During the first half of the 20th
80
century, relevant studies were conducted, leading to the development of liquid
81
chromatography (LC), followed by gas chromatography (GC) [2,3]. In the following
82
decades, chromatography would be separated into these two main categories [3]. The
83
GC advance in terms of analytical performance is credited to studies about capillary
84
columns performed by Golay et al. [4], which resulted in the development of the open
85
tubular gas chromatography (OT-GC). On the other hand, LC had a slower
86
development owing to technological limitations related to high backpressure rates
87
generated by the small solid particles packed into an analytical column. Both practical
88
and theoretical developments did not halt, which have spurred new studies, including
89
those towards the technique miniaturization.
90
As it is known, the cornerstone of miniaturized LC is predicated on gains of
91
analysis efficiency, as described by the chromatographic theory [5,6]. According to
92
van Deemter et al. [5], three terms might be held accountable for the column
93
efficiency:
94
resistance to mass transfer. A thorough discussion about these relations is performed
95
by Gritti and Guiochon [6], which is utilized to evaluate the performance of a
96
chromatographic column as a function of H ("height equivalent of a theoretical plate,"
97
or "plate height"), equation (1).
term A, eddy diffusion, term B, longitudinal diffusion, and term C,
98
H A
μ
(1) μ
99
4
100
Considering this assumption, Marcel Golay [4] later realized that replacing the
101
densely packed bed by a thin layer of stationary phase coated onto the internal column
102
wall, the efficiency increased. This finding suggests that such an approach can also be
103
utilized to prepare highly efficient columns. At the same time, it was observed that
104
column efficiency could be improved by reducing column inner diameter (i.d.) or
105
stationary phase thickness, attenuating the band broadening effects as described by
106
van Deemter's equation. Another significant contribution was made by Giddings [7]
107
by comparing LC and GC's evolving potential. Giddings has underscored the LC
108
capacity to reach higher plate numbers (N) as compared to GC (values above 105
109
times higher), which would be achieved only by downscaling the chromatographic
110
columns and, consequently, the whole analytical system. Therefore, since the 1960s,
111
researches focusing on the LC progress have been published, leading to a new LC
112
approach named High-Performance Liquid Chromatography (HPLC) [8–10] [11–13].
113
It was clear that LC should be steered towards more efficient systems,
114
including improvements in instrumental apparatus and decreasing of the analytical
115
columns’ dimensions. Therefore, after approximately forty years of reported efforts,
116
in the 1990s, several studies based on LC miniaturization allied to column
117
technological advances ushered to the creation of Ultra High-Performance Liquid
118
Chromatography (UHPLC) by MacNair et al. [14]. This LC mode has emerged to
119
corroborate in practice the theoretical aspects underscored in the literature, reflected
120
on enhanced efficiency and analysis time. The UHPLC started to gain attention after
121
experiments carried out in fused-silica capillaries down to 12 um i.d. with lengths
122
between 25 - 66 cm packed with sub 2 µm solid particles [15]. These columns were
123
applied over ultra high-pressure rates up to 20000 psi to obtain higher
124
chromatographic efficiencies at shorter analysis time. In the first UHPLC description
5
125
(1997), MacNair et al. [14] packed 1.5 µm nonporous octadecylsilane-modified silica
126
particles into a 30 µm i.d. fused silica capillary of up to 66 cm of length capable of
127
generating up to 300.000 theoretical plates. Hence, the UHPLC creation reinforced
128
the theory by practical applications, which was a differential aspect to boost the
129
studies over capillary columns, mainly in the field of packed ones. A review of the
130
early days of miniaturized LC can be found in a recent manuscript by Novotny [16].
131
Apart from the discussed advantages, a scale reduction on the analytical
132
column also brings the possibility to inject reduced sample volumes representing an
133
excellent alternative for fields with a volume-limited sample such as omics science,
134
forensic, chiral separation, and medicine, as herein discussed in the topic 3. Another
135
critical feature related to LC miniaturization is improved heat dissipation through
136
reduced id columns when compared to conventional LC, which allows the use of
137
temperature control to improve analytical performance [17,18]. Moreover, as the
138
miniaturized LC flow rates are roughly thousand times lower than in HPLC (from mL
139
min-1 scale to nL min-1), significant reductions in solvent consumption and waste
140
generation are expected as well as enhancements on sensitivity due to a more
141
concentrated analytical band [19].
142
The usual terminology for liquid chromatography spans from classical modes
143
to the miniaturized ones. In general, these nomenclatures are based on the column i.d.,
144
the nature of the stationary phase, or the typical mobile flow rate applied throughout
145
the analysis. The general term capillary liquid chromatography (cLC) is often used to
146
refer to any mode of miniaturized LC in which the analytical column possesses an i.d.
147
lower than 1 mm (capillary dimensions), whereas from these values up the technique
148
is named as conventional LC or HPLC. Although these large denominations have
6
149
been successfully applied in some cases, other LC denominations have been carried
150
out by different authors [20–23].
151
Table 1 shows a modification of the classification initially proposed by
152
Chervet et al. [22] and Vissers [23] in which the analytical column i.d. is correlated to
153
the flow rate. Today, this classification is one of the most popular and mostly used in
154
miniaturized LC.
155 156
TABLE 1
157 158
Despite the several advantages of its miniaturization, the LC practical
159
applications continue to be dominated by HPLC or UHPLC scales until the present
160
days. An important fact that can negatively contribute to this outlook was the
161
industrial sector preferences. Although the UHPLC development has its principles
162
based on capillary conditions, as shown in several reports [14,15,20], at that time, the
163
industry opted to commercialize (shorter) columns for faster separations without
164
remarkable gains on efficiency. This option was achieved by maintaining the columns
165
i.d. at the HPLC scale (~ 2.1 mm i.d.), only reducing the particle diameter down to 1.7
166
µm, which have delayed the real miniaturized LC development.
167
168
2. Miniaturized column technology and coupling to MS
169
2.1 Miniaturized analytical columns
170
As our focus is on miniaturized LC, a brief discussion about the stationary
171
phases and how they are inserted or generated inside the analytical columns will be
172
presented.
7
173
Over the last decades, there was remarkable progress over new stationary
174
phases obtained by different chemical mechanisms. New stationary phase includes
175
several different types such as the chiral polysaccharides-based materials, metal-
176
organic and covalent-organic frameworks [24]; the molecular-shape selective
177
particles mostly obtained by adding weak interaction sites into the alkyl or non-alkyl
178
chains [25]; the nanomaterials such as the carbon-, silica-, zirconia-, titanium-, or
179
alumina-based nanoparticles [26]; the ionic liquid-functionalized materials [27], and
180
the HILIC stationary phases based on silica gel or chemically modified silica
181
particles, amino acids, amine-bonded, peptides, cyclopeptides, polymer-coated, and
182
zwitterionic stationary phases to mixed-mode liquid chromatography, among others
183
[28]. It must be highlighted that all these stationary phases were synthesized with the
184
primary goal of improving retention and separation.
185
Nowadays, as the applications based on miniaturized LC spanning several
186
research fields (omics science, toxicology, medicine, food safety and quality,
187
environmental surveillance, among others), the works focused on the development of
188
new analytical columns are also encouraged. Both capillary and nano-LC can be
189
considered amongst the most recent topics of interest on liquid chromatography. Due
190
to these facts, there is an increasing interest in column technology, which represents a
191
significant branch to improving the overall quality of miniaturized LC [29]. Packed
192
columns continue to be the most applied type; however considering the new
193
possibilities open due to the miniaturization, new column technologies begin to spring
194
up. These types, including open tubular and monolithic columns, represent a
195
promising alternative for enhanced efficiency and versatility [29]. Additionally, new
196
approaches such as micro-chips and especially pillar array columns are emerging as
197
highly miniaturized and suitable column types for in-field or real-time analysis. This
8
198
increase in the search for new stationary phases and analytical column technologies
199
are helping miniaturized LC to popularize and spanning in several application fields
200
of analytical chemistry. In the following text, we discuss the most important
201
achievements and trends in miniaturized analytical columns.
202
The chromatographic analytical columns can be divided into two main groups:
203
those named as filled or those supported onto the inner walls of the analytical column.
204
Another recent approach based on microchips has emerged as a potential tool for
205
liquid chromatography separations. Considering this fact, more detailed information
206
about these platforms will be presented in section 1.2.
207
Classified as filled columns is the packed group that represents the most
208
utilized in liquid chromatography nowadays. These columns are constituted of solid
209
particles densely packed into the tube under high pressure, resulting in high sample
210
capacity and significant interaction with the target analytes, even considering the
211
expected problems of high backpressure rates [30]. Their main advantages are the
212
several types of particles available with different properties, which can improve the
213
selectivity/performance of the chromatographic separation. Recent studies employing
214
packed capillary columns have been developed for diversified purposes [31–34]. As
215
an example, Zhang et al. [31–33] carried out experiments in order to optimize both
216
HILIC and RPLC packed capillary columns for proteomic analysis, which has
217
resulted in efficient columns with high peak capacity. Likewise, the separation of
218
polar and non-polar compounds by a capillary column packed with octadecylsilane
219
and taurine derivatized silica was investigated by Wang et al. [34], aiming to produce
220
a hybrid reversed-normal phase column suitable for such separation. This high
221
interest in capillary packed-LC can be attributed to constant studies on this area since
9
222
the early years of HPLC development, as well as to the industries which embraced
223
this approach as the most practical miniaturized LC mode.
224
Another filled type is represented by the monolithic columns, which have
225
emerged as an alternative of permeable material to minimize the system’s
226
backpressure. These monoliths are defined as continuous solid structure seemingly as
227
a rod-like porous filling material [35,36]. The analytical columns containing
228
monoliths are considered to have a higher permeability than packed ones, as well as
229
presenting lower analyte's mass transfer resistance when a chromatographic analysis
230
is performed [35,36]. Due to these features, several applications based on them are
231
currently springing up [37–42]. A tendency to produce hybrid monolithic columns to
232
work under two distinct LC retention mechanisms - reversed/normal phase - can be
233
underscored. An interesting study was performed by Wang et al. [38] aiming to
234
produce hybrid monolith capillary columns suitable to analyze both small molecules
235
as well as tryptic digest from biological samples. Another interesting approach is
236
based on the addition of synthesized materials (ionic liquids, carbon-based, and
237
natural compounds) into the monolith structure to enhance selectivity and
238
performance to analyze complex samples as biological fluids or enantiomeric
239
mixtures, as shown in references [39,42,43].
240
In contrast to the filled columns are the open tubular ones, which are basically
241
divided into those made by porous phases chemically bonded onto the capillary inner
242
walls, named as Porous Layer Open Tubular (PLOT), or those constituted by a thin
243
film of stationary phase, known as Wall Coated Open Tubular (WCOT) [35,44].
244
According to Ishii et al. [21], these columns can include i.d.s. from 0.006 mm to 0.06
245
mm while Saito et al. [45] define an i.d. range between 0.005 – 0.05 mm. Based on
246
the chromatography theory, these columns represent one of the most promising
10
247
alternatives for applications in miniaturized LC and, therefore, are currently gaining
248
attention [44,46–53]. As only the tubes’ inner surface is coated, they are extremely
249
permeable, reporting backpressure ranges lower than the filled columns.
250
Consequently, this fact allows the use of longer lengths combined with lower i.d.,
251
which can result in higher chromatographic efficiencies [44]. As an example, Yang et
252
al. [54,55] recently published two works reporting the use of 1 and 2 µm i.d. fused
253
silica capillaries in open tubular liquid chromatography. The authors underscore the
254
high chromatographic efficiency obtained in so reduced inner diameters under
255
backpressure rates down to 50 bars. As already demonstrated in thorough study
256
conduct by Causon et al. [56], OT columns can reach N values higher than the filled
257
ones. However, the authors emphasized that a commitment between efficiency and
258
analysis time must be considered. Hence two strategies are suggested: (1) the
259
development of OT columns with sub 5 µm i.d. or (2) the employment of temperature
260
control nearly to 90 ºC for OT column up to 10 µm i.d. in order to increase the
261
workable flow rate and consequently reduce analysis time. Apart from these, the use
262
of an oven designed to temperature programming is another useful way to enhance
263
chromatographic efficiency through the modification of other parameters such as
264
mobile phase viscosity and analyte’s diffusion, for instance [57]. On miniaturized LC,
265
the heat dissipation into the analytical column is more effective since lower i.d. fused-
266
silica tubing is usually employed. This tube material is more suitable than stainless-
267
steel in terms of heat transfer, which improves the thermal homogeneity inside the
268
column, suggesting temperature programming as an important parameter to be further
269
explored [57].
270
Regardless of the advantages already discussed, the reduced sample capacity
271
of the OT columns must be considered once they have only a very thin layer of
11
272
stationary phase available for interactions [51]. Also, there are still few applications
273
utilizing OTLC columns owing to the absence of proper instrumental apparatus to
274
operate on conditions of extremely low flow rates and injection volumes, which may
275
have stunted its development until the last years of the 1990s. Another point is that
276
the success of packed capillary columns achieved by the rising of UHPLC has
277
become a hurdle for the OTs’ growth. Even so, a favorable scenario can be expected
278
for the future once these columns have an already demonstrated potential to work
279
together with miniaturized LC, as herein referred [44,47–52]. Nowadays, manuscript
280
publications based on open tubular LC are increasing not only on omic sciences but
281
also for small molecule analysis, which can represent a tendency in miniaturized LC
282
for the subsequent decades [44,47–52,54,55,58–60].
283
Table 2 summarizes several characteristics of each type of analytical column
284
discussed [30,61–70]. Accordingly, Figure 1 shows an illustrative representation of
285
the miniaturized LC modes and the most common analytical columns. The application
286
areas highlighted in Table 2 were selected considering the recently published reports
287
on emerging areas of science, as well as the analytical fields in which these columns
288
are commonly used.
289 290
TABLE 2
291 292
FIGURE 1
293 294
Sequentially, Figure 2 gathers several publications reported in the last ten
295
years, considering the most applied types of chromatographic columns restrict to the
296
LC miniaturized modes. On the one hand, open tubular columns are still the lesser
297
applied among the miniaturized columns. On the other hand, it can be seen a relevant 12
298
number of applications, including either packed or monolithic miniaturized columns,
299
which reinforcers the current importance and tendency of the miniaturized liquid
300
chromatography. Likewise, the emergent strategy to perform liquid chromatography
301
separations on chip-based instruments already have a relevant number of publications
302
suggesting it as an established tool and a potential alternative to the traditional
303
approaches.
304 305
FIGURE 2
306 307 308
2.2 Chip-based liquid chromatography
309
Parallel to the downsizing of LC benchtop equipment (capillary and nano-LC)
310
is the development of chip-based systems which has gained attention in the last
311
decades. Several works based on the concept of “lab-on-chip” are being reported in
312
the literature [62,69,71,72]. The main goals are to increase portability, reliability,
313
analysis speed, meanwhile, reduce costs as well as simplify the chromatographic step
314
become it more comprehensible for fledgling operators [69]. An important advantage
315
of chip-based systems over those of the benchtop is the possibility to gather most LC
316
components onto a micro-sized planar structure, as shown in Figure 8 [62,73,74].
317
This fact allied to the reduced number of connections in the fluidic system can
318
attenuate void volume problems decreasing the chromatographic band broadening. In
319
specific cases, it can be used as a disposable device, which can sometimes avoid
320
sample contamination [62]. Although the known benefits of chip-based LC there are
321
also several challenges to overcome, as following mentioned: (i) simplify procedures
322
to fabricate chip-based LC at laboratory; (ii) reproducibility of packing process; (iii)
13
323
accuracy and precision on injection as well as pumping system; (iv) coupling to
324
detection or sample pre-treatment steps, (v) lack of chemically inert materials to
325
produce the platforms [68].
326
Nowadays, several chip-based platforms are available either on the market or
327
developed at research laboratories [68,69,75]. Moreover, different chip designs and
328
stationary phases (packed, monolithic, or open tubular, for instance) have been
329
already tested in those platforms [68,70,76,77]. Some recent applications include on-
330
chip analysis of glycated hemoglobin in human blood [78], caffeine transport
331
evaluation in human placenta [79], analysis of hemopexin glycopeptides [80],
332
separation of alkyl phenomes [81], quantification of osteoarthritis biomarkers [82],
333
evaluation of the wheat quality [83], and on-chip chromatographic enantioseparation
334
[84,85]. Other several applications using the microchips can be found in these well-
335
discussed reviews by Kecskemeti and Gaspar [68] and Lin et al. [86]. These facts,
336
combined with an increasing number of chip-based LC applications in different areas
337
of analytical chemistry, might represent a promising branch to leverage the
338
miniaturization of liquid chromatography.
339 340
FIGURE 8
341 342
2.3 Miniaturized systems integrating sample preparation
343
In a typical analytical workflow, the matrix complexity owing to the presence
344
of endogenous compounds, make a sample preparation step recommended or even
345
mandatory. For this reason, in addition to their use for chromatographic separations,
346
the miniaturized columns can also be coupled online with an analytical column,
347
through a switching valve, acting as an extraction device [87]. Considering that the 14
348
odds of clogging or contamination are higher in the miniaturized scale, applications of
349
miniaturized columns in online sample preparation represent a current trend aiming
350
for the miniaturization of the whole analytical system [87]. These automated
351
approaches aid in sample purification and improve the method accuracy/precision due
352
to the reduced handling [88].
353
As it is widely known, both capillary-LC and nano-LC have remarkable
354
advantages when compared to standard HPLC, including higher sensitivity (lowering
355
LOD and LOQ values), a decrease in stationary phase requirement and solvent
356
consumption. Besides that, recent investigations have been focused on the
357
development of miniaturized sample preparation methods to reduce the sample
358
volume required, solvent consumption, and, consequently, the costs [89]. Therefore,
359
automation using an online coupling approach, integrating sample preparation and
360
chromatography separation, has shown to avoid multistep procedures and time-
361
consuming analysis [90]. For these reasons, combining the advantages of LC and
362
sample
363
(multidimensional systems), arises as an attractive approach to perform direct
364
extraction, separation, detection, and quantification of the target analytes.
preparation
in
fully
automated
methods
at
miniaturized
scale
365
In short, these automated systems work as follows: firstly, the sample is
366
loaded into the extraction miniaturized column aiming to perform a sample clean-up,
367
extract, and pre-concentrate the target compounds. After this, an electrically assisted
368
switching valve is rotated to the elution position being the target compounds
369
transferred to the miniaturized analytical column for chromatographic separation and
370
detection. As examples, on-line solid-phase extraction (SPE), turbo flow
371
chromatography (TFC), and in-tube solid-phase microextraction (in-tube SPME) are
372
some sample preparation strategies used in multidimensional and automated
15
373
approaches [35,91–95]. In general, these systems allow the injection of many samples
374
in a short time, employing a larger volume of sample than that utilized in either direct
375
or on-column focusing injection strategies. Also, they can improve the method
376
recovery once more volume can be injected and the selectivity for the target
377
compounds by using specific sorbents in the miniaturized extraction column [96].
378
Nowadays, there are several applications of these multidimensional miniaturized
379
systems in the literature for many different purposes, such as environmental,
380
biological, food, and omics, for instance [97–100].
