Sensors and Actuators B 259 (2018) 677–702

Contents lists available at ScienceDirect

Sensors and Actuators B: Chemical

journal homepage: www.elsevier.com/locate/snb

Recent advances and applications of micromixers

Chia-Yen Lee a,b , Lung-Ming Fu b,c,∗
a
Department of Vehicle Engineering, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
b
Graduate Institute of Materials Engineering, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
c
Department of Biomechatronics Engineering, National Pingtung University of Science and Technology, Pingtung 912, Taiwan

a r t i c l e i n f o a b s t r a c t

Article history: Micromixers are crucial components within micro biomedical systems. This article presents a compre-
Received 10 September 2017 hensive review of the main state-of-the art applications of micromixers in biomedical systems over
Received in revised form the past ten years. The article commences by reviewing the fundamental fluidic behaviors involved in
27 November 2017
microfluidic mixing. The biomedical applications of micromixers are then described in regard to their
Accepted 4 December 2017
Available online 18 December 2017
use particularly for (1) sample concentration, (2) chemical synthesis, (3) chemical reaction, (4) polymer-
ization, (5) extraction and purification, (6) biological analysis, and (7) droplet/emulsion processes and
others. The review concludes with a brief statistical analysis of the published literature in the micromixer
Keywords:
Biomedical application field and an overview of the relative advantages of passive micromixers compared to active micromixers.
Microfluidic mixing © 2017 Elsevier B.V. All rights reserved.
Micromixer

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 677
2. Sample concentration [16–47] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679
3. Chemical synthesis [48–88] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683
4. Chemical reactors [89–128] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 686
5. Polymerization process [129–158] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 687
6. Extraction and purification processes [159–191] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689
7. Biological analysis processes [192–231] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691
8. Droplet/emulsion and other processes [232–260] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693
9. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698
Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702

1. Introduction
result in laminar flow, and hence species mixing occurs mainly
as a result of diffusion, which is an inherently slow process. Con-
Microfluidic devices have had a significant impact on the field
sequently, efficient microfluidic mixing schemes are required to
of biomedical diagnostics, and are widely used throughout the
increase the throughput of biomedical microsystems and make
drug development, drug delivery and bio-medical research indus-
possible the development of micro-total-analysis systems (␮TAS)
tries [1]. The diminutive scale of the flow channels in microfluidic
[4–6] and lab-on-a-chip (LOC) devices [7,8].
systems increases the surface-to-volume ratio, and is thus advan-
The Reynolds number, Re, and Peclet number, Pe, are two
tageous for many biomedical applications [2,3]. However, the very
of the most crucial parameters when designing and evaluating
low Reynolds number regimes produced in such microchannels
micromixers. The Reynolds number represents the ratio of the fluid
momentum to the viscous friction force, and is defined as
∗ Corresponding author at: Graduate Institute of Materials Engineering, Pingtung Re = VLh /, (1)
912, Taiwan.
E-mail addresses: loudyfu@mail.npust.edu.tw, loudyfu@yahoo.com.tw where V is the average flow velocity, Lh is the hydraulic diameter
(L.-M. Fu). and  is the kinematic viscosity. At the macroscale, turbulent flow

https://doi.org/10.1016/j.snb.2017.12.034
0925-4005/© 2017 Elsevier B.V. All rights reserved.
678 C.-Y. Lee, L.-M. Fu / Sensors and Actuators B 259 (2018) 677–702

Fig. 1. Schematic illustration of microfluidic cell culture device for investigating cell viability under different glucose concentration gradients. (Reprinted from Ref. [16] with
permission of Springer.).

Fig. 2. (a) Optical micrograph of microfluidic system, (b) Electrokinetic preconcentration mechanism at micro/nanochannel junction, (c) cross-sectional view of section
A-A’ in (b) showing overlapping EDL in nanochannel, and (d) variation over time of average fluorescence intensity within region of interest (shown by rectangle in inset).
(Reprinted from Ref. [19] with permission of Springer.).

is indicated by Reynolds numbers with a value of around Re ∼2000
in pipe flow. However, at the microscale, turbulent flow is seldom
achieved, and most applications involve laminar flow with a low
Reynolds number.
The Peclet number represents the ratio of mass transport due to
convection to that due to diffusion, and is expressed as
Pe = VL/D,
where V is again the average flow velocity, L is the length of the mix-
ing path and D is the diffusion coefficient [9]. Nguyen and Wu [10]
proposed a discussion of the operation conditions in more detail for
micromixer between the Reynolds number Re and Peclet number
Pe.
Mixing methods commonly depend on the generation of chaotic
advection, in which the fluid motion varies irregularly and thus
causes quantities such as the pressure and velocity to vary ran-
domly in both space and time. Some important review literatures
(2)
[10–12] interpreted the microfluidic mixing mechanisms and
methods of the micromixer in detail. Chaotic advection can be
generated by stirring the flow, and is highly effective at low
 C.-Y. Lee, L.-M. Fu / Sensors and Actuators B 259 (2018) 677–702 679

Fig. 3. Diffusive gradient mixer used to perfuse cells cultured in downstream microchambers with different concentrations of drugs either sequentially or in combination.
(Reprinted from Ref. [21] with permission of Royal Society of Chemistry.).

Fig. 4. Bacteria growth in oxygen gradient-generating microfluidic platform fabricated using multi-layer soft lithography technique. (Reprinted from Ref. [24] with permission
of Royal Society of Chemistry.).

Reynolds numbers due to the resulting splitting, stretching, folding
and breaking up of the species streams. However, besides chaotic
advection, molecular diffusion also plays a key role in accomplish-
ing mass transfer in micromixers. In fact, in flow regimes where the
flow is strictly laminar, species mixing occurs almost entirely as a
result of molecular diffusion between layers of different concentra-
tions. Under such conditions, it is easier to achieve a more effective
mixing performance if the thickness of the fluid layers is less √ than
the characteristic diffusion length (generally approximated as Dt,
where D is the diffusion coefficient and t is the residence time of
the species). It is thus desirable to design the microchannel in such
a way as to increase the contact surface area between adjacent fluid
layers; thereby minimizing the length of the diffusion path between
them.
When evaluating the degree of mixing at a cross-section in a
mixing channel, the mixing index, M, can be quantified as [13–15].
⎛  ⎞
 N 
 1  C − C̄
M = ⎝1 −  ⎠ × 100%
i herringbone structure patterned in the ceiling of the microchan-
(3)
N C̄
i=1
where N is the total number of sampling points, and Ci and C̄ are the
normalized concentration and expected normalized concentration,
respectively. The mixing index ranges from 0 (0%, fully unmixed)
to 1 (100%, fully mixed).
The following sections of this paper present a detailed review
of seven of the most common applications of micromixers in
biomedical systems, namely (1) sample concentration, (2) chemical
synthesis, (3) chemical reaction, (4) polymerization, (5) extraction
and purification, (6) biological analysis, and (7) droplet/emulsion
processes and others.
2. Sample concentration [16–47]
Concentration gradients of diffusible substances play an impor-
tant role in biological pattern formation and angiogenesis [16,17].
However, despite the importance of concentration gradients in
biology, relatively few techniques are available for generating and
maintaining gradients in low fluid flow rate regimes. Jiang et al.
[18] constructed a microfluidic chip in which diffusive mixing was
enhanced by a chaotic advection effect generated by an asymmetric
nel. The experimental results showed that the chip enabled both
the composition and the shape of the immobilized gradient to be
precisely controlled.
Yeh et al. [16] fabricated a polydimethylsiloxane (PDMS) con-
centration gradient microfluidic chip for determining the optimal
680 C.-Y. Lee, L.-M. Fu / Sensors and Actuators B 259 (2018) 677–702

Fig. 5. Schematic representation of chemical reaction circuit used for parallel screening of in situ click chemistry library. (Reprinted from Ref. [55] with permission of Royal
Society of Chemistry.).