381 382
2.4 Coupling to mass spectrometry
383
After a description of the analytical column considered one of the most critical
384
parts of a chromatography system, we must point out that such reduction on the
385
analytical work-scale will demand a high sensitivity detector suitable to work in low
386
flow rates as well as lower concentration levels.
387
Although the traditional LC detectors (UV-Vis, FLD, i.e.) work at
388
miniaturized scale, the mass spectrometer (MS) is in practice the detector responsible
389
for fulfilling the current requirements of sensitivity/sensibility demanded, thus
390
becoming an ideal detector for miniaturized LC [101]. Mass spectrometry is a reliable
391
technique for qualitative and quantitative analysis of ionizable compounds through
392
the obtained fragmentation (m/z ratio) of the analytes. The main advantages of LC-
393
MS are (1) the capacity to identify unknown compounds from complex matrices
394
(food, environmental, biological samples, i.e.); (2) resolve coelution problems once
395
there are two identification parameters (retention time and fragmentation (m/z
396
structural information)) highlighting the fragmentation where it is possible to select
397
and separate the desired transitions even if in the total ion chromatogram the 16
398
compounds are coeluted; (3) the ability to analyze thermally labile compounds not
399
amenable to GC-MS [102]. In general, three different modes of ionization are recently
400
being applied to LC-MS: electron ionization (EI - most applied in GC under vacuum
401
condition); atmospheric pressure chemical ionization (APCI) and electrospray
402
ionization (ESI), being the last two performed under atmospheric pressure condition.
403
Despite the existence of these suitable modes, the ESI process can be considered
404
today as the most important and applied one [102,103].
405
A prominent landmark of the LC-MS coupling is attributed to electrospray
406
ionization experiments carried out by Bruins et al. [104] and Fenn et al. [105]. In
407
these reports, ESI was presented as a soft ionization mode that would later come to be
408
a relevant LC-MS interface mainly due to its sensitivity to solute concentration,
409
independently of the mobile phase flow rate becoming adequate to work with LC
410
mobile phases. However, some LC-ESI drawbacks are the ionization suppression by
411
matrix effect and the dependency of solvent composition in which both can affect the
412
signal response [106]. Therefore, the miniaturized systems would become a promising
413
way to overcome these drawbacks since low flow rates tend to downplay them.
414
Figure 3 illustrates the sampling efficiency in a triple quadrupole mass spectrometer
415
as a function of the applied flow rate. It can be seen a positive effect when
416
miniaturized LC flow rates are used, resulting in more efficient ionization processes
417
as well as an enhancement of ion transfer to the MS. These facts result in a more
418
intense analyte signal and, consequently, sensitive methods [107,108]. Therefore, this
419
characteristic of miniaturized ESI-MS detectors reinforces the interest in their
420
hyphenation to both capillary and nano-LC.
421 422
FIGURE 3
17
423 424
Studies on a nano-ESI interface performed by Wilm and Mann [109] in the
425
middle of the 1990s lead researches to reliable and robust miniaturized LC-ESI
426
systems over the subsequent years. Nowadays, several different nano-ESI systems are
427
commercially available, designed to improve ion emissions, creating steady flows
428
from the miniaturized LC effluent to the ion source [108,110]. However, even with
429
this successful coupling between these two techniques, the analysis of complex
430
samples still demands more accurate and selective results, which have boosted the
431
development of tandem LC-MS/MS [111]. These "in tandem" configuration results in
432
higher levels of specificity once the ions from the analytes can be traced in two
433
different stages (molecular and transition ion) which are an essential identification
434
parameter. For this reason, LC-MS/MS is often employed in the analysis of complex
435
samples as such types aimed by miniaturized LC [112].
436
Although the well-known advantages of mass spectrometry coupled to
437
miniaturized LC, the complexity of their physical communication still represents an
438
obstacle to the development of sufficiently miniaturized systems. This obstacle is
439
mainly because LC works at a higher pressure in the liquid phase, while the MS
440
demands a vacuum condition for proper operation [113]. Therefore, efforts emerged
441
as a promising way to overcome communications drawbacks [114–116]. In the past
442
few years, alternative systems were reported, including ambient pressure ionization
443
mode, and tandem systems aggregating two analyzers [102,117–122], as already
444
described [102,117–122]. The ambient pressure ionization stands out as a promising
445
alternative to be used, particularly in portable instruments to "in-field" analysis owing
446
to its simplicity and reduced size. A more detailed discussion about efforts on
18
447
miniaturized MS and its coupling to liquid chromatography is presented in section
448
2.4.1.
449
A trend that has been attracting researchers over the last decades was the use
450
of the electron ionization mode in LC analysis. The LC-EI-MS coupling attempt has
451
its roots in the 1970s, with several studies being reported until now [103,106,123–
452
127]. The eluent from LC always represented a difficulty due to the usual LC flow of
453
1 mL min-1 be transformed in approximately 1200 mL min-1 of vapor, which can be
454
harmful inside the ion source [127]. Ideally, the solvent must be fully vaporized
455
before entering the MS to maintain the vacuum conditions. Nowadays, EI is
456
becoming a feasible option considering the remarkable reductions in the mobile phase
457
flow rate of nano-LC.
458
For this reason, some works have been current published focused on the
459
development of interfaces to effectively transfer the nano-LC eluent to the EI source,
460
as referred [103,106,127–130]. The main advantages over API techniques are the
461
highly reproducible and fragmented mass spectra obtained as well as the lower
462
influence of matrix interferents. These facts are beneficial in cases of polar or
463
thermolabile substances, or when the target compounds are poorly ionized on API
464
techniques. Also, the significant EI mass fragmentation helps to elucidate unknown
465
compounds by comparing it with the MS spectra libraries. In the last ten years, some
466
applications include determination of pharmaceutical drugs in alcoholic beverages
467
[131], hormones in water [132], isoflavones in plants [133,134], alkaloids in botanical
468
extracts [135], catechins and caffeine in green tea [136], organochlorine pesticides in
469
water [137], arsenic species in marine plants [138], pyrolysis compounds from
470
biomass [124], and the elucidation of free fatty acid in mussels, marine sentinels,
471
human plasma [139–141].
19
472
Apart from the mass spectrometers, recent works also present UV-light
473
detectors described as "miniaturized and portable" as a potentially cheaper and
474
practical alternative for miniaturized liquid chromatography systems [142–144].
475
In our opinion, full miniaturization of the analytical system will be positive to
476
enhance the analysis performance, at the same time that complying with the green
477
chemistry, so important nowadays. In this manuscript, we discuss issues about
478
miniaturized liquid chromatography from the brief history to instrumental technology
479
development as well as present several applications. It is essential to highlight that
480
this review considered the last decade as the primary time frame to discuss
481
technological
482
chromatography.
advances
and
applications
based
on
miniaturized
liquid
483 484
2. Miniaturized instrumentation
485
Great efforts have been made in the LC miniaturized aiming to achieve better
486
separation efficiencies, lower solvent consumption, and waste generation. In this
487
context, capillary and nano-LC have become an efficient system to hyphenation with
488
electrospray-mass spectrometry increasing the mass sensitivity and allowing to
489
decrease the limits of detection. The following topics will discuss the main aspects of
490
miniaturized LC instrumentation related to the benchtop equipment.
491 492
2.1 Pumps
493
Solvent delivery instrumentation for miniaturized LC requires precise,
494
accurate, and pulseless pumping at low flow rates. Besides, the system must have
495
minimum void volumes to avoid gradient delay [102].
20
496
The first commercial devices developed consisted of simple adaptations of
497
conventional LC systems. Therefore, to achieve a nano and capillary flow rate, a
498
mobile phase split valve was coupled in the pump outlet. Although still widely used,
499
this adaptation did not save the solvent, and any changing in mobile phase
500
composition may alter the analytes retention time.
501
Over the years, the evolution of instrumentation and accessories dedicated to
502
capillary and nano-LC encourage researchers to use miniaturized systems in different
503
applications [19,145]. The pumps now may operate up to 400 bar or even 1000 bar
504
with a flow rate from microliter per minute to nanoliter per minute.
505
Nowadays, the miniaturized dual-piston reciprocating pump is the primary
506
type commercially available due to the constant solvent delivering and low-pressure
507
pulsation. The electronic controller assures a reproducible flow rate under both
508
isocratic and gradient elution without splitters. It is important to note that some
509
commercial pumps have a splitter before the mixer chamber and can save the mobile
510
phase; however, most systems still use a splitter after the mixer chamber, and most of
511
the mobile phase (99%) go to waste [13].
512
Syringe pumps can drive the mobile phase without pulsation, but they have a
513
limited volume of solvent in the inner reservoir [57]. Aiming to overcome this
514
limitation, miniaturized HPLC can be configured with two or more syringe pumps.
515
This feature allows a continuous mobile phase flow in isocratic mode or performing
516
gradient mode with a finite volume of solvent [18,102].
517
A recent trend to achieve precise miniaturized flow rates is the use of
518
electroosmotic pumps (EOPs) associated with a chip-based column. The mobile phase
519
is pumped through the miniaturized column using an electroosmotic flow (EOF)
520
obtained under specific voltages. Although EOPs are pulseless, show low dwell
21
521
volume and small size, they have some limitations, including non-reproducible
522
elution gradient and incompatibility with a high percentage of organic solvent in the
523
mobile phase [13,146]. Most applications of EOPs are performed in “lab-on-chip” and
524
portable LC systems [69]. As an example, Figure 4 illustrates a battery-operated
525
electroosmotic pump developed by Ishida et al. [147] to work in a portable
526
miniaturized LC system. The authors highlight the cheap battery-based module
527
designed for the pumping system, which represents an interesting approach to use
528
EOPs without expensive power supplies.
529 530
FIGURE 4
531 532
2.2 Injector and connectors
533
The injectors must have low void volume, minimal flow disturbance, and
534
precision to guarantee maximum separation performance [13,148]. Sometimes due to
535
the down-scaling in miniaturized LC, an injection valve with an internal loop ranging
536
from 4 to 60 nL is recommended to avoid column overloading. Unlike the external
537
loop configuration, in this approach to modify the internal loop volume is necessary
538
to replace the entire valve. Therefore, an analytical strategy to increase the injection
539
sample volume using an external loop valve is the on-column focusing or column
540
switching approaches. The first strategy is based on the retention of the target
541
compounds in the inlet region of the analytical column with posterior elution in a
542
narrow band by an elution gradient [18,102]. Conversely, in the column switching
543
mode, a multidimensional setup consisting of an electrically assisted six-port valve is
544
usually used to pre-concentrate the compounds before the elution inside the analytical
545
column. 22
546
The on-column focusing has the advantage of no commutation valve or
547
additional pump to perform the analysis. However, the time for loading the sample
548
volume is dependent on the analysis flow rate. On the other hand, the column
549
switching mode requires an additional pump and commutation valve for analysis, but
550
the loading sample step is faster due to the low backpressure of the trap column
551
[19,102]. A recent trend in nano-scale separation covers the chip-based
552
chromatography [69]. The integration between the injection port and a chip-column
553
drastically reduces the extra-column void volume. Several manufacturers have
554
already commercialized chromatographic systems integrated with a chip-based
555
platform [13]. Figure 5 illustrates an onboard LC system developed by Li et al. [148].
556
An electrically assisted injection valve was developed using fused silica capillaries as
557
an external injection loop resulting in a remarkable miniaturized module. This lab-
558
made strategy favors the loop replacement as well as can enhance the portability of
559
the miniaturized LC systems, as highlighted by the authors.
560 561
FIGURE 5
562 563
In miniaturized LC, the extra-column dispersion must be attenuated as much
564
as possible since it strongly influences the chromatographic band broadening [149].
565
Therefore, these systems usually require tubing and fittings with void volume and
566
reduced inner diameter (from 25 to 75 µm c.a.). However, in this microscale, the
567
system backpressure is very high, increasing the risk of clogging. Besides, if the
568
connections are not fitted well, mobile phase leakage or the formation of void volume
569
may occur [149,150].
570
23
571
2.3 Oven
572
Although selectivity in LC can be modified through several parameters (such
573
as stationary phase, mobile phase composition, pH, and nature of the organic solvent),
574
the temperature has been neglected as a parameter of selectivity control. Most
575
commercial devices operate up to 100 ºC under isothermal conditions to ensure the
576
analyte retention time repeatability [102]. Several studies have been shown the
577
potential of high temperature and temperature programming (or temperature gradient)
578
in capillary and nano-LC [151–154].
579
The use of temperature programming to adjust the separation of the analytes
580
may be advantageous when the detection system does not allow mobile phase
581
gradient elution. Further, no organic solvent in the mobile phase composition makes it
582
possible to use UV-Vis, FID, and NMR detectors [155–157].
583
Performing a high-temperature analysis may cause band broadening or
584
fluctuation on the detector signal due to temperature variations. To overcome these
585
problems, a mobile phase preheating and eluent cooling devices, before and after the
586
analytical column, respectively, are implemented [158].
587 588
2.4 Detectors
589
In order to maximize the detectability, resolution, and efficiency, the detectors
590
must be downscaled. For example, the UV-Vis absorption detector has the cell
591
volume reduced to 2 - 50 nL. Unfortunately, according to the Lambert-Beer law, the
592
reduction of the optical pathway diminishes the absorption of the analytes and
593
compromises the detectability [13]. Other techniques such as light-emitting diodes
594
(LEDs), laser-induced fluorescence (LIF), and electrochemical detection (ECD) have
595
been used in the capillary, nano, or chip-based LC [159,160]. As a drawback, 24
596
inadequate qualitative information about the target compounds is obtained. However,
597
recent studies report size-reduced detectors capable of maintaining good signal
598
response representing a promising alternative to use in portable miniaturized LC
599
[142,144,161]. Figure 6 depicts an LED-UV absorption detector developed by Xie et
600
al. [142]. It can be seen that instruments with reduced dimensions enhance their
601
compatibility with portable LC-systems.
602 603
FIGURE 6
604 605
Following this trend, a portable miniaturized LC designed for “in-field”
606
measurements was reported by Li et al. [161] using an LED-based detector, as shown
607
in Figure 7.
608 609
FIGURE 7
610 611
Although the mass spectrometer is considered as the most expensive detector
612
for LC, it presents good selectivity, detectability, and can generate additional
613
chemical structural information. The MS or tandem MS can confirm the chemical
614
identity of target analytes based on their molecular mass and specific ion fragments.
615
Due to these intrinsic characteristics, several reports focusing on projects aiming to
616
miniaturize mass spectrometry begun to spring up over the past decade, in which
617
valuable reviews about this subject have been published [116,162–164]. The main
618
goal herein is to bring a discussion about the recent advancements in portable LC-MS
619
systems. Some aspects must be considered when developing reliable and suitable MS
620
portable
instruments.
Firstly,
it
must
ensure
the
minimal
acceptable 25
621
sensitivity/specificity expected to a mass spectrometry analysis. Moreover, to be
622
portable, these systems have to be reduced in size and weight, condensing all the
623
electronic parts into a fieldable platform operated from a battery power [163]. For "in-
624
field" analysis, the sample must be efficiently ionized (similar to what happens in a
625
benchtop system) and transported to the mass analyzer under vacuum conditions
626
[162]. For this purpose, several ionization modes and interfaces to cope with these
627
critical demands have been developed [163,165–169].
628
The ambient ionization (AI) emerged as a promising ionization mode to be
629
used in portable instruments once it requires a minimum sample preparation step. Due
630
to its simplicity, it allows a fast ionization process representing a useful way for high
631
throughput “in-field” analysis. Several different ionization modes were proposed
632
predicated on AI, including direct analysis in real-time (DART), desorption
633
electrospray ionization (DESI), extractive electrospray ionization (EESI), laser
634
ablation electrospray ionization (LAESI), plasma-induced, paper spray ionization,
635
among others [73,170–176]. Although most of these AI-based instruments are
636
currently used without chromatography coupling, portable LC-MS based on these
637
approaches can emerge soon since the two correlated areas have been reporting
638
remarkable advancements towards miniaturized systems. Apart from the applications
639
based on AI techniques, interfaces designed to become the traditional ionization
640
process (ESI, EI, APPCI, for instance) more feasible in miniaturized instruments have
641
also been reported [163,165,166,169]. As a result, mass spectrometry is becoming a
642
more universal and accessible technique in miniaturized scale.
643
Among the atmospheric pressure ionization methods, the electrospray is
644
currently the most popular due to the broad mass range, variety of compound class,
645
and the possibility to generate ions with multiple charges [177]. Moreover, the flow
26
646
rate reduction to the order of microliter or nanoliter per minute results in the
647
formation of submicrometer droplets, generating a maximal surface-area-to-volume
648
ratio of column effluent. As a result, the micro/nanospray generates an improvement
649
in analytes ionization and signal-to-noise response. Furthermore, under a miniaturized
650
scale, the ESI aerosol plume generated is in the same dimensional scale of MS inlet.
651
This feature promotes an increase in method sensitivity [178,179]. The sensitivity and
652
repeatability of ESI analysis depend on the spray quality, the tip geometry, and the id.
653
of the spray tubing. For chip-based columns, a direct nanospray tip from the column
654
to the ionization source has been used to avoid any extra band broadening, improving
655
the sensitivity [19,177]. Another advantage of the low flow rate is the possibility of
656
using an electron ionization source (EI). As a result, a higher degree of fragmentation
657
occurs, and an MS spectrum is generated with a single stage of MS analyzer
658
[127,178].
659
In the past few years, several commercial and noncommercial miniaturized
660
instruments have been reported, such as ion-trap systems (linear, rectilinear, 3D,
661
cylindrical, and others), quadrupole, time-of-flight, among others [75,162,168,180–
662
183]. The development of miniaturized or portable LC-MS systems can represent a
663
significant achievement for the "in-field" analysis of forensic, environmental, food,
664
medicine, military, and public interest samples [75,163,176]. Moreover, the coupling
665
to LC can become the miniaturized MS more sensitive by decreasing the signal to
666
noise ratio while increasing the sample cleanup resulting in limits of quantification
667
similar to the benchtop MS instruments reinforcing the trend towards full
668
miniaturized systems.
27
669
3. Miniaturized LC applications
670
In the last years, the use of miniaturized liquid chromatography has increased
671
in analytical chemistry. It has been applied in several areas, including environmental,
672
biological, food, omics, among others. The biological niche stands out because one of
673
the advantages of miniaturized liquid chromatography is the low volume of samples
674
required, a fact relevant to this field.
675
In this review, we selected and briefly discussed some recent capillary and
676
nano-LC applications highlighting their advantages and drawbacks as well as the
677
future trends on using this approach in the analysis of complex matrices. Although
678
omic sciences are considered one of the most applied areas in miniaturized LC we
679
tried to gather the applications over the small molecule analysis. However, interesting
680
studies describing the use of miniaturized liquid chromatography, including some
681
over omic sciences, were carefully selected to demonstrate the growth of this field in
682
several applications as following [184–188]
683 684
3.1 Biological samples
685
So far, bioanalytical chemistry is one of the most explored fields in the
686
miniaturized modes of LC. Several recent works analyzing biological samples have
687
been reported [189–198]. In general, capillary and nano-LC shows high peak
688
resolution, which is an essential parameter in cases like metabolomics and
689
proteomics, for instance. Compared to traditional HPLC, the miniaturized systems,
690
when coupled to MS, are more sensitive, improving the metabolite profile or
691
fingerprinting, allowing to quantify more compounds.