glucose concentration in endothelial cell (EC) viability tests (Fig. 1).
In the proposed device, the adhesive/non-adhesive areas of the
EC detection zone were patterned using a micro-contact printing
(␮CP) method and the glucose concentration gradient was adjusted
by changing the flow rate. It was found that the optimal glucose
concentration for EC viability tests ranged from 8.66–15%.
Anwar et al. [19] fabricated an integrated micro-nano-fluidic
system for the mixing and preconcentration of dissolved proteins.
The system consisted of an integrated micromixer (IMM) based on
an unbalanced split and cross-collision of the fluid streams and a
preconcentrator with nanochannels formed by the electrical break-
down of a PDMS membrane (Fig. 2(a)). Fig. 2(b) illustrates the basic
 C.-Y. Lee, L.-M. Fu / Sensors and Actuators B 259 (2018) 677–702 681

Table 1
Summery of micromixer for concentration applications.

Ref. and First Year Micromixer type Flow rate Index (%) Objective Materials
author

[28] Schertzer 2012 Dielectric mixer N/R M: 99.7% Particle concentration AP, pNPP
(Active) detection
[29] Hong 2010 Circular mixer Re = 4 M: 95.8% Methanol Methanol, MOX
(Passive) concentration
detection
[30] Hou 2011 Circular mixer Re = 8–14 M: 92.5% Glucose concentration Glucose, DNS
(Passive) detection
[31] Wang 2012 Circular mixer Re = 0.5–10 M: 95% Methanol Methanol, MOX
(Passive) concentration
detection
[32] Pang 2013 Laminar mixer 20–120 ␮L/min N/R Gaseous carbonyl GLY, PFBHA
(Passive) analysis
[33] Lok 2011 SHM mixer (Passive) 1.67–16.7 ␮L/min M: 90% Luminol-peroxide Luminol, H2 O2 /Co(II)
detection
[34] Fu 2013 Circular mixer Re = 0.5–10 M: 95% CH2 O concentration CH2 O, Fuchsine
(Passive) detection
[35] Chiu 2013 EOF mixer (Active) Applied voltage 50 V M: 90% Preconcetration Rh B, Rh 6G, HCl
[36] La 2013 CSM mixer (Passive) Re = 42 M: 90% Colorimetric analysis Phenolphthalein,pH
indicator
[37] Javanmard 2014 Chaotic mixer (Passive) 18–60 ␮L/h M: 95% Sample preparation Beads, Blood
[38] Fu 2014 Circular mixer Re = 0.5–8 M: 95% CH2 O concentration CH2 O, Fluoral-P
(Passive) detection
[39] Fu 2014 Vortex mixer (Passive) Gas pressure driving M:100% SO2 and CH4 O SO2 , CH4 O, Methylene
force of 1.5 kg/cm2 concentration blue, MOX
detection
[40] Abed 2016 Serpentine mixer 0.2–24.8 mL/min N/R Heat transfer and W/GLY, W/SUC
(Passive) pressure-drop
measurements
[41] Floque 2016 N/R 30–150 ␮L/min M: 95% Boron concentration Boron, sulfuric acid
detection
[42] Ibarlucea 2016 Tesla mixer (Passive) 10 ␮L/min N/R Glucose concentration Glucose, GOx, HRP,
detection ABTS
[43] Gonzalez 2016 Spiral mixer (Passive) Driving force by N/R Glucose concentration Glucose, GOx, HRP, KI
capillarity detection
[44] Anh 2016 Serpentine mixer 0.1–10 mL/h M: >90% Carcinoembryonic CEA, SEB
(Passive) antigen detection
[45] Wang 2016 Chaotic mixer (Passive) 50 ␮L/min M: >90% Isothermal titration BaCl2, RNase A, 2 CMP
calorimetry
[46] Kuo 2017 Square-wave mixer 7.3 mm/s M: 76% Blood plasma mixing Blood plasma, DI water
(Passive)
[47] Kuo 2017 Square-wave mixer 400 rpm (CD mixer) M: 91.4% Blood plasma mixing Blood plasma, DI water
(Passive)

N/R: not report; M: Mixing index.

operation of the ion-selective protein concentration mechanism
within the proposed device [20]. Moreover, Fig. 2(c) shows the for-
mation of an overlapping electrical double layer (EDL) within the
nanochannel, which effectively creates an ion-selective membrane
and hence produces a concentration effect. The preconcentra-
tion performance of the proposed device was evaluated using an
FITC-BSA sample; with the measured fluorescence intensity being
compared with that of standard solutions with concentrations of
50 ␮M and 100 ␮M, respectively (Fig. 2(d)).
Kim et al. [21] presented a programmable microfluidic cell array
for combinatorial drug screening (Fig. 3). The device incorporated
64 individually addressable cell culture chambers, in which the cells
were exposed either sequentially or simultaneously to 64 pair-wise
concentration combinations of two drugs. The cell culture array was
used to screen and optimize various combinatorial drug treatments
for PC3 prostate cancer cells. However, the authors stated that the
proposed device could be equally applied to identify combinatorial
drug treatments for a much wider variety of diseases.
Friedrich et al. [22] developed a novel microfluidic concen-
tration gradient generator capable of producing either linear
or exponential concentration ranges. The device consisted of a
microfluidic channel with two inputs and a single obliquely-angled
surface groove micromixer within the base of the channel to induce
secondary flows and create the required concentration gradient.
Notably, the device contained only one mixing stage, and was thus
relatively small and easily integrated with LOC platforms. Friedrich
et al. [23] presented a surface plasmon resonance (SPR)-based
biosensor with an integrated microfluidic concentration gradi-
ent generator for the quantitative assessment of ovarian cancer
biomarkers. The biosensor was used to detect the immobilization
of ovarian cancer marker antibodies and to quantify the concen-
tration of r-PAX8. The results showed that the device achieved a
detection limit of around 5 nM and a dynamic range with around 1
order of magnitude.
Polinkovsky et al. [24] presented two PDMS-based microfluidic
devices capable of generating a series of nine gas mixtures with dif-
ferent oxygen concentrations by means of a gas-mixing effect. Both
devices comprised a two-layer structure, i.e., a flow layer for liquids
and cell cultures and a gas layer for gas mixtures (Fig. 4). Moreover,
in both cases, the two layers were separated by a thin PDMS mem-
brane, which allowed molecular diffusion to take place from the
gas layer to the flow layer and produced a subsequent change in
the absorbed oxygen concentration of the liquid/cell culture as a
result. The two devices were designed in such a way as to produce
nitrogen-oxygen mixtures with oxygen concentrations varying lin-
early between 0 and 100% (Device 1) and exponentially between 0
and 20.9% (Device 2), respectively. In both cases, the devices were
designed to facilitate cell culturing in semi-permeable microcham-
682 C.-Y. Lee, L.-M. Fu / Sensors and Actuators B 259 (2018) 677–702

Fig. 6. (a) Silicon-based SU8 master mold for PDMS synthesis chip. (b) Mixing effect within first two mixing chambers of micromixer. (Reprinted from Ref. [59] with permission
of Elsevier.).

Fig. 7. Photographs of: (a) X-micro mixer (LTF), (b) micro residence time module (LTF), and (c) PTFE tube reactor. (Reprinted from Ref. [60] with permission of Elsevier.).

Fig. 8. (a) Geometry of multi-inlet vortex mixer, and (b) MoS2 nanoparticle synthesis. (Reprinted from Ref. [61] with permission of Elsevier.).