692
Due to the lower volume of sample commonly required the miniaturized LC
693
are showing great potential to decrease evasiveness of some analytical methods, 28
694
which is very interesting for medical applications. In cases like exhaled air and breath
695
condensate analysis used to identify respiratory diseases, the nanoLC was
696
successfully applied to identify 119 proteins and 164 metabolites, only requiring 2 µL
697
of samples collected from intubated newborns [189]. Other exciting cases when
698
nanoLC is gaining attention are fields with low quantities of available cells such as
699
stem cells, tumor cells, and primary cells from tissues [190]. In these studies, the
700
capacity to perform quantitative analyses in a reduced number of cells can save time
701
and money as well as allow to perform more replicate analyses, which could improve
702
the overall experiment reliability. Furthermore, the high sensitivity of nanoLC-MS
703
was successfully used to monitor disturbance on urine profile to identify potential
704
biomarkers of diseases as well as collateral effects of medical treatments [191]. Due
705
to the sensitive and resolution obtained, a well-informative chromatogram containing
706
metabolic information can be generated. As an example, urine from HIV-patients
707
submitted to combination antiretroviral therapy (cART) is analyzed by nanoLC,
708
allowing to detect metabolites or parent compounds from the applied cART, which
709
can be related to significant reductions in several endogenous compounds such as bile
710
acids, lipids, nucleosides, and other analytes. This kind of disturbance, when
711
compared to healthy individuals, reveals the possibility to identify potential disease
712
biomarkers applying these highly sensitive analytical methods (nanoLC-MS, for
713
instance) in omic sciences [191]. In addition to the potential already showed, another
714
new strategy to improve miniaturized LC-MS sensitivity is the use of a sample
715
preparation method to pre-concentrate the compounds from the complex biological
716
matrices. This approach is beneficial when a full range of metabolites must be
717
detected. In recent work, Chetwynd et al. [192] had compared the analysis of neat or
718
diluted urine with the SPE-pre concentrate samples, which revealed an enhanced
29
719
metabolic profile when the last case was applied. This approach allowed the authors
720
to detect additional metabolites (bile acids, pharmaceuticals, and markers of lifestyle)
721
without substantial losses of the metabolites observed for neat or diluted urine, which
722
reinforces the importance of developed also miniaturized sample preparation methods
723
compatible to cap and nanoLC-MS.
724
Guan et al. [193] investigated intact proteins for online proteomic analysis
725
using capillary liquid chromatography. The authors developed different monolithic
726
trapping columns to extract four mouse liver proteins using the thin-layer sol-gel
727
method. The methodology developed demonstrated that the columns present high
728
efficiencies to proteomics analysis using a miniaturized liquid chromatography
729
equipment couple to a multi-wave UV detector with an 80-nL flow cell.
730
Another work using nano liquid chromatography and mass spectrometry for
731
proteomics analysis was developed by Delport et al. [194]. The authors compared
732
nanochip columns with traditional LC columns using proteomics extracts from
733
atheroma plaques. The authors concluded that with the advances in miniaturized
734
liquid chromatography, it was possible to improve mass-spectrometry sensitive,
735
selectivity, resolution, and consequently bring interesting results to the area and
736
increase the technique application field.
737
A method using capillary liquid chromatography for the determination of
738
seven antidepressants in just a drop of human blood was developed by Murtada et al.
739
[195]. The miniaturized analytical method enabled the separation and detection of
740
seven analytes in less than 20 minutes. Besides that, the limits of detection, which
741
ranged from 0.018 to 0.038 µg mL-1 demonstrated high analytical sensitivity when
742
compared with a conventional liquid chromatography analysis. One disadvantage of
743
this method is the online sample preparation approach utilized by the authors, once an
30
744
online extraction combined with capillary liquid chromatography would further
745
improve the sensitivity, precision, and accuracy of the developed method.
746
Wu et al. [196] coupled a capillary liquid chromatography with a tandem mass
747
spectrometer for analyzing 7-aminoflunitrazepam in human urine samples. The
748
authors used a simple liquid-liquid extraction (LLE) procedure as the sample
749
preparation step and a monolithic column for capillary analysis. When compared with
750
conventional liquid chromatography, the cLC presented several advantages as less
751
solvent consumption, development of methods to reduce analysis time, and reduced
752
sample volume. As a function of the cLC characteristics and employing a monolithic
753
column (15 cm length and 250 µm i.d.), it was possible to perform more than 200
754
injections of urine samples without carryover or changes in the efficiency of
755
separation.
756
Another work that presented satisfactory results using capillary liquid
757
chromatography coupled to mass spectrometry was reported by Qi et al. [197] to
758
confirm possible RNA modifications in a complex matrix (human blood).
759
Simultaneous quantification of two compounds (m6A and 5-mC) was performed with
760
detection limits of 0.06 and 0.10 fmol, respectively, achieved using just 0.5 ng of the
761
RNA sample. These findings corroborate that miniaturized liquid chromatography
762
coupled with mass spectrometry is an analytical technique that achieves high
763
sensitivity, even using a small amount of sample.
764
Chen et al. [198] developed an ecofriendly analytical method using capillary
765
liquid chromatography. In this work, it can be seen that miniaturized liquid
766
chromatography can significantly assist in determining the presence of substances in
767
the human body without requiring large amounts of samples. The authors determined
768
glutathione (GSH) and glutathione disulfide (GSSG) in biomatrix samples
31
769
(erythrocytes, HaCaT cells, BALB/3T3 cells, and 3T3-L1 fibroblasts) and human red
770
blood cells (RBCs) using just 10 µL of biomatrix samples or 1.5 µL human RBCs.
771
Moreover, due to the high efficiency of a derivatization step together with
772
miniaturized liquid chromatography, the method presented 750-fold higher sensitivity
773
when compared with other methods. This approach is currently being evaluated in a
774
patent application in the United States of America.
775
An online system employing capillary liquid chromatography has been
776
successfully described by Hakobyan et al. [92]. These authors determined meropenem
777
antibiotic in endotracheal tubes in order to estimate the penetration capability into the
778
biofilm and the treatment efficacy using in-tube solid-phase microextraction coupled
779
to capillary liquid chromatography fitted with DAD detector. The online system as a
780
sensitive tool to determine antimicrobials in invasive medical devices presented
781
adequate detection and quantification, in the order of 0.003 and 0.01 µg mL-1,
782
respectively.
783 784
Table 3 summarizes some of the miniaturized liquid chromatography recent applications to the analysis of biological matrices.
785 786
TABLE 3
787 788
Undoubtedly, miniaturized LC-MS have gained a relevant position among the
789
techniques used to perform biological or biomedical analysis. The remarkable gains
790
of sensitive and chromatographic resolution have been allowing us to reach higher
791
levels of detectability using low volumes of samples. In addition to the time and
792
money saved due to the reduced volume of samples and reagents needed, there is the
793
possibility to realize a high assessment of the patient's health from well-informative
32
794
chromatograms obtained of evasiveness samples such as urine instead of other
795
biological fluids. This fact stands out as one of the most important features that are
796
boosting the employment of miniaturized LC-MS in the biological field. Therefore,
797
the combination of these two powerful techniques to improve bioanalytical surveys
798
over-identification of biomarkers in the early stage of several diseases as well as
799
monitoring patient conditions stands out as a potential area for the future of practical
800
miniaturized LC-MS applications.
801 802
3.2 Food research and quality
803
Food analysis using miniaturized LC is an interesting combination to monitor
804
residues and contaminants at low concentration levels as well as to perform studies
805
about the human food dietaries and its effects on metabolism. It is widely known that
806
several natural foods have positive effects on human health, such as olive oil, fruits,
807
juices, rosemary flowers, and salvia [199–203]. For this reason, it is crucial to study
808
how their intake can affect our metabolism; thus, modern analytical methods have
809
been developed reporting good results so far [203–208]. As an example, researches
810
focused on the influence of olive oil and rosemary flower intake by humans are
811
suggesting new strategies to combat potential carcinogenic cells [205,206,208]. In this
812
context, miniaturized LC-MS arises as a well-suited tool mainly due to the lower
813
volume of the sample required, which is an interesting feature when cultures of
814
carcinogenic or stem cells are investigated, for instance. Further, miniaturized LC can
815
be applied to monitor food safety and quality to control authenticity, origin, and to
816
evaluate nutritional and toxicological characteristics of food-based products through
817
the well-informative chromatograms [209,210].
33
818
Apart from the researchers focused on foodomics, miniaturized LC has also
819
been used to analyze residues of veterinary drugs, pesticides, mycotoxins, and other
820
toxic analytes in several food samples such as fruits, vegetables, juices, alcoholic
821
beverages, milk, honey, nuts, among others. Tejada-Casado et al. [211] separated
822
sixteen benzimidazoles and metabolites in milk samples with proper resolution in less
823
than 32 minutes using capillary liquid chromatography. Compared with conventional
824
liquid chromatography, the proposed method presents lower limits of detection and
825
solvent consumption being considered a green and useful method for routine analysis.
826
Miniaturized liquid chromatography combined with MS allows the
827
achievement of better sensitivity and selectivity and in many cases, can even reduce
828
the matrix effect of some complex samples. Alcántara-Durán et al. [212] employed a
829
nanoflow liquid chromatography coupled to high-resolution mass spectrometry to
830
analyze 16 multiclass mycotoxins in less than seventeen minutes. Different edible
831
nuts samples such as pistachio, peanut, and almond were analyzed with nano LC-
832
HRMS, allowing them to determinate the analytes of interest at very low
833
concentrations.
834
Alcántara-Durán et al. [213] developed another study using a miniaturized
835
approach to analyze a suite of 87 veterinary drug residues in honey, veal muscle, egg,
836
and milk samples. A particular feature to be highlighted in this work is the use of high
837
dilution factors of up to 1:100 (sample/solvent) that was possible due to the increased
838
sensitivity provided by the use of nanoflow LC. Besides that, due to the high dilution
839
factor, the matrix effects were insignificant for all compounds.
840
Moreno-González et al. [214] reported work using nanoflow liquid
841
chromatography with high-resolution mass spectrometry in a Q-Exactive Orbitrap
842
equipment. In this publication, an interesting detail was that the authors analyzed 64
34
843
representative multiclass pesticides in less than 35 minutes with limits of
844
quantification below 0.01 µg kg-1 for 80% of the analytes. Even analyzing five
845
complex and quite distinct matrices (tomato, baby food, orange, fruit-based jam, and
846
olive oil) it was possible to obtain a significant reduction in matrix effects (negligible
847
for 90% of compounds using a 1:20 dilution) with the high sample dilution factors
848
that can be configured with the nanoflow liquid chromatography approach.
849
A capillary liquid chromatography-UV detection was successfully applied to
850
the determination of parabens in oyster and soy sauces using two different sample
851
preparation microextraction methods (VA-DLLME-SFO and SA-CPE) by Chen et al.
852
[215]. This environmentally friendly micro method was applied to the analysis of
853
different food products. The method presented some advantages such as reduced
854
solvent consumption, high sensitivity with limits of detection ranged from 10 to 30 ng
855
mL-1, calibration range of 0.1-10 µg L-1, and excellent linearity (r2 = 0.998).
856 857
Table 4 summarizes some miniaturized liquid chromatography recent applications to the analysis of food matrices.
858 859
TABLE 4
860 861
3.3 Environmental analysis
862
Environmental concerning the presence of pollutants in aquatic and terrestrial
863
ecosystems is a subject of constant researches nowadays [216,217]. These compounds
864
can be spread through the environment contaminating the living organisms, which
865
may affect their health [218]. So far, liquid chromatography showed satisfactory
866
results in most common cases like monitoring pharmaceutical drugs, cosmetics,
867
preservatives, and related analytes. However, the modern analytical techniques as 35
868
miniaturized LC coupled to MS (in most cases), arises as promising tools when more
869
sensitive methods are required to detect several toxic compounds at trace levels. Also,
870
the high detectability of capillary or nano-LC-MS is improving metabolomic
871
researches focused on the interactions between these organisms and their potentially
872
contaminated ecosystems [219]. Considering this outlook, modern analytical methods
873
to cope with small masses samples (i.e., insects, aquatic organisms) or to detect
874
several compounds at trace levels can be improved when miniaturized LC is used.
875
Other positive aspects to consider in these cases are the low injection volume and
876
flow rate usually employed. As interesting examples, analysis of the metabolomic
877
profile of fish and benthic invertebrates are carried out to investigate the influence of
878
wastewater treatment plant effluents (WWTP) over them [218,220]. In these cases,
879
due to the organism’s exposure by the contaminants, it was observed changings on
880
endogenous biomarkers, which leads to metabolite disruption affecting their
881
physiological system or even causing death. For these reasons, the use of miniaturized
882
LC allied to a suitable sample preparation can improve the metabolomic profile
883
observed in the chromatograms being useful to complex environmental analysis such
884
as ecotoxicological studies in living organisms [221]. Therefore, miniaturized LC is
885
open to new possibilities on targeted or non-targeted metabolomic studies to identify
886
less abundant components in environmental samples [222].
887
As previously shown in 1.3, a particular approach in cLC and nano-LC is the
888
possibility of using column switching systems. The online configuration employing
889
miniaturized liquid chromatographic has been a widely used approach in several
890
applications, particularly in the environmental analysis area. These online systems
891
present better sensitivity and improved environmental analysis performance once the
36
892
sample preparation step is reduced since injection, extraction, preconcentration,
893
separation, and detection are carried out in a single step.
894
Besides that, miniaturized liquid chromatography in the online configuration
895
allows a higher sample injection volume making it possible to concentrate the
896
analytes of interest in the extraction column (first dimension), thus increasing the
897
analytical sensitivity of the miniaturized online method.
898
Some recent reports show satisfactory results utilizing this miniaturized online
899
coupling, such as the one described by Serra-Mora et al. [93]. The authors compared
900
the performance of in-tube solid-phase microextraction coupled with both
901
miniaturized LC techniques to determine triazines and their degradation products in
902
water and recovered struvite samples. In this case, both systems were employed in a
903
similar configuration, changing only the flow rate, injection volume, and columns
904
dimensions (two columns for cLC and one for Nano-LC). The results showed that the
905
IT-SPME-nanoLC system presented higher sensitivity while showing a higher
906
performance when compared with IT-SPME-cLC. The column switching approach in
907
miniaturized liquid chromatography is one of the main promising approaches in
908
current analytical separation science. It allows a further reduction in the analysis time
909
by using the online sample preparation approach, a decrease in the consumption of
910
toxic solvents, and more efficient coupling to the mass spectrometer.
911
Another recent work that combined online IT-SPME with nano LC-DAD for
912
environmental analysis was reported by González-Fuenzalida et al. [223]. The authors
913
employed several capillaries with different sorbent phases containing nanomaterials to
914
determine diclofenac in river water samples. The results showed good extraction
915
efficiency, near 80%, that can be considered a high value because it involves online
916
miniaturized sample preparation and a miniaturized analytical technique.
37
917
Pla-Tolós et al. [224] developed a sustainable online method using capillary
918
liquid chromatography with diode array detection for quantifying two antifouling
919
agents (irgarol-1051 and diuron) in less than ten minutes. The authors evaluated water
920
samples from different ports or marinas, and the results showed that the analytes were
921
detected in concentrations below the LOQs, demonstrating a successful analytical
922
performance. An interesting and innovative approach utilized in this work was the
923
determination of the carbon footprint for the in-tube SPME CapLC-DAD method,
924
which was compared with previous reports demonstrating that this work presented the
925
lowest carbon footprint value (1.10 kg CO2). An additional advantage of the
926
employed miniaturized systems was the short analysis time, a little amount of sample,
927
and satisfactory precision (RSD < 3.5%).
928
Another environmentally friendly method was developed by Moliner-Martínez
929
et al. [225] using capillary liquid chromatography in a multidimensional approach.
930
Three different extractive coatings (commercial GC columns) have been evaluated in
931
the online system for the determination of triazines and degradation products in water
932
samples. The combination of large injection volume with capillary LC usually
933
improve the preconcentration of the analytes and consequently achieve higher
934
sensitivity. A limitation noticed in this work is the reduced sensitivity obtained for the
935
highly polar degradation products, which cannot be increased through the loading of
936
larger sample volume.
937
A different approach for automated online SPE nano LC-HRMS with peak
938
refocusing was demonstrated by Stravs et al. [226] during the analysis of
939
micropollutants in surface water, Microcystis aeruginosa cell lysate and spent
940
Microcystis growth medium samples. In this method only a very small fraction of the
941
sample was required to analyze 41 analytes (88 µL for water and 26 µg for biological
38
942
samples) in order to obtain low detection limits (ng g-1 or ng L-1) with lower
943
consumption of samples and solvents (flow rate ranging from 120 to 900 µL min-1).
944 945
Table 5 summarizes some miniaturized liquid chromatography recent applications to the analysis of environmental samples.
946 947
TABLE 5
948 949
3.4 Other analytical applications
950
Capillary and nano liquid chromatography have shown significant advances in
951
biological, food, environmental, and other fields such as pharmaceutical and cosmetic
952
areas. Besides that, miniaturized liquid chromatography has made possible the union
953
of analytical chemistry with green chemistry through faster and more efficient
954
analysis of complex samples with a considerable reduction in the volume of toxic
955
solvents and samples used.
956
Xu et al. [227] demonstrated this assumption by evaluating the
957
enantioseparation of amino acids by nano liquid chromatography. The authors
958
developed an O-[2-(methacryloyloxy)-ethylcarbamoyl]-10,11-dihydroquinidine-silica
959
hybrid monolithic column combined good enantioresolution and efficiency with
960
shorter analysis time. In this case, with the use of a nano-LC system, it was possible
961
to achieve a baseline enantioseparation of 44 analytes in an MQD-silica hybrid
962
monolithic column within 100 µm i.d. capillary. The same research group [228] also
963
developed another work describing the fabrication of vancomycin functionalized
964
polymer as a chiral monolithic stationary phase to be used in nano liquid
965
chromatography for baseline separation of selected enantiomers. In this report, it is
966
possible to realize the importance of miniaturized liquid chromatography in the 39
967
different parameters evaluated (such as permeability, resolution, efficiency, retention
968
time, pressure, and others) employing the analytical columns developed in the
969
laboratory and consequently ensuring a satisfactory column performance.
970
Reversed-phase capillary liquid chromatography was applied by Salih et al.
971
[229] using a polymethacrylate monolithic home-made capillary column (200 mm
972
length x 100 µm i.d.). It is possible to highlight in this work that the analytes of
973
interest (paracetamol and chlorzoxazone) were separated in less than seven minutes of
974
analysis with a chromatographic resolution of 2.37 and using a 3 nL in the nano-UV
975
cell. Besides that, the method can be considered a green approach, once it was
976
possible to reduce the environmental impact and analytical costs using a monolithic
977
column in a miniaturized liquid chromatographic format.