bers connected to the flow channel. In general, the experimental
results revealed that the division rate of bacteria exposed to a
nitrogen-oxygen gas mixture with a 12% oxygen concentration was
approximately 5 times higher than that of bacteria exposed to a
mixture containing no oxygen. Lam et al. [25] developed a PDMS
microfluidic device incorporating a differential oxygenator for the
culturing of anaerobic and aerobic species. In the proposed device,
a mixed nitrogen-oxygen gas was flowed through a microchannel
network and used to regulate the dissolved oxygen concentration
in an adjacent channel filled with culture media via a process of
molecular diffusion. The feasibility of the proposed device was
demonstrated by culturing three bacteria samples with different
oxygen requirements, namely E. coli, A. viscosus and F. nucleatum.
Toh et al. [26] developed a microfluidic 3-D gradient-generating
multiplexed device for studying drug hepatotoxicity. The proposed
device contained a multiplexed microchannel consisting of cell
culture compartments and medium perfusion compartments to
perform the simultaneous screening of multiple dose-dependent
drug responses. The hepatotoxicity analysis results obtained for
five model hepatotoxic drugs (i.e., acetaminophen, diclofenac,
quinidine, rifampin and ketoconazole) showed that drug-based
hepatotoxicity is strongly affected by the drug metabolism. It was
 C.-Y. Lee, L.-M. Fu / Sensors and Actuators B 259 (2018) 677–702 683

Table 2
Summery of micromixer for chemical synthesis applications.

Ref. and First Year Micromixer type Flow rate Index (%) Objective Materials
author

[69] Daito 2006 K-M mixer (Passive) Re = 200–800 M: 90% Bisphenol F synthesis Bisphenol F, HBA
[70] Luty 2011 SIMM-V2 mixer 0.1–10 mL/min N/R Gold nanoparticles HAuCl4 , NaBH4
(Passive) synthesis
[71] Jung 2012 SAR mixer (Passive) Re ∼50 M:∼ 90% Recrystallization of LDPE, 1-dodecanol
polyethylene
submicron particles
[72] Kumar 2012 4-way mixer (Passive) 35–1000 ␮L/min N/R Ag nanoparticles AgNO3 , KOH, oleic acid
synthesis
[73] Yamamoto 2013 T-mixer (Passive) Re ∼2000 N/R ZIF-8 nanoparticles ZIF-8, Zn2+, 2-MeIM
synthesis
[74] Haroun 2013 Full-loop mixer 2–15 mL/min N/R [11 C]raclopride DMR, [11 C]Mel
(Passive) synthesis
[75] Ono 2014 T-mixer (Passive) 5–75 g/min N/R Ca1−x Srx TiO3 Ca(NO3 )2 , TiO2,
nanoparticles synthesis Sr(NO3 )2 , NaOH
[76] Yang 2015 Tesla mixer (Passive) Re = 0.1–100 M: 94% Immunofluorescence H1975 cancer cells,
analysis L858R
[77] Deng 2015 T-mixer (Passive) 333–667 mL/min M: 99% 2,4,5-trifluorobenzoic EtMgBr,
acid synthesis 2,4,5-Trifluoro-
bromobenzene
[78] Maeki 2015 SHM mixer (Passive) 0.1–1 mL/min M: >95% Lipid nanoparticles POPC, ethanol, NaCl
synthesis
[79] Santana 2015 3-types T-channel Re = 1–160 M: 99% J. curcas oil conversion J. curcas oil, ethanol
mixer (Passive)
[80] Thiele 2015 T, SAR, and Dean flow Re = 27–457 M: 93% Silver seed particles TSC, PSSS, NaBH4 ,
mixer (Passive) synthesis AgNO3
[81] Veldurthi 2015 Circular mixer (Active) Re = 0.006 M: 90% RIF loaded TiO2 RIF, TiO2
synthesis
[82] Kim 2016 T-shape mixer 4.5 mL/min M:80% Y: 91% Organic synthesis PhLi, CICO2 Me, Bu3 SnCI
(passive)
[83] Baek 2016 SHM mixer (Passive) Re = 1.76–10.6 M: 90% PDA nanoparticles PCDA, DMSO, ␣-CD
synthesis
[84] Thiele 2016 Dean flow mixer 13.3–41.7 ␮L/s M: ∼100% Au nanoparticles CTAC, HAuCl4 , NaBH4
(Passive) synthesis
[85] Santana 2017 T-mixer with static Re = 100 M: 99% Biodiesel synthesis Sunflower oil, ethanol,
elements (Passive) NaOH
[86] Thiele 2017 Dean flow mixer Re = 5–350 M: 100% (Re >250) Au nanoparticles CTAC, HAuCl4 , NaBH4
(Passive) synthesis
[87] Pessoa 2017 D, D-bends, D-barriers 25–90 ␮L/min M: 85% Chitosan/ATP CHI, ATP
mixer (Passive) nanoparticles synthesis
[88] Thiermann 2017 SFIMM mixer (Passive) 0.2–2.4 mL/min N/R Block copolymer PB130 -b-PEO66 H,
synthesis acetic acid