978
Another application using capillary liquid chromatography was reported by
979
Ma et al. [230]. The authors developed and evaluated several hybrid monolithic
980
columns via photo-initiated thiol-yne polymerization, and the best column was tested
981
to separate BSA tryptic digest by cLC-MS/MS. With this configuration, it was
982
possible to obtain satisfactory separation and high column efficiency (76.000 plates
983
per meter).
984
In an article described by Rogeberg et al. [231], the authors used a porous
985
layer open tubular column and miniaturized LC instrumentation for the separation of
986
intact proteins. The miniaturized analytical instrumentation employed a flow rate of
987
20 nL min-1, 5 nL of injection volume, and a PLOT analytical column with 3 m length
988
x 10 µm i.d. dimensions. This miniaturized combination provided good repeatability,
989
low carryover, and narrow peaks. In less than 32 minutes, the separation of intact
990
proteins in skimmed milk was achieved, thus demonstrating good efficiency of the
991
open tubular column.
40
992
Yang et al. [54,55] developed two works using narrow open tubular columns
993
for liquid chromatography to evaluate the separation of some analytes with an elution
994
pressure of less than 50 bar. The authors utilized a lab-made miniaturized liquid
995
chromatography to test the OT columns and obtained high efficiencies and sharp
996
peaks.
997
The recent instrumental advances in miniaturized LC allowed the application
998
of the technique in several areas of social interest, such as the detection of different
999
compounds in the biological niche, and analysis of contaminants in the environment
1000
and food. More recently, the spread out of the miniaturized instrumentation has
1001
allowed a better evaluation of new analytical columns format and stationary phases
1002
where some reports already show promising results mainly using packed columns but
1003
yet with limited attention to open tubular columns.
1004 1005
4. Concluding remarks and future trends
1006
Nowadays, analytical chemistry stands for developments over fully automated
1007
and miniaturized methods since they are related to more efficient and greener
1008
outcomes. Likewise, the liquid chromatography considered one of the most critical
1009
tools for target compounds determination follows this same trend. Since the ending of
1010
the twentieth century, several works are being reported in the literature, which might
1011
be ushering a new era of miniaturized liquid chromatography [14,15,20,53]. This
1012
scale reduction from traditional HPLC to UHPLC, capillary, or nano chromatography,
1013
have many general qualities related such as reduction on solvent consumption and
1014
consequently waste generation, gains on chromatographic efficiency, enhancement on
1015
the analytical signal, the capacity to produce portable LC systems for “in-field”
1016
analysis, the use of temperature programming to improve efficiency and analysis 41
1017
time, among others. The miniaturized liquid chromatography is characterized by
1018
decreases in the physical dimensions of the columns (i.d. and length), stationary phase
1019
thickness, particle diameter, and the development of dedicated instrumentation.
1020
Notwithstanding all these advantages, it has some drawbacks such as time-consuming
1021
analysis, not frequently employed in routine methods, difficulty in identifying and
1022
stopping leaks in the equipment, clogging of tubing and fittings, expensive
1023
consumables, and few commercially available instruments.
1024
Many studies demonstrating satisfactory results are reporting recent advances
1025
in miniaturized analytical columns, but a further development to be still considered is
1026
the reduction of particle diameter, since the majority of the works use particles of 5,
1027
3.5 and 3 µm, yet [31–34,37–42,44,46–52]. As remarkable examples are the
1028
production of packed or monolithic capillary and nanocolumns containing hybrid
1029
stationary phase to work in reverse and normal phase; the rising of chip-based
1030
approaches to contribute for portability and consequently in-field analysis;
1031
improvements and new developments on open tubular columns to application in
1032
omics science, medicine, biomedicine, and small molecules since it seems to be a
1033
highly efficient future LC mode [44,47–52,54,55,58–60]. Moreover, in the last
1034
decade, the instrumental evolving was a critical achievement to improve the
1035
miniaturized liquid chromatography technique. Different lab-made platforms have
1036
been developed from well-designed pumps, injectors, valves, and detectors to fully
1037
portable LC systems. Detectors based on UV-light emission are rising as a practical
1038
alternative due to its capacity to be reduced in size and weight, representing a
1039
promising couple to the above-mentioned portable LC systems [142,144,159–161] —
1040
otherwise, mass spectrometry still representing the most effective detector for
1041
miniaturized LC. Despite the improvements in the well-established ESI and APCI
42
1042
sources, recent studies are evaluating the use of EI as a source for LC owing its
1043
known qualities: a hard ionization process, fragmentation pattern, decreasing on
1044
matrix effect, and so on [127,178,179]. Besides, efforts towards MS miniaturization
1045
are also being reported based on specific interfaces, and improvements on ionization
1046
stand out ambient pressure ionization and adaptation of the traditional ESI, APCI, and
1047
EI sources [163,165,166,169][73,170–176].
1048
Thus, total automation of the analytical system emerges as the current focus
1049
embracing modern sample preparation methods, miniaturized LC and MS,
1050
respectively. This approach is considered suitable for reduced sample volumes (from
1051
nano to picolitres), which is excellent in areas such as medicine, forensic, and chiral
1052
separations. In this way, an increasing interest over miniaturized LC-MS employment
1053
to a large number of distinct analytical purposes is of utmost importance as an
1054
intended goal in the coming years.
1055 1056
Acknowledgments
1057
This research project was financed in part by the Coordenação de
1058
Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001.
1059
The authors are grateful to FAPESP (Grants 2017/02147-0, 2015/15462-5, and
1060
2014/07347-9) and CNPq (307293/2014-9) for the financial support provided.
1061 1062
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1063
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1944 1945
Figure Captions
1946 1947
Figure 1 - Schematic drawing illustrating the main liquid chromatography modes
1948
discussed in this work emphasizing its features: tubing scale and applied materials as
1949
well as types of analytical columns.
1950 1951
Figure 2 - Publications in the last ten years related to miniaturized LC divided among
1952
the main types of capillary columns. Source: Web of Science. Used generic
1953
algorithm: (TI=("type of column*") AND TI=("capillary liquid chromatography" OR "nano
1954
liquid chromatography" OR "micro liquid chromatography" OR "miniaturized liquid
1955
chromatography")) AND Document types: (Article)
1956 1957
Figure 3 - A plot showing ESI sampling efficiency vs.mobile phase flow rate
1958
illustrating the advantage of working in a capillary-LC and nano-LC scale to
1959
maximize compatibility with mass spectrometry detection. Reprinted from Ref.
1960
[107,108] Copyright with kind permission from John Wiley and Sons.
1961 1962
Figure 4 - A portable miniaturized lab-made LC system (a) photography of the
1963
complete system; (b) representative diagram of the battery-based electroosmotic
1964
pumping system. Reprinted from Ref. [147] Copyright with kind permission from
1965
Elsevier.
1966 79
1967
Figure 5 - An integrated miniaturized LC system (a) the electrically controlled
1968
injection valve; (b) the wholly integrated miniaturized LC system. Reprinted from
1969
Ref. [148] Copyright with kind permission from Elsevier.
1970 1971
Figure 6 - Images of an LED-UV absorption detector (a) schematic drawing; (b) Dual
1972
approach of LED-UV absorption detector; (c) Actual detector photograph and (d)
1973
Comparative scheme to bring an idea about the reduced dimensions of the proposed
1974
detector hardware. Reprinted from Ref. [142] Copyright with kind permission from
1975
Elsevier.
1976 1977
Figure 7 - Image of a portable LC system with LED-based micro detector (a)
1978
schematic drawing; (b) photography of the miniaturized system. Reprinted from Ref.
1979
[161] Copyright with kind permission from Elsevier.
1980 1981
Figure 8 - Representative illustration of a chip-based platform used in miniaturized
1982
liquid chromatography separations. Reprinted from Ref. [73] Copyright with kind
1983
permission from Elsevier.
1984
80
Table 1 - Liquid chromatography current denominations as a function of column inner diameter
Column i.d. (mm)
Flow rate (mL min-1)
Denomination
4.6 – 3.2
2.0 – 0.5
HPLC
3.2 – 1.5
0.5 – 0.1
Microbore LC
1.5 – 0.5
0.1 – 0.01
Micro LC
0.5 – 0.15
0.01 – 0.001
Capillary LC
0.15 – 0.01
0.001 – 0.0001
Nano LC
0.05 – 0.005
< 0.0001
Open Tubular LC
Table 2 – Main types of analytical columns currently used in miniaturized liquid chromatography, including some selected features. Column types
Typical stationary phases (sp)
Applications
Packed
Alkyl-bonded (C8, C18), Phenil-hexyl, Cholesterol-hydride, amino, diol, and cyano
Food, environmental, pharmaceutical and drug analysis
Many sp available with different selectivity, plenty of chromatographic methods already published.
High backpressure rates, lesser permeable than the other column types
[30,61,65]
Monolithic
Organic- and silicabased monoliths; hybrid monoliths: MIM, ILs, nanoparticles, aptamer, and boronatebased
Chiral separations, affinity chromatography for bioanalysis, and biomolecules
High permeability, fast mass transfer, low separation time, tunable properties and simple production
Swelling possibility in organic solvents, unfavorable changes in pore structure and mechanical instability
[61–64]
Open tubular
WCOT: physically adsorbed polymeric phases and nanoparticles; PLOT: chemically bonded polymeric phases.
Scant samples: forensic, medicine, biomedicine and natural products
High chromatographic efficiency, optimal permeability, and low backpressure rates, potentially more suitable for LC-EI-MS
Low sample capacity, non-commercialized yet, less sp and production procedure available than the other column types
[46,66]
Chip-based
Alkyl-bonded (C8, C18), organic-based monoliths, polymeric pillar arrays
Separation of macromolecules, scant samples, and "in-field" analysis
Portables for "in-field" applications, fast analysis, possible to use several sp, few connections, and reduced band broadening effect
Complex manufacturing, difficult reproducibility between dispositive, lack of chemically inert materials to print the platforms
[67–70]
Main advantages
Main disadvantages
References
Table 3 - Applications of miniaturized liquid chromatography to biological matrices. Miniaturized analytical Sample technique
Compounds class
Analytical column dimensions (L x i.d. x d.p.)
Injection Flow rate volume
Capillary LC
Blood
Antidepressants
250 mm x 500 µm x 4 µm
5 µL
20 µL min-1
[117]
Capillary LC
Urine
Antidepressant
150 mm x 250 µmMC
4 µL
4 µL min-1
[118]
Capillary LC
Blood
RNA modifications ( m6A and 5mC)
300 mm x 75 µmMC
*
15 µL min-1
[119]
Capillary LC
Biomatrix samples and human red blood cells
Antioxidant
100 mm x 500 µm x 5 µm
0.5 µL
20 µL min-1
[120]
Capillary LC
Endotracheal Antimicrobial tubes
150 mm x 500 µm x 5 µm
500 µL
8 µL min-1
[108]
Capillary LC
Serum
Human transferrin
150 mm x 300 µm x 3.5 µm
0.15 µL
4 µL min-1
[135]
Nano LC
Urine
Psychoactive substances
150 mm x 75 µm x 2.6 µm
1 µL
0.7 – 1.0 µL min-1
[136]
Nano LC
Blood, plasma, serum, and urine
Protein biomarker hCG
150 mm x 75 µm x 3.0 µm
< 50 µL
0.3 µL min-1
[137]
Nano LC
Urine
Peptides
150 mm x 75 µm x 3.0 µm
*
2 µL min-1
[138]
Nano LC
Serum
Polyunsaturated 500 mm x 75 µm x 2.0 µm fatty acids
1 µL
0.15 - 0.3 µL min-1
[139]
* Not available MC
Monolithic column
Ref.
Table 4 - Applications of miniaturized liquid chromatography to food matrices. Miniaturized analytical Sample technique
Compounds class
Analytical column dimensions (L x i.d. x d.p.)
Injection Flow rate volume
Capillary LC
Milk
Anthelmintics
150 mm x 500 µm x 5.0 µm
6 µL
9 µL min-1
[121]
Capillary LC
Vegetarian oyster sauces and soy sauces
Parabens
150 mm x 500 µm x 0.5 µm
0.5 µL
15 µL min-1
[125]
Capillary LC
Wine
Herbicides
150 mm x 300 µm x 5.0 µm
3 µL
10 µL min-1
[140]
Capillary LC
Cheese
Biogenic amines
150 mm x 500 µm x 5.0 µm
1 µL
10 µL min-1
[110]
Capillary LC
Beverages
Benzodiazepines 150 mm x 300 µm x 3.5 µm
100 nL
4 µL min-1
[141]
Nano LC
Edible nuts
Mycotoxins
150 mm x 75 µm x 3.0 µm
100 nL
200 nL min-1 [122]
Pesticides
150 mm x 75 µm x 3.0 µm
1 µL
300 nL min-1 [124]
Nano LC
Honey, veal muscle, egg, and milk
Veterinary drugs
150 mm x 75 µm x 3.0 µm
1 µL
200 nL min-1 [123]
Nano LC
Egg yolk
Hormones
150 mm x 75 µm x 5.0 µm
5 µL
300 nL min-1 [142]
Nano LC
Tomato, baby food, orange, fruit-based jam, and olive oil
Ref.
Table 5 - Applications of miniaturized liquid chromatography to environmental matrices. Miniaturized analytical Sample technique
Compounds class
Analytical column dimensions (L x i.d. x d.p.)
Injection Flow rate volume
Capillary LC
Water
Antifouling agents
35 mm x 500 µm x 5.0 µm
4 mL*
20 µL min-1
[127]
Capillary LC
Water
Degradation products of di-(2-ethylhexyl) phthalate
150 mm x 200 µmMC
4 mL*
5 µL min-1
[143]
Capillary LC
Water
Herbicides
150 mm x 200 µmMC
4 mL*
5 µL min-1
[128]
Capillary LC
Water
Chloramines
150 mm x 500 µm x 5.0 µm
0.1 mL 4 mL*
3 µL min-1
[144]
Capillary and Nano LC
Water and recovered struvite
Herbicides
150 mm x 200 µmMC 150 mm x 500 µm x 5.0 µm 50 mm x 75 µm x 3.5 µm
4 mL* 500 µL
5 µL min-1 0.7 µL min-1
[109]
Nano LC
Water
Anti-inflammatory
50 mm x 75 µm x 3.5 µm
0.94 µL
0.2 µL min-1
[126]
Nano LC
Water, Microcystis aeruginosa cell lysate and spent Microcystis growth medium
Micropollutants
150 mm x 100 µm x 3.0 µm
88 µL
120 - 900 nL [129] min-1
* In these articles it was possible to combine larger injection volumes and miniaturized LC because it was used on-line systems with larger dimensions of extraction column than the analytical column MC
Monolithic column
Ref.
Highlights •
Main advantages of liquid chromatography miniaturization
•
Recent advances in the development of capillary analytical columns
•
Future trends in LC-dedicated instrumental and stationary phases
•
This review highlights different aspects of miniaturized liquid chroamography
Ana Lúcia de Toffoli graduated with a Degree in Environmental Chemistry from the “Julio de Mesquita Filho” State University of São Paulo (São José do Rio Preto, Brazil) in 2011. She received the Ph.D. degree in Analytical Chemistry in 2018 from the Institute of Chemistry of São Carlos - University of São Paulo (São Carlos, Brazil). Her main research interests are in analytical chemistry and chromatographic techniques.
Carlos Eduardo D. Nazario graduated with a Degree in chemistry in 2005 and received the Ph.D. Degree in Analytical Chemistry in 2013 from the Universidade de São Paulo (IQSC/USP, Brazil). He has been a Professor of Chemistry at the Universidade Federal de Mato Grosso do Sul (Campo Grande, Brazil), since 2015. His main research interests are in miniaturized sample preparation techniques with application in environmental, biological and food matrices.
Eduardo Sobieski Neto graduated with a Degree in analytical chemistry from the Universidade Estadual de Maringá (Maringá, Brazil) in 2016. Since 2016, he is a Ph.D. student at the Universidade Federal de Mato Grosso do Sul (Campo Grande, Brazil). His main research area of interest is environmental analytical chemistry.
Edvaldo Vasconcelos Soares Maciel graduated in 2014 with a degree in chemistry and received his MSc degree in Analytical and Inorganic Chemistry in 2017, both from University of Sao Paulo. Nowadays is a Doctoral student at University of Sao Paulo and his main research field are liquid chromatography miniaturization focuses on development of chromatographic capillary columns and subsequently application in fully automated methods for small molecules analysis.
.
.
Fernando Mauro Lanças is the leader of the Chromatography Group and full Professor at the Institute of Chemistry of the University of São Paulo at São Carlos, Brazil. He started and is Chairman of several meetings including COLACRO and SIMCRO, and is co-Chairman of WARPA. Prof. Lanças advised ca. 130 Ph.D. and Master Thesis; published more than 300 papers and 7 books. His main research interest at the moment is focused on the full miniaturization of sample preparation-chromatography-mass spectrometry and their online full automation towards the Unified Chromatography.
Declaration of interests ☐ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
S0003-2670(19)31534-X
DOI:
https://doi.org/10.1016/j.aca.2019.12.064
Reference:
ACA 237347
To appear in:
Analytica Chimica Acta
Received Date: 12 June 2019 Revised Date:
19 December 2019
Accepted Date: 20 December 2019
Please cite this article as: E.V. Soares Maciel, A. Lúcia de Toffoli, E. Sobieski, C.E. Domingues Nazário, F.M. Lanças, Miniaturized Liquid Chromatography Focusing on Analytical Columns and Mass Spectrometry: A review, Analytica Chimica Acta, https://doi.org/10.1016/j.aca.2019.12.064. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier B.V. All rights reserved.
1
Miniaturized Liquid Chromatography Focusing on
2
Analytical Columns and Mass Spectrometry: A review
3 4
Edvaldo Vasconcelos Soares Maciela, Ana Lúcia de Toffolia, Eduardo Sobieskib Neto,
5
Carlos Eduardo Domingues Nazáriob and Fernando Mauro Lançasa*
6 7
a
University of São Paulo, São Carlos, Institute of Chemistry of São Carlos, SP, Brazil
8
b
Federal University of Mato Grosso do Sul, Institute of Chemistry, Campo Grande,
9
MS, Brazil
10 11
*Corresponding author. Tel: +(55) 16 3373 9983; Fax: +(55) 16 3373 9984
12
E-mail address: [email protected] (F. M. Lanças)
13 14
Abstract
15
The technological advances achieved over the last decades boosted the
16
development of suitable benchtop platforms to work at miniaturized liquid
17
chromatography scale (capillary and nano-LC). Under the right conditions,
18
miniaturized LC can offer higher analysis efficiency resulting in superior
19
chromatographic resolution and overall sensitivity than conventional LC. Among the
20
main advantages are the reduced reagents and sample requirement, the decreasing on
21
analytical column dimensions, and consequently flow rates and the easer coupling to
22
mass spectrometry. This review describes fundamental aspects and advances over
23
miniaturized LC technology with a focus on the last decade. Therefore, relevant
24
characteristics of the most common analytical column, covering both filled (packed
25
and monolithic) and open tubular (PLOT and WCOT) columns, are herein discussed.