N/R: not report; M: Mixing index; Y: Yield efficiency.

also shown that the device was more sensitive to drug-mediated
hepatotoxicity than a conventional multi-well plate.
Yan et al. [27] developed a two-layer microfluidic slipchip-based
reaction microarray in which the sample and reagent formed two
orthogonal concentration gradients, respectively, and mixing was
achieved by sliding the two layers of the device relative to one
another. The performance of the proposed device was investigated
by injecting solutions of 45 nM ˇ-gal and 45 ␮M FDG (Fluores-
cein di-ˇ-d-galactoside) into the upper and lower layers of the
device, respectively. The reaction products were found to be con-
sistent with those obtained in a 384-well plate; thereby confirming
the reliability of the platform as a tool for investigating the enzy-
matic reactions of ˇ-gal. Table 1 presents a brief comparison of the
micromixer-based concentration systems reported in [28–47].
3. Chemical synthesis [48–88]
Chemical synthesis in microchannel networks has attracted sig-
nificant interest in the literature over the past few decades [48–52].
Notably, the use of microfluidic platforms for chemical synthesis
has benefits which extend beyond the laboratory and into industry
since microfluidics increases the yield and selectivity of the synthe-
sis process through more rapid mixing and an improved thermal
management. Furthermore, the efficiency of the mixing process can
be enhanced simply by adjusting the diffusion distance or strength-
ening the convection effects in the flow mixing regions.
Kim et al. [53] developed a PDMS-based micromixer to facili-
tate the reaction of glucose and glucose oxidase (GOX) in which
the mixing channel was patterned with an alligator tooth struc-
ture designed to produce an alternate stretching and folding of the
species stream. The mixing index was found to range from 81–92%
for Reynolds numbers of Re = 0.08–16. Moreover, a mixing index
of more than 70% was obtained within a mixing distance of less
than 2.3 mm. Wang et al. [54] presented a microfluidic chemical
reaction device consisting of a nanoliter mixer, a chaotic mixer, a
microfluidic multiplexer and a 32-microvessel array integrated on
a single microfluidic platform (Fig. 5). It was shown that the pro-
posed device enabled up to 32 click reactions to be performed in a
parallel manner. In a later study [55], the same group developed a
2nd-generation device capable of performing 1024 in situ click reac-
tions in parallel using a bovine carbonic anhydrous II click system.
Compared to the first device, the 2nd-generation device reduced
the time required to prepare a single click reaction from 1 min to
17 s. Furthermore, the use of SPE purification and electrospray-
ionization mass spectrometry with multiple reaction monitoring
(ESI-MRM) enhanced the hit sensitivity of the device and there-
fore enabled a significant reduction to be made in the enzyme and
reactant consumption.
684 C.-Y. Lee, L.-M. Fu / Sensors and Actuators B 259 (2018) 677–702

Fig. 9. (a) Experimental setup for recipitation of nanoparticles, and (b) photograph of applied microfluidic T-mixer. (Reprinted from Ref. [95] with permission of Elsevier.).

Fig. 10. Schematic illustration of reaction process in high-pressure, high-temperature microfluidic water system. (Reprinted from Ref. [97] with permission of John Wiley
and Sons.).

Fig. 11. Experimental setup and geometric design of SAR micromixer in microreactor. (Reprinted from Ref. [98] with permission of Elsevier.).

Kawasaki et al. [56] presented a two-step, high-temperature first mixing process was designed to produce a supercritical aque-
micromixing process for the synthesis of anatase TiO2 nanopar- ous KOH solution from supercritical water (SC-H2 O) and KOH, while
ticles with a controlled size and a highly crystalline structure. The the second mixing process combined this KOH solution with aque-
 C.-Y. Lee, L.-M. Fu / Sensors and Actuators B 259 (2018) 677–702
Fig. 12. Split-and-recombine micromixer used to create multiple layers of mixtures
of cyclohexanone oxime and cyclooctane and oleum and ε-caprolacta. (Reprinted
from Ref. [105] with permission of John Wiley and Sons.).
ous Ti(SO4 )2 to form TiO2 nanoparticles. It was shown that the
average particle size could be controlled in the range of 13–30 nm
by adjusting the concentration of the KOH solution used in the first
mixing process. Li et al. [57] developed a micro-continuous flow
method for the synthesis of ZnO nanoparticles by first mixing the
precursor solution using a static mixer and then injecting the mix-
ture into a carrier stream. The feasibility of the proposed method
was demonstrated using Zn(Ac)2 and NaOH as reactants and binary
solvents of water and ethylene glycol. The results showed that
ZnO nanoparticles with a homogeneous size distribution could be
obtained given the use of a binary solvent with a water content of
less than 50 v%. The high homogeneity was attributed to a rapid
mixing of the reactants and solvent in the static micro-mixer and
the fast heat transfer produced within the small droplets of the
reaction mixture as a result of a flow-induced segment-internal
convection effect.
Kawasaki et al. [58] presented a continuous supercritical
hydrothermal method based on a T-shaped microfluidic mixer for
the synthesis of NiO nanoparticles. It was shown that the size of
the synthesized particles reduced from 54.3 to 20.1 nm as the inner
diameter of the T-shaped mixer was decreased from 2.3 to 0.3 mm
and the flow rate was increased from 30 to 60 g/min. The experi-
mental and CFD simulation results revealed that the reduction in
the particle size was the result mainly of a higher heating rate,
which increased the primary nucleation rate while simultaneously
Fig. 13. Characteristics of five micromixers and four types of flow regime observed in different micromixers. (Reprinted from Ref. [107] with permission of Elsevier.).
685
suppressing secondary nucleation and growth. Chung et al. [59]
developed a simple microreactor based on short-mixing-length
baffles for the synthesis of silica nanoparticles (Fig. 6). The simula-
tion and experimental results showed that the use of three mixing
units with a gap size of 50 ␮m was sufficient to achieve a mix-
ing index of more than 90% via molecular diffusion effects in the
low Reynolds number regime (Re < 0.1) or chaotic and convection
effects in the high Reynolds number regime (Re > 40). In addition,
it was shown that the size of the synthesized particles could be
controlled by tuning the flow rate, reaction time and reaction tem-
perature, respectively.
Baumgard et al. [60] developed two microstructured devices for
the continuous synthesis of platinum (Pt) nanoparticles consisting
of X-type mixers and two different residence time modules, namely
a micro residence time module and a PTFE tube reactor, respectively
(Fig. 7). In the proposed devices, Pt-salt solution was first mixed
with ethylene glycol in the X-type micromixer to produce Pt-seeds
and the resulting acidic solution was then flowed to the residence
time module to prompt Pt nanoparticle synthesis. To adjust the
temperature during the synthesis process, the residence time mod-
ules were immersed in thermostats (Huber Polystat CC3) filled with
silicone oil. The experimental results showed that the proposed
two-step process allowed for the preparation of nanoparticles with
a tunable particle size and a narrow size distribution. Bensaidet
et al. [61,62] developed a multi-inlet vortex microfluidic mixer for
the synthesis of molybdenum sulfide nanoparticles (Fig. 8). The per-
formance of the proposed device was evaluated under both laminar
and turbulent flow conditions by means of experiments and CFD
simulations. The results showed that nanoparticles with average
diameters of 135 nm, 84 nm and 64 nm were obtained given inlet
flows with Reynolds numbers of Re = 832, 4160 and 8320, respec-
tively. In addition, it was shown that an optimal mixing of the
reactants was obtained for a Reynolds number of Re = 8320.
Santana et al. [63] conducted a numerical investigation into
the mixing and