26
Alternatively, other modern approaches based on microchip separations or 2D 1
27
configurations aiming for the sample preparation on the first dimension, are also
28
introduced. Likewise, some positive and negative aspects of these systems over HPLC
29
are underscored. Besides, considering the necessity to developed components to work
30
at capillary or nanoscale, without significant dead-volumes, the most critical features
31
of specially designed instrumentation for benchtop instruments are briefly discussed
32
highlighting connectors, pumping, injections, oven and detection systems. Also, a
33
more detailed section is presented focused on mass spectrometry efforts towards its
34
miniaturization and how this trend can be useful working together with miniaturized
35
LC. Finally, applications of capillary and nano-LC involving bioanalytical,
36
environmental, and food methods are discussed to support the miniaturized LC as a
37
powerful and emergent separation technique for the years ahead.
38 39 40
Keywords: miniaturized; capillary liquid chromatography; instrumentation; mass
41
spectrometry, nano liquid chromatography; open tubular liquid chromatography.
42 43
Abbreviations
44
cLC - Capillary liquid chromatography; EOPs - Electroosmotic pumps; FLD -
45
Fluorescence detection; GSH - Glutathione; GSSG - Glutathione disulfide; IT-SPME
46
- In-tube solid-phase microextraction; LLE - Liquid-liquid extraction; MRM -
47
Multiple reaction monitoring; nano-LC - Nano liquid chromatography; OT-GC -
48
Open tubular gas chromatography; PLOT - Porous layer open tubular; RBCs - Red
49
blood cells; TFC - Turbo flow chromatography; WCOT - Wall coated open tubular.
50 51 2
52
Summary
53
1. INTRODUCTION
4
54
2. MINIATURIZED COLUMN TECHNOLOGY AND COUPLING TO MS
7
55
2.1 Miniaturized analytical columns
7
56
2.2 Chip-based liquid chromatography
13
57
2.3 Miniaturized systems integrating sample preparation
14
58
2.4 Coupling to mass spectrometry
16
59
2. MINIATURIZED INSTRUMENTATION
20
60
2.1 Pumps
20
61
2.2 Injector and connectors
22
62
2.3 Oven
24
63
2.4 Detectors
24
64
3. MINIATURIZED LC APPLICATIONS
28
65
3.1 Biological samples
28
66
3.2 Food research and quality
33
67
3.3 Environmental analysis
35
68
3.4 Other analytical applications
39
69
4. CONCLUDING REMARKS AND FUTURE TRENDS
41
70
ACKNOWLEDGMENTS
43
71
REFERENCES
43
72 73
FIGURE CAPTIONS
79
74 75 76 3
77
1. Introduction
78
Liquid chromatography is in constant development since its beginning in the
79
year of 1906, proposed by Mikhail Tswett [1]. During the first half of the 20th
80
century, relevant studies were conducted, leading to the development of liquid
81
chromatography (LC), followed by gas chromatography (GC) [2,3]. In the following
82
decades, chromatography would be separated into these two main categories [3]. The
83
GC advance in terms of analytical performance is credited to studies about capillary
84
columns performed by Golay et al. [4], which resulted in the development of the open
85
tubular gas chromatography (OT-GC). On the other hand, LC had a slower
86
development owing to technological limitations related to high backpressure rates
87
generated by the small solid particles packed into an analytical column. Both practical
88
and theoretical developments did not halt, which have spurred new studies, including
89
those towards the technique miniaturization.
90
As it is known, the cornerstone of miniaturized LC is predicated on gains of
91
analysis efficiency, as described by the chromatographic theory [5,6]. According to
92
van Deemter et al. [5], three terms might be held accountable for the column
93
efficiency:
94
resistance to mass transfer. A thorough discussion about these relations is performed
95
by Gritti and Guiochon [6], which is utilized to evaluate the performance of a
96
chromatographic column as a function of H ("height equivalent of a theoretical plate,"
97
or "plate height"), equation (1).
term A, eddy diffusion, term B, longitudinal diffusion, and term C,
98
H A
μ
(1) μ
99
4
100
Considering this assumption, Marcel Golay [4] later realized that replacing the
101
densely packed bed by a thin layer of stationary phase coated onto the internal column
102
wall, the efficiency increased. This finding suggests that such an approach can also be
103
utilized to prepare highly efficient columns. At the same time, it was observed that
104
column efficiency could be improved by reducing column inner diameter (i.d.) or
105
stationary phase thickness, attenuating the band broadening effects as described by
106
van Deemter's equation. Another significant contribution was made by Giddings [7]
107
by comparing LC and GC's evolving potential. Giddings has underscored the LC
108
capacity to reach higher plate numbers (N) as compared to GC (values above 105
109
times higher), which would be achieved only by downscaling the chromatographic
110
columns and, consequently, the whole analytical system. Therefore, since the 1960s,
111
researches focusing on the LC progress have been published, leading to a new LC
112
approach named High-Performance Liquid Chromatography (HPLC) [8–10] [11–13].
113
It was clear that LC should be steered towards more efficient systems,
114
including improvements in instrumental apparatus and decreasing of the analytical
115
columns’ dimensions. Therefore, after approximately forty years of reported efforts,
116
in the 1990s, several studies based on LC miniaturization allied to column
117
technological advances ushered to the creation of Ultra High-Performance Liquid
118
Chromatography (UHPLC) by MacNair et al. [14]. This LC mode has emerged to
119
corroborate in practice the theoretical aspects underscored in the literature, reflected
120
on enhanced efficiency and analysis time. The UHPLC started to gain attention after
121
experiments carried out in fused-silica capillaries down to 12 um i.d. with lengths
122
between 25 - 66 cm packed with sub 2 µm solid particles [15]. These columns were
123
applied over ultra high-pressure rates up to 20000 psi to obtain higher
124
chromatographic efficiencies at shorter analysis time. In the first UHPLC description
5
125
(1997), MacNair et al. [14] packed 1.5 µm nonporous octadecylsilane-modified silica
126
particles into a 30 µm i.d. fused silica capillary of up to 66 cm of length capable of
127
generating up to 300.000 theoretical plates. Hence, the UHPLC creation reinforced
128
the theory by practical applications, which was a differential aspect to boost the
129
studies over capillary columns, mainly in the field of packed ones. A review of the
130
early days of miniaturized LC can be found in a recent manuscript by Novotny [16].
131
Apart from the discussed advantages, a scale reduction on the analytical
132
column also brings the possibility to inject reduced sample volumes representing an
133
excellent alternative for fields with a volume-limited sample such as omics science,
134
forensic, chiral separation, and medicine, as herein discussed in the topic 3. Another
135
critical feature related to LC miniaturization is improved heat dissipation through
136
reduced id columns when compared to conventional LC, which allows the use of
137
temperature control to improve analytical performance [17,18]. Moreover, as the
138
miniaturized LC flow rates are roughly thousand times lower than in HPLC (from mL
139
min-1 scale to nL min-1), significant reductions in solvent consumption and waste
140
generation are expected as well as enhancements on sensitivity due to a more
141
concentrated analytical band [19].
142
The usual terminology for liquid chromatography spans from classical modes
143
to the miniaturized ones. In general, these nomenclatures are based on the column i.d.,
144
the nature of the stationary phase, or the typical mobile flow rate applied throughout
145
the analysis. The general term capillary liquid chromatography (cLC) is often used to
146
refer to any mode of miniaturized LC in which the analytical column possesses an i.d.
147
lower than 1 mm (capillary dimensions), whereas from these values up the technique
148
is named as conventional LC or HPLC. Although these large denominations have
6
149
been successfully applied in some cases, other LC denominations have been carried
150
out by different authors [20–23].
151
Table 1 shows a modification of the classification initially proposed by
152
Chervet et al. [22] and Vissers [23] in which the analytical column i.d. is correlated to
153
the flow rate. Today, this classification is one of the most popular and mostly used in
154
miniaturized LC.
155 156
TABLE 1
157 158
Despite the several advantages of its miniaturization, the LC practical
159
applications continue to be dominated by HPLC or UHPLC scales until the present
160
days. An important fact that can negatively contribute to this outlook was the
161
industrial sector preferences. Although the UHPLC development has its principles
162
based on capillary conditions, as shown in several reports [14,15,20], at that time, the
163
industry opted to commercialize (shorter) columns for faster separations without
164
remarkable gains on efficiency. This option was achieved by maintaining the columns
165
i.d. at the HPLC scale (~ 2.1 mm i.d.), only reducing the particle diameter down to 1.7
166
µm, which have delayed the real miniaturized LC development.
167
168
2. Miniaturized column technology and coupling to MS
169
2.1 Miniaturized analytical columns
170
As our focus is on miniaturized LC, a brief discussion about the stationary
171
phases and how they are inserted or generated inside the analytical columns will be
172
presented.
7
173
Over the last decades, there was remarkable progress over new stationary
174
phases obtained by different chemical mechanisms. New stationary phase includes
175
several different types such as the chiral polysaccharides-based materials, metal-
176
organic and covalent-organic frameworks [24]; the molecular-shape selective
177
particles mostly obtained by adding weak interaction sites into the alkyl or non-alkyl
178
chains [25]; the nanomaterials such as the carbon-, silica-, zirconia-, titanium-, or
179
alumina-based nanoparticles [26]; the ionic liquid-functionalized materials [27], and
180
the HILIC stationary phases based on silica gel or chemically modified silica
181
particles, amino acids, amine-bonded, peptides, cyclopeptides, polymer-coated, and
182
zwitterionic stationary phases to mixed-mode liquid chromatography, among others
183
[28]. It must be highlighted that all these stationary phases were synthesized with the
184
primary goal of improving retention and separation.
185
Nowadays, as the applications based on miniaturized LC spanning several
186
research fields (omics science, toxicology, medicine, food safety and quality,
187
environmental surveillance, among others), the works focused on the development of
188
new analytical columns are also encouraged. Both capillary and nano-LC can be
189
considered amongst the most recent topics of interest on liquid chromatography. Due
190
to these facts, there is an increasing interest in column technology, which represents a
191
significant branch to improving the overall quality of miniaturized LC [29]. Packed
192
columns continue to be the most applied type; however considering the new
193
possibilities open due to the miniaturization, new column technologies begin to spring
194
up. These types, including open tubular and monolithic columns, represent a
195
promising alternative for enhanced efficiency and versatility [29]. Additionally, new
196
approaches such as micro-chips and especially pillar array columns are emerging as
197
highly miniaturized and suitable column types for in-field or real-time analysis. This
8
198
increase in the search for new stationary phases and analytical column technologies
199
are helping miniaturized LC to popularize and spanning in several application fields
200
of analytical chemistry. In the following text, we discuss the most important
201
achievements and trends in miniaturized analytical columns.
202
The chromatographic analytical columns can be divided into two main groups:
203
those named as filled or those supported onto the inner walls of the analytical column.
204
Another recent approach based on microchips has emerged as a potential tool for
205
liquid chromatography separations. Considering this fact, more detailed information
206
about these platforms will be presented in section 1.2.
207
Classified as filled columns is the packed group that represents the most
208
utilized in liquid chromatography nowadays. These columns are constituted of solid
209
particles densely packed into the tube under high pressure, resulting in high sample
210
capacity and significant interaction with the target analytes, even considering the
211
expected problems of high backpressure rates [30]. Their main advantages are the
212
several types of particles available with different properties, which can improve the
213
selectivity/performance of the chromatographic separation. Recent studies employing
214
packed capillary columns have been developed for diversified purposes [31–34]. As
215
an example, Zhang et al. [31–33] carried out experiments in order to optimize both
216
HILIC and RPLC packed capillary columns for proteomic analysis, which has
217
resulted in efficient columns with high peak capacity. Likewise, the separation of
218
polar and non-polar compounds by a capillary column packed with octadecylsilane
219
and taurine derivatized silica was investigated by Wang et al. [34], aiming to produce
220
a hybrid reversed-normal phase column suitable for such separation. This high
221
interest in capillary packed-LC can be attributed to constant studies on this area since
9
222
the early years of HPLC development, as well as to the industries which embraced
223
this approach as the most practical miniaturized LC mode.
224
Another filled type is represented by the monolithic columns, which have
225
emerged as an alternative of permeable material to minimize the system’s
226
backpressure. These monoliths are defined as continuous solid structure seemingly as
227
a rod-like porous filling material [35,36]. The analytical columns containing
228
monoliths are considered to have a higher permeability than packed ones, as well as
229
presenting lower analyte's mass transfer resistance when a chromatographic analysis
230
is performed [35,36]. Due to these features, several applications based on them are
231
currently springing up [37–42]. A tendency to produce hybrid monolithic columns to
232
work under two distinct LC retention mechanisms - reversed/normal phase - can be
233
underscored. An interesting study was performed by Wang et al. [38] aiming to
234
produce hybrid monolith capillary columns suitable to analyze both small molecules
235
as well as tryptic digest from biological samples. Another interesting approach is
236
based on the addition of synthesized materials (ionic liquids, carbon-based, and
237
natural compounds) into the monolith structure to enhance selectivity and
238
performance to analyze complex samples as biological fluids or enantiomeric
239
mixtures, as shown in references [39,42,43].
240
In contrast to the filled columns are the open tubular ones, which are basically
241
divided into those made by porous phases chemically bonded onto the capillary inner
242
walls, named as Porous Layer Open Tubular (PLOT), or those constituted by a thin
243
film of stationary phase, known as Wall Coated Open Tubular (WCOT) [35,44].
244
According to Ishii et al. [21], these columns can include i.d.s. from 0.006 mm to 0.06
245
mm while Saito et al. [45] define an i.d. range between 0.005 – 0.05 mm. Based on
246
the chromatography theory, these columns represent one of the most promising
10
247
alternatives for applications in miniaturized LC and, therefore, are currently gaining
248
attention [44,46–53]. As only the tubes’ inner surface is coated, they are extremely
249
permeable, reporting backpressure ranges lower than the filled columns.
250
Consequently, this fact allows the use of longer lengths combined with lower i.d.,
251
which can result in higher chromatographic efficiencies [44]. As an example, Yang et
252
al. [54,55] recently published two works reporting the use of 1 and 2 µm i.d. fused
253
silica capillaries in open tubular liquid chromatography. The authors underscore the
254
high chromatographic efficiency obtained in so reduced inner diameters under
255
backpressure rates down to 50 bars. As already demonstrated in thorough study
256
conduct by Causon et al. [56], OT columns can reach N values higher than the filled
257
ones. However, the authors emphasized that a commitment between efficiency and
258
analysis time must be considered. Hence two strategies are suggested: (1) the
259
development of OT columns with sub 5 µm i.d. or (2) the employment of temperature
260
control nearly to 90 ºC for OT column up to 10 µm i.d. in order to increase the
261
workable flow rate and consequently reduce analysis time. Apart from these, the use
262
of an oven designed to temperature programming is another useful way to enhance
263
chromatographic efficiency through the modification of other parameters such as
264
mobile phase viscosity and analyte’s diffusion, for instance [57]. On miniaturized LC,
265
the heat dissipation into the analytical column is more effective since lower i.d. fused-
266
silica tubing is usually employed. This tube material is more suitable than stainless-
267
steel in terms of heat transfer, which improves the thermal homogeneity inside the
268
column, suggesting temperature programming as an important parameter to be further
269
explored [57].
270
Regardless of the advantages already discussed, the reduced sample capacity
271
of the OT columns must be considered once they have only a very thin layer of
11
272
stationary phase available for interactions [51]. Also, there are still few applications
273
utilizing OTLC columns owing to the absence of proper instrumental apparatus to
274
operate on conditions of extremely low flow rates and injection volumes, which may
275
have stunted its development until the last years of the 1990s. Another point is that
276
the success of packed capillary columns achieved by the rising of UHPLC has
277
become a hurdle for the OTs’ growth. Even so, a favorable scenario can be expected
278
for the future once these columns have an already demonstrated potential to work
279
together with miniaturized LC, as herein referred [44,47–52]. Nowadays, manuscript
280
publications based on open tubular LC are increasing not only on omic sciences but
281
also for small molecule analysis, which can represent a tendency in miniaturized LC
282
for the subsequent decades [44,47–52,54,55,58–60].
283
Table 2 summarizes several characteristics of each type of analytical column
284
discussed [30,61–70]. Accordingly, Figure 1 shows an illustrative representation of
285
the miniaturized LC modes and the most common analytical columns. The application
286
areas highlighted in Table 2 were selected considering the recently published reports
287
on emerging areas of science, as well as the analytical fields in which these columns
288
are commonly used.
289 290
TABLE 2
291 292
FIGURE 1
293 294
Sequentially, Figure 2 gathers several publications reported in the last ten
295
years, considering the most applied types of chromatographic columns restrict to the
296
LC miniaturized modes. On the one hand, open tubular columns are still the lesser
297
applied among the miniaturized columns. On the other hand, it can be seen a relevant 12
298
number of applications, including either packed or monolithic miniaturized columns,
299
which reinforcers the current importance and tendency of the miniaturized liquid
300
chromatography. Likewise, the emergent strategy to perform liquid chromatography
301
separations on chip-based instruments already have a relevant number of publications
302
suggesting it as an established tool and a potential alternative to the traditional
303
approaches.
304 305
FIGURE 2
306 307 308
2.2 Chip-based liquid chromatography
309
Parallel to the downsizing of LC benchtop equipment (capillary and nano-LC)
310
is the development of chip-based systems which has gained attention in the last
311
decades. Several works based on the concept of “lab-on-chip” are being reported in
312
the literature [62,69,71,72]. The main goals are to increase portability, reliability,
313
analysis speed, meanwhile, reduce costs as well as simplify the chromatographic step
314
become it more comprehensible for fledgling operators [69]. An important advantage
315
of chip-based systems over those of the benchtop is the possibility to gather most LC
316
components onto a micro-sized planar structure, as shown in Figure 8 [62,73,74].
317
This fact allied to the reduced number of connections in the fluidic system can
318
attenuate void volume problems decreasing the chromatographic band broadening. In
319
specific cases, it can be used as a disposable device, which can sometimes avoid
320
sample contamination [62]. Although the known benefits of chip-based LC there are
321
also several challenges to overcome, as following mentioned: (i) simplify procedures
322
to fabricate chip-based LC at laboratory; (ii) reproducibility of packing process; (iii)
13
323
accuracy and precision on injection as well as pumping system; (iv) coupling to
324
detection or sample pre-treatment steps, (v) lack of chemically inert materials to
325
produce the platforms [68].
326
Nowadays, several chip-based platforms are available either on the market or
327
developed at research laboratories [68,69,75]. Moreover, different chip designs and
328
stationary phases (packed, monolithic, or open tubular, for instance) have been
329
already tested in those platforms [68,70,76,77]. Some recent applications include on-
330
chip analysis of glycated hemoglobin in human blood [78], caffeine transport
331
evaluation in human placenta [79], analysis of hemopexin glycopeptides [80],
332
separation of alkyl phenomes [81], quantification of osteoarthritis biomarkers [82],
333
evaluation of the wheat quality [83], and on-chip chromatographic enantioseparation
334
[84,85]. Other several applications using the microchips can be found in these well-
335
discussed reviews by Kecskemeti and Gaspar [68] and Lin et al. [86]. These facts,
336
combined with an increasing number of chip-based LC applications in different areas
337
of analytical chemistry, might represent a promising branch to leverage the
338
miniaturization of liquid chromatography.
339 340
FIGURE 8
341 342
2.3 Miniaturized systems integrating sample preparation
343
In a typical analytical workflow, the matrix complexity owing to the presence
344
of endogenous compounds, make a sample preparation step recommended or even
345
mandatory. For this reason, in addition to their use for chromatographic separations,
346
the miniaturized columns can also be coupled online with an analytical column,
347
through a switching valve, acting as an extraction device [87]. Considering that the 14
348
odds of clogging or contamination are higher in the miniaturized scale, applications of
349
miniaturized columns in online sample preparation represent a current trend aiming
350
for the miniaturization of the whole analytical system [87]. These automated
351
approaches aid in sample purification and improve the method accuracy/precision due
352
to the reduced handling [88].
353
As it is widely known, both capillary-LC and nano-LC have remarkable
354
advantages when compared to standard HPLC, including higher sensitivity (lowering
355
LOD and LOQ values), a decrease in stationary phase requirement and solvent
356
consumption. Besides that, recent investigations have been focused on the
357
development of miniaturized sample preparation methods to reduce the sample
358
volume required, solvent consumption, and, consequently, the costs [89]. Therefore,
359
automation using an online coupling approach, integrating sample preparation and
360
chromatography separation, has shown to avoid multistep procedures and time-
361
consuming analysis [90]. For these reasons, combining the advantages of LC and
362
sample
363
(multidimensional systems), arises as an attractive approach to perform direct
364
extraction, separation, detection, and quantification of the target analytes.
preparation
in
fully
automated
methods
at
miniaturized
scale
365
In short, these automated systems work as follows: firstly, the sample is
366
loaded into the extraction miniaturized column aiming to perform a sample clean-up,
367
extract, and pre-concentrate the target compounds. After this, an electrically assisted
368
switching valve is rotated to the elution position being the target compounds
369
transferred to the miniaturized analytical column for chromatographic separation and
370
detection. As examples, on-line solid-phase extraction (SPE), turbo flow
371
chromatography (TFC), and in-tube solid-phase microextraction (in-tube SPME) are
372
some sample preparation strategies used in multidimensional and automated
15
373
approaches [35,91–95]. In general, these systems allow the injection of many samples
374
in a short time, employing a larger volume of sample than that utilized in either direct
375
or on-column focusing injection strategies. Also, they can improve the method
376
recovery once more volume can be injected and the selectivity for the target
377
compounds by using specific sorbents in the miniaturized extraction column [96].
378
Nowadays, there are several applications of these multidimensional miniaturized
379
systems in the literature for many different purposes, such as environmental,
380
biological, food, and omics, for instance [97–100].
381 382
2.4 Coupling to mass spectrometry
383
After a description of the analytical column considered one of the most critical
384
parts of a chromatography system, we must point out that such reduction on the
385
analytical work-scale will demand a high sensitivity detector suitable to work in low
386
flow rates as well as lower concentration levels.
387
Although the traditional LC detectors (UV-Vis, FLD, i.e.) work at
388
miniaturized scale, the mass spectrometer (MS) is in practice the detector responsible
389
for fulfilling the current requirements of sensitivity/sensibility demanded, thus
390
becoming an ideal detector for miniaturized LC [101]. Mass spectrometry is a reliable
391
technique for qualitative and quantitative analysis of ionizable compounds through
392
the obtained fragmentation (m/z ratio) of the analytes. The main advantages of LC-
393
MS are (1) the capacity to identify unknown compounds from complex matrices
394
(food, environmental, biological samples, i.e.); (2) resolve coelution problems once
395
there are two identification parameters (retention time and fragmentation (m/z
396
structural information)) highlighting the fragmentation where it is possible to select
397
and separate the desired transitions even if in the total ion chromatogram the 16
398
compounds are coeluted; (3) the ability to analyze thermally labile compounds not
399
amenable to GC-MS [102]. In general, three different modes of ionization are recently
400
being applied to LC-MS: electron ionization (EI - most applied in GC under vacuum
401
condition); atmospheric pressure chemical ionization (APCI) and electrospray
402
ionization (ESI), being the last two performed under atmospheric pressure condition.
403
Despite the existence of these suitable modes, the ESI process can be considered
404
today as the most important and applied one [102,103].
405
A prominent landmark of the LC-MS coupling is attributed to electrospray
406
ionization experiments carried out by Bruins et al. [104] and Fenn et al. [105]. In
407
these reports, ESI was presented as a soft ionization mode that would later come to be
408
a relevant LC-MS interface mainly due to its sensitivity to solute concentration,
409
independently of the mobile phase flow rate becoming adequate to work with LC
410
mobile phases. However, some LC-ESI drawbacks are the ionization suppression by
411
matrix effect and the dependency of solvent composition in which both can affect the
412
signal response [106]. Therefore, the miniaturized systems would become a promising
413
way to overcome these drawbacks since low flow rates tend to downplay them.
414
Figure 3 illustrates the sampling efficiency in a triple quadrupole mass spectrometer
415
as a function of the applied flow rate. It can be seen a positive effect when
416
miniaturized LC flow rates are used, resulting in more efficient ionization processes
417
as well as an enhancement of ion transfer to the MS. These facts result in a more
418
intense analyte signal and, consequently, sensitive methods [107,108]. Therefore, this
419
characteristic of miniaturized ESI-MS detectors reinforces the interest in their
420
hyphenation to both capillary and nano-LC.
421 422
FIGURE 3
17
423 424
Studies on a nano-ESI interface performed by Wilm and Mann [109] in the
425
middle of the 1990s lead researches to reliable and robust miniaturized LC-ESI
426
systems over the subsequent years. Nowadays, several different nano-ESI systems are
427
commercially available, designed to improve ion emissions, creating steady flows
428
from the miniaturized LC effluent to the ion source [108,110]. However, even with
429
this successful coupling between these two techniques, the analysis of complex
430
samples still demands more accurate and selective results, which have boosted the
431
development of tandem LC-MS/MS [111]. These "in tandem" configuration results in
432
higher levels of specificity once the ions from the analytes can be traced in two
433
different stages (molecular and transition ion) which are an essential identification
434
parameter. For this reason, LC-MS/MS is often employed in the analysis of complex
435
samples as such types aimed by miniaturized LC [112].
436
Although the well-known advantages of mass spectrometry coupled to
437
miniaturized LC, the complexity of their physical communication still represents an
438
obstacle to the development of sufficiently miniaturized systems. This obstacle is
439
mainly because LC works at a higher pressure in the liquid phase, while the MS
440
demands a vacuum condition for proper operation [113]. Therefore, efforts emerged
441
as a promising way to overcome communications drawbacks [114–116]. In the past
442
few years, alternative systems were reported, including ambient pressure ionization
443
mode, and tandem systems aggregating two analyzers [102,117–122], as already
444
described [102,117–122]. The ambient pressure ionization stands out as a promising
445
alternative to be used, particularly in portable instruments to "in-field" analysis owing
446
to its simplicity and reduced size. A more detailed discussion about efforts on
18
447
miniaturized MS and its coupling to liquid chromatography is presented in section
448
2.4.1.
449
A trend that has been attracting researchers over the last decades was the use
450
of the electron ionization mode in LC analysis. The LC-EI-MS coupling attempt has
451
its roots in the 1970s, with several studies being reported until now [103,106,123–
452
127]. The eluent from LC always represented a difficulty due to the usual LC flow of
453
1 mL min-1 be transformed in approximately 1200 mL min-1 of vapor, which can be
454
harmful inside the ion source [127]. Ideally, the solvent must be fully vaporized
455
before entering the MS to maintain the vacuum conditions. Nowadays, EI is
456
becoming a feasible option considering the remarkable reductions in the mobile phase
457
flow rate of nano-LC.
458
For this reason, some works have been current published focused on the
459
development of interfaces to effectively transfer the nano-LC eluent to the EI source,
460
as referred [103,106,127–130]. The main advantages over API techniques are the
461
highly reproducible and fragmented mass spectra obtained as well as the lower
462
influence of matrix interferents. These facts are beneficial in cases of polar or
463
thermolabile substances, or when the target compounds are poorly ionized on API
464
techniques. Also, the significant EI mass fragmentation helps to elucidate unknown
465
compounds by comparing it with the MS spectra libraries. In the last ten years, some
466
applications include determination of pharmaceutical drugs in alcoholic beverages
467
[131], hormones in water [132], isoflavones in plants [133,134], alkaloids in botanical
468
extracts [135], catechins and caffeine in green tea [136], organochlorine pesticides in
469
water [137], arsenic species in marine plants [138], pyrolysis compounds from
470
biomass [124], and the elucidation of free fatty acid in mussels, marine sentinels,
471
human plasma [139–141].
19
472
Apart from the mass spectrometers, recent works also present UV-light
473
detectors described as "miniaturized and portable" as a potentially cheaper and
474
practical alternative for miniaturized liquid chromatography systems [142–144].
475
In our opinion, full miniaturization of the analytical system will be positive to
476
enhance the analysis performance, at the same time that complying with the green
477
chemistry, so important nowadays. In this manuscript, we discuss issues about
478
miniaturized liquid chromatography from the brief history to instrumental technology
479
development as well as present several applications. It is essential to highlight that
480
this review considered the last decade as the primary time frame to discuss
481
technological
482
chromatography.
advances
and
applications
based
on
miniaturized
liquid
483 484
2. Miniaturized instrumentation
485
Great efforts have been made in the LC miniaturized aiming to achieve better
486
separation efficiencies, lower solvent consumption, and waste generation. In this
487
context, capillary and nano-LC have become an efficient system to hyphenation with
488
electrospray-mass spectrometry increasing the mass sensitivity and allowing to
489
decrease the limits of detection. The following topics will discuss the main aspects of
490
miniaturized LC instrumentation related to the benchtop equipment.
491 492
2.1 Pumps
493
Solvent delivery instrumentation for miniaturized LC requires precise,
494
accurate, and pulseless pumping at low flow rates. Besides, the system must have
495
minimum void volumes to avoid gradient delay [102].
20
496
The first commercial devices developed consisted of simple adaptations of
497
conventional LC systems. Therefore, to achieve a nano and capillary flow rate, a
498
mobile phase split valve was coupled in the pump outlet. Although still widely used,
499
this adaptation did not save the solvent, and any changing in mobile phase
500
composition may alter the analytes retention time.
501
Over the years, the evolution of instrumentation and accessories dedicated to
502
capillary and nano-LC encourage researchers to use miniaturized systems in different
503
applications [19,145]. The pumps now may operate up to 400 bar or even 1000 bar
504
with a flow rate from microliter per minute to nanoliter per minute.
505
Nowadays, the miniaturized dual-piston reciprocating pump is the primary
506
type commercially available due to the constant solvent delivering and low-pressure
507
pulsation. The electronic controller assures a reproducible flow rate under both
508
isocratic and gradient elution without splitters. It is important to note that some
509
commercial pumps have a splitter before the mixer chamber and can save the mobile
510
phase; however, most systems still use a splitter after the mixer chamber, and most of
511
the mobile phase (99%) go to waste [13].
512
Syringe pumps can drive the mobile phase without pulsation, but they have a
513
limited volume of solvent in the inner reservoir [57]. Aiming to overcome this
514
limitation, miniaturized HPLC can be configured with two or more syringe pumps.
515
This feature allows a continuous mobile phase flow in isocratic mode or performing
516
gradient mode with a finite volume of solvent [18,102].
517
A recent trend to achieve precise miniaturized flow rates is the use of
518
electroosmotic pumps (EOPs) associated with a chip-based column. The mobile phase
519
is pumped through the miniaturized column using an electroosmotic flow (EOF)
520
obtained under specific voltages. Although EOPs are pulseless, show low dwell
21
521
volume and small size, they have some limitations, including non-reproducible
522
elution gradient and incompatibility with a high percentage of organic solvent in the
523
mobile phase [13,146]. Most applications of EOPs are performed in “lab-on-chip” and
524
portable LC systems [69]. As an example, Figure 4 illustrates a battery-operated
525
electroosmotic pump developed by Ishida et al. [147] to work in a portable
526
miniaturized LC system. The authors highlight the cheap battery-based module
527
designed for the pumping system, which represents an interesting approach to use
528
EOPs without expensive power supplies.
529 530
FIGURE 4
531 532
2.2 Injector and connectors
533
The injectors must have low void volume, minimal flow disturbance, and
534
precision to guarantee maximum separation performance [13,148]. Sometimes due to
535
the down-scaling in miniaturized LC, an injection valve with an internal loop ranging
536
from 4 to 60 nL is recommended to avoid column overloading. Unlike the external
537
loop configuration, in this approach to modify the internal loop volume is necessary
538
to replace the entire valve. Therefore, an analytical strategy to increase the injection
539
sample volume using an external loop valve is the on-column focusing or column
540
switching approaches. The first strategy is based on the retention of the target
541
compounds in the inlet region of the analytical column with posterior elution in a
542
narrow band by an elution gradient [18,102]. Conversely, in the column switching
543
mode, a multidimensional setup consisting of an electrically assisted six-port valve is
544
usually used to pre-concentrate the compounds before the elution inside the analytical
545
column. 22
546
The on-column focusing has the advantage of no commutation valve or
547
additional pump to perform the analysis. However, the time for loading the sample
548
volume is dependent on the analysis flow rate. On the other hand, the column
549
switching mode requires an additional pump and commutation valve for analysis, but
550
the loading sample step is faster due to the low backpressure of the trap column
551
[19,102]. A recent trend in nano-scale separation covers the chip-based
552
chromatography [69]. The integration between the injection port and a chip-column
553
drastically reduces the extra-column void volume. Several manufacturers have
554
already commercialized chromatographic systems integrated with a chip-based
555
platform [13]. Figure 5 illustrates an onboard LC system developed by Li et al. [148].
556
An electrically assisted injection valve was developed using fused silica capillaries as
557
an external injection loop resulting in a remarkable miniaturized module. This lab-
558
made strategy favors the loop replacement as well as can enhance the portability of
559
the miniaturized LC systems, as highlighted by the authors.
560 561
FIGURE 5
562 563
In miniaturized LC, the extra-column dispersion must be attenuated as much
564
as possible since it strongly influences the chromatographic band broadening [149].
565
Therefore, these systems usually require tubing and fittings with void volume and
566
reduced inner diameter (from 25 to 75 µm c.a.). However, in this microscale, the
567
system backpressure is very high, increasing the risk of clogging. Besides, if the
568
connections are not fitted well, mobile phase leakage or the formation of void volume
569
may occur [149,150].
570
23
571
2.3 Oven
572
Although selectivity in LC can be modified through several parameters (such
573
as stationary phase, mobile phase composition, pH, and nature of the organic solvent),
574
the temperature has been neglected as a parameter of selectivity control. Most
575
commercial devices operate up to 100 ºC under isothermal conditions to ensure the
576
analyte retention time repeatability [102]. Several studies have been shown the
577
potential of high temperature and temperature programming (or temperature gradient)
578
in capillary and nano-LC [151–154].
579
The use of temperature programming to adjust the separation of the analytes
580
may be advantageous when the detection system does not allow mobile phase
581
gradient elution. Further, no organic solvent in the mobile phase composition makes it
582
possible to use UV-Vis, FID, and NMR detectors [155–157].
583
Performing a high-temperature analysis may cause band broadening or
584
fluctuation on the detector signal due to temperature variations. To overcome these
585
problems, a mobile phase preheating and eluent cooling devices, before and after the
586
analytical column, respectively, are implemented [158].
587 588
2.4 Detectors
589
In order to maximize the detectability, resolution, and efficiency, the detectors
590
must be downscaled. For example, the UV-Vis absorption detector has the cell
591
volume reduced to 2 - 50 nL. Unfortunately, according to the Lambert-Beer law, the
592
reduction of the optical pathway diminishes the absorption of the analytes and
593
compromises the detectability [13]. Other techniques such as light-emitting diodes
594
(LEDs), laser-induced fluorescence (LIF), and electrochemical detection (ECD) have
595
been used in the capillary, nano, or chip-based LC [159,160]. As a drawback, 24
596
inadequate qualitative information about the target compounds is obtained. However,
597
recent studies report size-reduced detectors capable of maintaining good signal
598
response representing a promising alternative to use in portable miniaturized LC
599
[142,144,161]. Figure 6 depicts an LED-UV absorption detector developed by Xie et
600
al. [142]. It can be seen that instruments with reduced dimensions enhance their
601
compatibility with portable LC-systems.
602 603
FIGURE 6
604 605
Following this trend, a portable miniaturized LC designed for “in-field”
606
measurements was reported by Li et al. [161] using an LED-based detector, as shown
607
in Figure 7.
608 609
FIGURE 7
610 611
Although the mass spectrometer is considered as the most expensive detector
612
for LC, it presents good selectivity, detectability, and can generate additional
613
chemical structural information. The MS or tandem MS can confirm the chemical
614
identity of target analytes based on their molecular mass and specific ion fragments.
615
Due to these intrinsic characteristics, several reports focusing on projects aiming to
616
miniaturize mass spectrometry begun to spring up over the past decade, in which
617
valuable reviews about this subject have been published [116,162–164]. The main
618
goal herein is to bring a discussion about the recent advancements in portable LC-MS
619
systems. Some aspects must be considered when developing reliable and suitable MS
620
portable
instruments.
Firstly,
it
must
ensure
the
minimal
acceptable 25
621
sensitivity/specificity expected to a mass spectrometry analysis. Moreover, to be
622
portable, these systems have to be reduced in size and weight, condensing all the
623
electronic parts into a fieldable platform operated from a battery power [163]. For "in-
624
field" analysis, the sample must be efficiently ionized (similar to what happens in a
625
benchtop system) and transported to the mass analyzer under vacuum conditions
626
[162]. For this purpose, several ionization modes and interfaces to cope with these
627
critical demands have been developed [163,165–169].
628
The ambient ionization (AI) emerged as a promising ionization mode to be
629
used in portable instruments once it requires a minimum sample preparation step. Due
630
to its simplicity, it allows a fast ionization process representing a useful way for high
631
throughput “in-field” analysis. Several different ionization modes were proposed
632
predicated on AI, including direct analysis in real-time (DART), desorption
633
electrospray ionization (DESI), extractive electrospray ionization (EESI), laser
634
ablation electrospray ionization (LAESI), plasma-induced, paper spray ionization,
635
among others [73,170–176]. Although most of these AI-based instruments are
636
currently used without chromatography coupling, portable LC-MS based on these
637
approaches can emerge soon since the two correlated areas have been reporting
638
remarkable advancements towards miniaturized systems. Apart from the applications
639
based on AI techniques, interfaces designed to become the traditional ionization
640
process (ESI, EI, APPCI, for instance) more feasible in miniaturized instruments have
641
also been reported [163,165,166,169]. As a result, mass spectrometry is becoming a
642
more universal and accessible technique in miniaturized scale.
643
Among the atmospheric pressure ionization methods, the electrospray is
644
currently the most popular due to the broad mass range, variety of compound class,
645
and the possibility to generate ions with multiple charges [177]. Moreover, the flow
26
646
rate reduction to the order of microliter or nanoliter per minute results in the
647
formation of submicrometer droplets, generating a maximal surface-area-to-volume
648
ratio of column effluent. As a result, the micro/nanospray generates an improvement
649
in analytes ionization and signal-to-noise response. Furthermore, under a miniaturized
650
scale, the ESI aerosol plume generated is in the same dimensional scale of MS inlet.
651
This feature promotes an increase in method sensitivity [178,179]. The sensitivity and
652
repeatability of ESI analysis depend on the spray quality, the tip geometry, and the id.
653
of the spray tubing. For chip-based columns, a direct nanospray tip from the column
654
to the ionization source has been used to avoid any extra band broadening, improving
655
the sensitivity [19,177]. Another advantage of the low flow rate is the possibility of
656
using an electron ionization source (EI). As a result, a higher degree of fragmentation
657
occurs, and an MS spectrum is generated with a single stage of MS analyzer
658
[127,178].
659
In the past few years, several commercial and noncommercial miniaturized
660
instruments have been reported, such as ion-trap systems (linear, rectilinear, 3D,
661
cylindrical, and others), quadrupole, time-of-flight, among others [75,162,168,180–
662
183]. The development of miniaturized or portable LC-MS systems can represent a
663
significant achievement for the "in-field" analysis of forensic, environmental, food,
664
medicine, military, and public interest samples [75,163,176]. Moreover, the coupling
665
to LC can become the miniaturized MS more sensitive by decreasing the signal to
666
noise ratio while increasing the sample cleanup resulting in limits of quantification
667
similar to the benchtop MS instruments reinforcing the trend towards full
668
miniaturized systems.
27
669
3. Miniaturized LC applications
670
In the last years, the use of miniaturized liquid chromatography has increased
671
in analytical chemistry. It has been applied in several areas, including environmental,
672
biological, food, omics, among others. The biological niche stands out because one of
673
the advantages of miniaturized liquid chromatography is the low volume of samples
674
required, a fact relevant to this field.
675
In this review, we selected and briefly discussed some recent capillary and
676
nano-LC applications highlighting their advantages and drawbacks as well as the
677
future trends on using this approach in the analysis of complex matrices. Although
678
omic sciences are considered one of the most applied areas in miniaturized LC we
679
tried to gather the applications over the small molecule analysis. However, interesting
680
studies describing the use of miniaturized liquid chromatography, including some
681
over omic sciences, were carefully selected to demonstrate the growth of this field in
682
several applications as following [184–188]
683 684
3.1 Biological samples
685
So far, bioanalytical chemistry is one of the most explored fields in the
686
miniaturized modes of LC. Several recent works analyzing biological samples have
687
been reported [189–198]. In general, capillary and nano-LC shows high peak
688
resolution, which is an essential parameter in cases like metabolomics and
689
proteomics, for instance. Compared to traditional HPLC, the miniaturized systems,
690
when coupled to MS, are more sensitive, improving the metabolite profile or
691
fingerprinting, allowing to quantify more compounds.
692
Due to the lower volume of sample commonly required the miniaturized LC
693
are showing great potential to decrease evasiveness of some analytical methods, 28
694
which is very interesting for medical applications. In cases like exhaled air and breath
695
condensate analysis used to identify respiratory diseases, the nanoLC was
696
successfully applied to identify 119 proteins and 164 metabolites, only requiring 2 µL
697
of samples collected from intubated newborns [189]. Other exciting cases when
698
nanoLC is gaining attention are fields with low quantities of available cells such as
699
stem cells, tumor cells, and primary cells from tissues [190]. In these studies, the
700
capacity to perform quantitative analyses in a reduced number of cells can save time
701
and money as well as allow to perform more replicate analyses, which could improve
702
the overall experiment reliability. Furthermore, the high sensitivity of nanoLC-MS
703
was successfully used to monitor disturbance on urine profile to identify potential
704
biomarkers of diseases as well as collateral effects of medical treatments [191]. Due
705
to the sensitive and resolution obtained, a well-informative chromatogram containing
706
metabolic information can be generated. As an example, urine from HIV-patients
707
submitted to combination antiretroviral therapy (cART) is analyzed by nanoLC,
708
allowing to detect metabolites or parent compounds from the applied cART, which
709
can be related to significant reductions in several endogenous compounds such as bile
710
acids, lipids, nucleosides, and other analytes. This kind of disturbance, when
711
compared to healthy individuals, reveals the possibility to identify potential disease
712
biomarkers applying these highly sensitive analytical methods (nanoLC-MS, for
713
instance) in omic sciences [191]. In addition to the potential already showed, another
714
new strategy to improve miniaturized LC-MS sensitivity is the use of a sample
715
preparation method to pre-concentrate the compounds from the complex biological
716
matrices. This approach is beneficial when a full range of metabolites must be
717
detected. In recent work, Chetwynd et al. [192] had compared the analysis of neat or
718
diluted urine with the SPE-pre concentrate samples, which revealed an enhanced
29
719
metabolic profile when the last case was applied. This approach allowed the authors
720
to detect additional metabolites (bile acids, pharmaceuticals, and markers of lifestyle)
721
without substantial losses of the metabolites observed for neat or diluted urine, which
722
reinforces the importance of developed also miniaturized sample preparation methods
723
compatible to cap and nanoLC-MS.
724
Guan et al. [193] investigated intact proteins for online proteomic analysis
725
using capillary liquid chromatography. The authors developed different monolithic
726
trapping columns to extract four mouse liver proteins using the thin-layer sol-gel
727
method. The methodology developed demonstrated that the columns present high
728
efficiencies to proteomics analysis using a miniaturized liquid chromatography
729
equipment couple to a multi-wave UV detector with an 80-nL flow cell.
730
Another work using nano liquid chromatography and mass spectrometry for
731
proteomics analysis was developed by Delport et al. [194]. The authors compared
732
nanochip columns with traditional LC columns using proteomics extracts from
733
atheroma plaques. The authors concluded that with the advances in miniaturized
734
liquid chromatography, it was possible to improve mass-spectrometry sensitive,
735
selectivity, resolution, and consequently bring interesting results to the area and
736
increase the technique application field.
737
A method using capillary liquid chromatography for the determination of
738
seven antidepressants in just a drop of human blood was developed by Murtada et al.
739
[195]. The miniaturized analytical method enabled the separation and detection of
740
seven analytes in less than 20 minutes. Besides that, the limits of detection, which
741
ranged from 0.018 to 0.038 µg mL-1 demonstrated high analytical sensitivity when
742
compared with a conventional liquid chromatography analysis. One disadvantage of
743
this method is the online sample preparation approach utilized by the authors, once an
30
744
online extraction combined with capillary liquid chromatography would further
745
improve the sensitivity, precision, and accuracy of the developed method.
746
Wu et al. [196] coupled a capillary liquid chromatography with a tandem mass
747
spectrometer for analyzing 7-aminoflunitrazepam in human urine samples. The
748
authors used a simple liquid-liquid extraction (LLE) procedure as the sample
749
preparation step and a monolithic column for capillary analysis. When compared with
750
conventional liquid chromatography, the cLC presented several advantages as less
751
solvent consumption, development of methods to reduce analysis time, and reduced
752
sample volume. As a function of the cLC characteristics and employing a monolithic
753
column (15 cm length and 250 µm i.d.), it was possible to perform more than 200
754
injections of urine samples without carryover or changes in the efficiency of
755
separation.
756
Another work that presented satisfactory results using capillary liquid
757
chromatography coupled to mass spectrometry was reported by Qi et al. [197] to
758
confirm possible RNA modifications in a complex matrix (human blood).
759
Simultaneous quantification of two compounds (m6A and 5-mC) was performed with
760
detection limits of 0.06 and 0.10 fmol, respectively, achieved using just 0.5 ng of the
761
RNA sample. These findings corroborate that miniaturized liquid chromatography
762
coupled with mass spectrometry is an analytical technique that achieves high
763
sensitivity, even using a small amount of sample.
764
Chen et al. [198] developed an ecofriendly analytical method using capillary
765
liquid chromatography. In this work, it can be seen that miniaturized liquid
766
chromatography can significantly assist in determining the presence of substances in
767
the human body without requiring large amounts of samples. The authors determined
768
glutathione (GSH) and glutathione disulfide (GSSG) in biomatrix samples
31
769
(erythrocytes, HaCaT cells, BALB/3T3 cells, and 3T3-L1 fibroblasts) and human red
770
blood cells (RBCs) using just 10 µL of biomatrix samples or 1.5 µL human RBCs.
771
Moreover, due to the high efficiency of a derivatization step together with
772
miniaturized liquid chromatography, the method presented 750-fold higher sensitivity
773
when compared with other methods. This approach is currently being evaluated in a
774
patent application in the United States of America.
775
An online system employing capillary liquid chromatography has been
776
successfully described by Hakobyan et al. [92]. These authors determined meropenem
777
antibiotic in endotracheal tubes in order to estimate the penetration capability into the
778
biofilm and the treatment efficacy using in-tube solid-phase microextraction coupled
779
to capillary liquid chromatography fitted with DAD detector. The online system as a
780
sensitive tool to determine antimicrobials in invasive medical devices presented
781
adequate detection and quantification, in the order of 0.003 and 0.01 µg mL-1,
782
respectively.
783 784
Table 3 summarizes some of the miniaturized liquid chromatography recent applications to the analysis of biological matrices.
785 786
TABLE 3
787 788
Undoubtedly, miniaturized LC-MS have gained a relevant position among the
789
techniques used to perform biological or biomedical analysis. The remarkable gains
790
of sensitive and chromatographic resolution have been allowing us to reach higher
791
levels of detectability using low volumes of samples. In addition to the time and
792
money saved due to the reduced volume of samples and reagents needed, there is the
793
possibility to realize a high assessment of the patient's health from well-informative
32
794
chromatograms obtained of evasiveness samples such as urine instead of other
795
biological fluids. This fact stands out as one of the most important features that are
796
boosting the employment of miniaturized LC-MS in the biological field. Therefore,
797
the combination of these two powerful techniques to improve bioanalytical surveys
798
over-identification of biomarkers in the early stage of several diseases as well as
799
monitoring patient conditions stands out as a potential area for the future of practical
800
miniaturized LC-MS applications.
801 802
3.2 Food research and quality
803
Food analysis using miniaturized LC is an interesting combination to monitor
804
residues and contaminants at low concentration levels as well as to perform studies
805
about the human food dietaries and its effects on metabolism. It is widely known that
806
several natural foods have positive effects on human health, such as olive oil, fruits,
807
juices, rosemary flowers, and salvia [199–203]. For this reason, it is crucial to study
808
how their intake can affect our metabolism; thus, modern analytical methods have
809
been developed reporting good results so far [203–208]. As an example, researches
810
focused on the influence of olive oil and rosemary flower intake by humans are
811
suggesting new strategies to combat potential carcinogenic cells [205,206,208]. In this
812
context, miniaturized LC-MS arises as a well-suited tool mainly due to the lower
813
volume of the sample required, which is an interesting feature when cultures of
814
carcinogenic or stem cells are investigated, for instance. Further, miniaturized LC can
815
be applied to monitor food safety and quality to control authenticity, origin, and to
816
evaluate nutritional and toxicological characteristics of food-based products through
817
the well-informative chromatograms [209,210].
33
818
Apart from the researchers focused on foodomics, miniaturized LC has also
819
been used to analyze residues of veterinary drugs, pesticides, mycotoxins, and other
820
toxic analytes in several food samples such as fruits, vegetables, juices, alcoholic
821
beverages, milk, honey, nuts, among others. Tejada-Casado et al. [211] separated
822
sixteen benzimidazoles and metabolites in milk samples with proper resolution in less
823
than 32 minutes using capillary liquid chromatography. Compared with conventional
824
liquid chromatography, the proposed method presents lower limits of detection and
825
solvent consumption being considered a green and useful method for routine analysis.
826
Miniaturized liquid chromatography combined with MS allows the
827
achievement of better sensitivity and selectivity and in many cases, can even reduce
828
the matrix effect of some complex samples. Alcántara-Durán et al. [212] employed a
829
nanoflow liquid chromatography coupled to high-resolution mass spectrometry to
830
analyze 16 multiclass mycotoxins in less than seventeen minutes. Different edible
831
nuts samples such as pistachio, peanut, and almond were analyzed with nano LC-
832
HRMS, allowing them to determinate the analytes of interest at very low
833
concentrations.
834
Alcántara-Durán et al. [213] developed another study using a miniaturized
835
approach to analyze a suite of 87 veterinary drug residues in honey, veal muscle, egg,
836
and milk samples. A particular feature to be highlighted in this work is the use of high
837
dilution factors of up to 1:100 (sample/solvent) that was possible due to the increased
838
sensitivity provided by the use of nanoflow LC. Besides that, due to the high dilution
839
factor, the matrix effects were insignificant for all compounds.
840
Moreno-González et al. [214] reported work using nanoflow liquid
841
chromatography with high-resolution mass spectrometry in a Q-Exactive Orbitrap
842
equipment. In this publication, an interesting detail was that the authors analyzed 64
34
843
representative multiclass pesticides in less than 35 minutes with limits of
844
quantification below 0.01 µg kg-1 for 80% of the analytes. Even analyzing five
845
complex and quite distinct matrices (tomato, baby food, orange, fruit-based jam, and
846
olive oil) it was possible to obtain a significant reduction in matrix effects (negligible
847
for 90% of compounds using a 1:20 dilution) with the high sample dilution factors
848
that can be configured with the nanoflow liquid chromatography approach.
849
A capillary liquid chromatography-UV detection was successfully applied to
850
the determination of parabens in oyster and soy sauces using two different sample
851
preparation microextraction methods (VA-DLLME-SFO and SA-CPE) by Chen et al.
852
[215]. This environmentally friendly micro method was applied to the analysis of
853
different food products. The method presented some advantages such as reduced
854
solvent consumption, high sensitivity with limits of detection ranged from 10 to 30 ng
855
mL-1, calibration range of 0.1-10 µg L-1, and excellent linearity (r2 = 0.998).
856 857
Table 4 summarizes some miniaturized liquid chromatography recent applications to the analysis of food matrices.
858 859
TABLE 4
860 861
3.3 Environmental analysis
862
Environmental concerning the presence of pollutants in aquatic and terrestrial
863
ecosystems is a subject of constant researches nowadays [216,217]. These compounds
864
can be spread through the environment contaminating the living organisms, which
865
may affect their health [218]. So far, liquid chromatography showed satisfactory
866
results in most common cases like monitoring pharmaceutical drugs, cosmetics,
867
preservatives, and related analytes. However, the modern analytical techniques as 35
868
miniaturized LC coupled to MS (in most cases), arises as promising tools when more
869
sensitive methods are required to detect several toxic compounds at trace levels. Also,
870
the high detectability of capillary or nano-LC-MS is improving metabolomic
871
researches focused on the interactions between these organisms and their potentially
872
contaminated ecosystems [219]. Considering this outlook, modern analytical methods
873
to cope with small masses samples (i.e., insects, aquatic organisms) or to detect
874
several compounds at trace levels can be improved when miniaturized LC is used.
875
Other positive aspects to consider in these cases are the low injection volume and
876
flow rate usually employed. As interesting examples, analysis of the metabolomic
877
profile of fish and benthic invertebrates are carried out to investigate the influence of
878
wastewater treatment plant effluents (WWTP) over them [218,220]. In these cases,
879
due to the organism’s exposure by the contaminants, it was observed changings on
880
endogenous biomarkers, which leads to metabolite disruption affecting their
881
physiological system or even causing death. For these reasons, the use of miniaturized
882
LC allied to a suitable sample preparation can improve the metabolomic profile
883
observed in the chromatograms being useful to complex environmental analysis such
884
as ecotoxicological studies in living organisms [221]. Therefore, miniaturized LC is
885
open to new possibilities on targeted or non-targeted metabolomic studies to identify
886
less abundant components in environmental samples [222].
887
As previously shown in 1.3, a particular approach in cLC and nano-LC is the
888
possibility of using column switching systems. The online configuration employing
889
miniaturized liquid chromatographic has been a widely used approach in several
890
applications, particularly in the environmental analysis area. These online systems
891
present better sensitivity and improved environmental analysis performance once the
36
892
sample preparation step is reduced since injection, extraction, preconcentration,
893
separation, and detection are carried out in a single step.
894
Besides that, miniaturized liquid chromatography in the online configuration
895
allows a higher sample injection volume making it possible to concentrate the
896
analytes of interest in the extraction column (first dimension), thus increasing the
897
analytical sensitivity of the miniaturized online method.
898
Some recent reports show satisfactory results utilizing this miniaturized online
899
coupling, such as the one described by Serra-Mora et al. [93]. The authors compared
900
the performance of in-tube solid-phase microextraction coupled with both
901
miniaturized LC techniques to determine triazines and their degradation products in
902
water and recovered struvite samples. In this case, both systems were employed in a
903
similar configuration, changing only the flow rate, injection volume, and columns
904
dimensions (two columns for cLC and one for Nano-LC). The results showed that the
905
IT-SPME-nanoLC system presented higher sensitivity while showing a higher
906
performance when compared with IT-SPME-cLC. The column switching approach in
907
miniaturized liquid chromatography is one of the main promising approaches in
908
current analytical separation science. It allows a further reduction in the analysis time
909
by using the online sample preparation approach, a decrease in the consumption of
910
toxic solvents, and more efficient coupling to the mass spectrometer.
911
Another recent work that combined online IT-SPME with nano LC-DAD for
912
environmental analysis was reported by González-Fuenzalida et al. [223]. The authors
913
employed several capillaries with different sorbent phases containing nanomaterials to
914
determine diclofenac in river water samples. The results showed good extraction
915
efficiency, near 80%, that can be considered a high value because it involves online
916
miniaturized sample preparation and a miniaturized analytical technique.
37
917
Pla-Tolós et al. [224] developed a sustainable online method using capillary
918
liquid chromatography with diode array detection for quantifying two antifouling
919
agents (irgarol-1051 and diuron) in less than ten minutes. The authors evaluated water
920
samples from different ports or marinas, and the results showed that the analytes were
921
detected in concentrations below the LOQs, demonstrating a successful analytical
922
performance. An interesting and innovative approach utilized in this work was the
923
determination of the carbon footprint for the in-tube SPME CapLC-DAD method,
924
which was compared with previous reports demonstrating that this work presented the
925
lowest carbon footprint value (1.10 kg CO2). An additional advantage of the
926
employed miniaturized systems was the short analysis time, a little amount of sample,
927
and satisfactory precision (RSD < 3.5%).
928
Another environmentally friendly method was developed by Moliner-Martínez
929
et al. [225] using capillary liquid chromatography in a multidimensional approach.
930
Three different extractive coatings (commercial GC columns) have been evaluated in
931
the online system for the determination of triazines and degradation products in water
932
samples. The combination of large injection volume with capillary LC usually
933
improve the preconcentration of the analytes and consequently achieve higher
934
sensitivity. A limitation noticed in this work is the reduced sensitivity obtained for the
935
highly polar degradation products, which cannot be increased through the loading of
936
larger sample volume.
937
A different approach for automated online SPE nano LC-HRMS with peak
938
refocusing was demonstrated by Stravs et al. [226] during the analysis of
939
micropollutants in surface water, Microcystis aeruginosa cell lysate and spent
940
Microcystis growth medium samples. In this method only a very small fraction of the
941
sample was required to analyze 41 analytes (88 µL for water and 26 µg for biological
38
942
samples) in order to obtain low detection limits (ng g-1 or ng L-1) with lower
943
consumption of samples and solvents (flow rate ranging from 120 to 900 µL min-1).
944 945
Table 5 summarizes some miniaturized liquid chromatography recent applications to the analysis of environmental samples.
946 947
TABLE 5
948 949
3.4 Other analytical applications
950
Capillary and nano liquid chromatography have shown significant advances in
951
biological, food, environmental, and other fields such as pharmaceutical and cosmetic
952
areas. Besides that, miniaturized liquid chromatography has made possible the union
953
of analytical chemistry with green chemistry through faster and more efficient
954
analysis of complex samples with a considerable reduction in the volume of toxic
955
solvents and samples used.
956
Xu et al. [227] demonstrated this assumption by evaluating the
957
enantioseparation of amino acids by nano liquid chromatography. The authors
958
developed an O-[2-(methacryloyloxy)-ethylcarbamoyl]-10,11-dihydroquinidine-silica
959
hybrid monolithic column combined good enantioresolution and efficiency with
960
shorter analysis time. In this case, with the use of a nano-LC system, it was possible
961
to achieve a baseline enantioseparation of 44 analytes in an MQD-silica hybrid
962
monolithic column within 100 µm i.d. capillary. The same research group [228] also
963
developed another work describing the fabrication of vancomycin functionalized
964
polymer as a chiral monolithic stationary phase to be used in nano liquid
965
chromatography for baseline separation of selected enantiomers. In this report, it is
966
possible to realize the importance of miniaturized liquid chromatography in the 39
967
different parameters evaluated (such as permeability, resolution, efficiency, retention
968
time, pressure, and others) employing the analytical columns developed in the
969
laboratory and consequently ensuring a satisfactory column performance.
970
Reversed-phase capillary liquid chromatography was applied by Salih et al.
971
[229] using a polymethacrylate monolithic home-made capillary column (200 mm
972
length x 100 µm i.d.). It is possible to highlight in this work that the analytes of
973
interest (paracetamol and chlorzoxazone) were separated in less than seven minutes of
974
analysis with a chromatographic resolution of 2.37 and using a 3 nL in the nano-UV
975
cell. Besides that, the method can be considered a green approach, once it was
976
possible to reduce the environmental impact and analytical costs using a monolithic
977
column in a miniaturized liquid chromatographic format.
978
Another application using capillary liquid chromatography was reported by
979
Ma et al. [230]. The authors developed and evaluated several hybrid monolithic
980
columns via photo-initiated thiol-yne polymerization, and the best column was tested
981
to separate BSA tryptic digest by cLC-MS/MS. With this configuration, it was
982
possible to obtain satisfactory separation and high column efficiency (76.000 plates
983
per meter).
984
In an article described by Rogeberg et al. [231], the authors used a porous
985
layer open tubular column and miniaturized LC instrumentation for the separation of
986
intact proteins. The miniaturized analytical instrumentation employed a flow rate of
987
20 nL min-1, 5 nL of injection volume, and a PLOT analytical column with 3 m length
988
x 10 µm i.d. dimensions. This miniaturized combination provided good repeatability,
989
low carryover, and narrow peaks. In less than 32 minutes, the separation of intact
990
proteins in skimmed milk was achieved, thus demonstrating good efficiency of the
991
open tubular column.
40
992
Yang et al. [54,55] developed two works using narrow open tubular columns
993
for liquid chromatography to evaluate the separation of some analytes with an elution
994
pressure of less than 50 bar. The authors utilized a lab-made miniaturized liquid
995
chromatography to test the OT columns and obtained high efficiencies and sharp
996
peaks.
997
The recent instrumental advances in miniaturized LC allowed the application
998
of the technique in several areas of social interest, such as the detection of different
999
compounds in the biological niche, and analysis of contaminants in the environment
1000
and food. More recently, the spread out of the miniaturized instrumentation has
1001
allowed a better evaluation of new analytical columns format and stationary phases
1002
where some reports already show promising results mainly using packed columns but
1003
yet with limited attention to open tubular columns.
1004 1005
4. Concluding remarks and future trends
1006
Nowadays, analytical chemistry stands for developments over fully automated
1007
and miniaturized methods since they are related to more efficient and greener
1008
outcomes. Likewise, the liquid chromatography considered one of the most critical
1009
tools for target compounds determination follows this same trend. Since the ending of
1010
the twentieth century, several works are being reported in the literature, which might
1011
be ushering a new era of miniaturized liquid chromatography [14,15,20,53]. This
1012
scale reduction from traditional HPLC to UHPLC, capillary, or nano chromatography,
1013
have many general qualities related such as reduction on solvent consumption and
1014
consequently waste generation, gains on chromatographic efficiency, enhancement on
1015
the analytical signal, the capacity to produce portable LC systems for “in-field”
1016
analysis, the use of temperature programming to improve efficiency and analysis 41
1017
time, among others. The miniaturized liquid chromatography is characterized by
1018
decreases in the physical dimensions of the columns (i.d. and length), stationary phase
1019
thickness, particle diameter, and the development of dedicated instrumentation.
1020
Notwithstanding all these advantages, it has some drawbacks such as time-consuming
1021
analysis, not frequently employed in routine methods, difficulty in identifying and
1022
stopping leaks in the equipment, clogging of tubing and fittings, expensive
1023
consumables, and few commercially available instruments.
1024
Many studies demonstrating satisfactory results are reporting recent advances
1025
in miniaturized analytical columns, but a further development to be still considered is
1026
the reduction of particle diameter, since the majority of the works use particles of 5,
1027
3.5 and 3 µm, yet [31–34,37–42,44,46–52]. As remarkable examples are the
1028
production of packed or monolithic capillary and nanocolumns containing hybrid
1029
stationary phase to work in reverse and normal phase; the rising of chip-based
1030
approaches to contribute for portability and consequently in-field analysis;
1031
improvements and new developments on open tubular columns to application in
1032
omics science, medicine, biomedicine, and small molecules since it seems to be a
1033
highly efficient future LC mode [44,47–52,54,55,58–60]. Moreover, in the last
1034
decade, the instrumental evolving was a critical achievement to improve the
1035
miniaturized liquid chromatography technique. Different lab-made platforms have
1036
been developed from well-designed pumps, injectors, valves, and detectors to fully
1037
portable LC systems. Detectors based on UV-light emission are rising as a practical
1038
alternative due to its capacity to be reduced in size and weight, representing a
1039
promising couple to the above-mentioned portable LC systems [142,144,159–161] —
1040
otherwise, mass spectrometry still representing the most effective detector for
1041
miniaturized LC. Despite the improvements in the well-established ESI and APCI
42
1042
sources, recent studies are evaluating the use of EI as a source for LC owing its
1043
known qualities: a hard ionization process, fragmentation pattern, decreasing on
1044
matrix effect, and so on [127,178,179]. Besides, efforts towards MS miniaturization
1045
are also being reported based on specific interfaces, and improvements on ionization
1046
stand out ambient pressure ionization and adaptation of the traditional ESI, APCI, and
1047
EI sources [163,165,166,169][73,170–176].
1048
Thus, total automation of the analytical system emerges as the current focus
1049
embracing modern sample preparation methods, miniaturized LC and MS,
1050
respectively. This approach is considered suitable for reduced sample volumes (from
1051
nano to picolitres), which is excellent in areas such as medicine, forensic, and chiral
1052
separations. In this way, an increasing interest over miniaturized LC-MS employment
1053
to a large number of distinct analytical purposes is of utmost importance as an
1054
intended goal in the coming years.
1055 1056
Acknowledgments
1057
This research project was financed in part by the Coordenação de
1058
Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001.
1059
The authors are grateful to FAPESP (Grants 2017/02147-0, 2015/15462-5, and
1060
2014/07347-9) and CNPq (307293/2014-9) for the financial support provided.
1061 1062
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1063
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Figure Captions
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Figure 2 - Publications in the last ten years related to miniaturized LC divided among
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chromatography")) AND Document types: (Article)
1956 1957
Figure 3 - A plot showing ESI sampling efficiency vs.mobile phase flow rate
1958
illustrating the advantage of working in a capillary-LC and nano-LC scale to
1959
maximize compatibility with mass spectrometry detection. Reprinted from Ref.
1960
[107,108] Copyright with kind permission from John Wiley and Sons.
1961 1962
Figure 4 - A portable miniaturized lab-made LC system (a) photography of the
1963
complete system; (b) representative diagram of the battery-based electroosmotic
1964
pumping system. Reprinted from Ref. [147] Copyright with kind permission from
1965
Elsevier.
1966 79
1967
Figure 5 - An integrated miniaturized LC system (a) the electrically controlled
1968
injection valve; (b) the wholly integrated miniaturized LC system. Reprinted from
1969
Ref. [148] Copyright with kind permission from Elsevier.
1970 1971
Figure 6 - Images of an LED-UV absorption detector (a) schematic drawing; (b) Dual
1972
approach of LED-UV absorption detector; (c) Actual detector photograph and (d)
1973
Comparative scheme to bring an idea about the reduced dimensions of the proposed
1974
detector hardware. Reprinted from Ref. [142] Copyright with kind permission from
1975
Elsevier.
1976 1977
Figure 7 - Image of a portable LC system with LED-based micro detector (a)
1978
schematic drawing; (b) photography of the miniaturized system. Reprinted from Ref.
1979
[161] Copyright with kind permission from Elsevier.
1980 1981
Figure 8 - Representative illustration of a chip-based platform used in miniaturized
1982
liquid chromatography separations. Reprinted from Ref. [73] Copyright with kind
1983
permission from Elsevier.
1984
80
Table 1 - Liquid chromatography current denominations as a function of column inner diameter
Column i.d. (mm)
Flow rate (mL min-1)
Denomination
4.6 – 3.2
2.0 – 0.5
HPLC
3.2 – 1.5
0.5 – 0.1
Microbore LC
1.5 – 0.5
0.1 – 0.01
Micro LC
0.5 – 0.15
0.01 – 0.001
Capillary LC
0.15 – 0.01
0.001 – 0.0001
Nano LC
0.05 – 0.005
< 0.0001
Open Tubular LC
Table 2 – Main types of analytical columns currently used in miniaturized liquid chromatography, including some selected features. Column types
Typical stationary phases (sp)
Applications
Packed
Alkyl-bonded (C8, C18), Phenil-hexyl, Cholesterol-hydride, amino, diol, and cyano
Food, environmental, pharmaceutical and drug analysis
Many sp available with different selectivity, plenty of chromatographic methods already published.
High backpressure rates, lesser permeable than the other column types
[30,61,65]
Monolithic
Organic- and silicabased monoliths; hybrid monoliths: MIM, ILs, nanoparticles, aptamer, and boronatebased
Chiral separations, affinity chromatography for bioanalysis, and biomolecules
High permeability, fast mass transfer, low separation time, tunable properties and simple production
Swelling possibility in organic solvents, unfavorable changes in pore structure and mechanical instability
[61–64]
Open tubular
WCOT: physically adsorbed polymeric phases and nanoparticles; PLOT: chemically bonded polymeric phases.
Scant samples: forensic, medicine, biomedicine and natural products
High chromatographic efficiency, optimal permeability, and low backpressure rates, potentially more suitable for LC-EI-MS
Low sample capacity, non-commercialized yet, less sp and production procedure available than the other column types
[46,66]
Chip-based
Alkyl-bonded (C8, C18), organic-based monoliths, polymeric pillar arrays
Separation of macromolecules, scant samples, and "in-field" analysis
Portables for "in-field" applications, fast analysis, possible to use several sp, few connections, and reduced band broadening effect
Complex manufacturing, difficult reproducibility between dispositive, lack of chemically inert materials to print the platforms
[67–70]
Main advantages
Main disadvantages
References
Table 3 - Applications of miniaturized liquid chromatography to biological matrices. Miniaturized analytical Sample technique
Compounds class
Analytical column dimensions (L x i.d. x d.p.)
Injection Flow rate volume
Capillary LC
Blood
Antidepressants
250 mm x 500 µm x 4 µm
5 µL
20 µL min-1
[117]
Capillary LC
Urine
Antidepressant
150 mm x 250 µmMC
4 µL
4 µL min-1
[118]
Capillary LC
Blood
RNA modifications ( m6A and 5mC)
300 mm x 75 µmMC
*
15 µL min-1
[119]
Capillary LC
Biomatrix samples and human red blood cells
Antioxidant
100 mm x 500 µm x 5 µm
0.5 µL
20 µL min-1
[120]
Capillary LC
Endotracheal Antimicrobial tubes
150 mm x 500 µm x 5 µm
500 µL
8 µL min-1
[108]
Capillary LC
Serum
Human transferrin
150 mm x 300 µm x 3.5 µm
0.15 µL
4 µL min-1
[135]
Nano LC
Urine
Psychoactive substances
150 mm x 75 µm x 2.6 µm
1 µL
0.7 – 1.0 µL min-1
[136]
Nano LC
Blood, plasma, serum, and urine
Protein biomarker hCG
150 mm x 75 µm x 3.0 µm
< 50 µL
0.3 µL min-1
[137]
Nano LC
Urine
Peptides
150 mm x 75 µm x 3.0 µm
*
2 µL min-1
[138]
Nano LC
Serum
Polyunsaturated 500 mm x 75 µm x 2.0 µm fatty acids
1 µL
0.15 - 0.3 µL min-1
[139]
* Not available MC
Monolithic column
Ref.
Table 4 - Applications of miniaturized liquid chromatography to food matrices. Miniaturized analytical Sample technique
Compounds class
Analytical column dimensions (L x i.d. x d.p.)
Injection Flow rate volume
Capillary LC
Milk
Anthelmintics
150 mm x 500 µm x 5.0 µm
6 µL
9 µL min-1
[121]
Capillary LC
Vegetarian oyster sauces and soy sauces
Parabens
150 mm x 500 µm x 0.5 µm
0.5 µL
15 µL min-1
[125]
Capillary LC
Wine
Herbicides
150 mm x 300 µm x 5.0 µm
3 µL
10 µL min-1
[140]
Capillary LC
Cheese
Biogenic amines
150 mm x 500 µm x 5.0 µm
1 µL
10 µL min-1
[110]
Capillary LC
Beverages
Benzodiazepines 150 mm x 300 µm x 3.5 µm
100 nL
4 µL min-1
[141]
Nano LC
Edible nuts
Mycotoxins
150 mm x 75 µm x 3.0 µm
100 nL
200 nL min-1 [122]
Pesticides
150 mm x 75 µm x 3.0 µm
1 µL
300 nL min-1 [124]
Nano LC
Honey, veal muscle, egg, and milk
Veterinary drugs
150 mm x 75 µm x 3.0 µm
1 µL
200 nL min-1 [123]
Nano LC
Egg yolk
Hormones
150 mm x 75 µm x 5.0 µm
5 µL
300 nL min-1 [142]
Nano LC
Tomato, baby food, orange, fruit-based jam, and olive oil
Ref.
Table 5 - Applications of miniaturized liquid chromatography to environmental matrices. Miniaturized analytical Sample technique
Compounds class
Analytical column dimensions (L x i.d. x d.p.)
Injection Flow rate volume
Capillary LC
Water
Antifouling agents
35 mm x 500 µm x 5.0 µm
4 mL*
20 µL min-1
[127]
Capillary LC
Water
Degradation products of di-(2-ethylhexyl) phthalate
150 mm x 200 µmMC
4 mL*
5 µL min-1
[143]
Capillary LC
Water
Herbicides
150 mm x 200 µmMC
4 mL*
5 µL min-1
[128]
Capillary LC
Water
Chloramines
150 mm x 500 µm x 5.0 µm
0.1 mL 4 mL*
3 µL min-1
[144]
Capillary and Nano LC
Water and recovered struvite
Herbicides
150 mm x 200 µmMC 150 mm x 500 µm x 5.0 µm 50 mm x 75 µm x 3.5 µm
4 mL* 500 µL
5 µL min-1 0.7 µL min-1
[109]
Nano LC
Water
Anti-inflammatory
50 mm x 75 µm x 3.5 µm
0.94 µL
0.2 µL min-1
[126]
Nano LC
Water, Microcystis aeruginosa cell lysate and spent Microcystis growth medium
Micropollutants
150 mm x 100 µm x 3.0 µm
88 µL
120 - 900 nL [129] min-1
* In these articles it was possible to combine larger injection volumes and miniaturized LC because it was used on-line systems with larger dimensions of extraction column than the analytical column MC
Monolithic column
Ref.
Highlights •
Main advantages of liquid chromatography miniaturization
•
Recent advances in the development of capillary analytical columns
•
Future trends in LC-dedicated instrumental and stationary phases
•
This review highlights different aspects of miniaturized liquid chroamography
Ana Lúcia de Toffoli graduated with a Degree in Environmental Chemistry from the “Julio de Mesquita Filho” State University of São Paulo (São José do Rio Preto, Brazil) in 2011. She received the Ph.D. degree in Analytical Chemistry in 2018 from the Institute of Chemistry of São Carlos - University of São Paulo (São Carlos, Brazil). Her main research interests are in analytical chemistry and chromatographic techniques.
Carlos Eduardo D. Nazario graduated with a Degree in chemistry in 2005 and received the Ph.D. Degree in Analytical Chemistry in 2013 from the Universidade de São Paulo (IQSC/USP, Brazil). He has been a Professor of Chemistry at the Universidade Federal de Mato Grosso do Sul (Campo Grande, Brazil), since 2015. His main research interests are in miniaturized sample preparation techniques with application in environmental, biological and food matrices.
Eduardo Sobieski Neto graduated with a Degree in analytical chemistry from the Universidade Estadual de Maringá (Maringá, Brazil) in 2016. Since 2016, he is a Ph.D. student at the Universidade Federal de Mato Grosso do Sul (Campo Grande, Brazil). His main research area of interest is environmental analytical chemistry.
Edvaldo Vasconcelos Soares Maciel graduated in 2014 with a degree in chemistry and received his MSc degree in Analytical and Inorganic Chemistry in 2017, both from University of Sao Paulo. Nowadays is a Doctoral student at University of Sao Paulo and his main research field are liquid chromatography miniaturization focuses on development of chromatographic capillary columns and subsequently application in fully automated methods for small molecules analysis.
.
.
Fernando Mauro Lanças is the leader of the Chromatography Group and full Professor at the Institute of Chemistry of the University of São Paulo at São Carlos, Brazil. He started and is Chairman of several meetings including COLACRO and SIMCRO, and is co-Chairman of WARPA. Prof. Lanças advised ca. 130 Ph.D. and Master Thesis; published more than 300 papers and 7 books. His main research interest at the moment is focused on the full miniaturization of sample preparation-chromatography-mass spectrometry and their online full automation towards the Unified Chromatography.
Declaration of interests ☐ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: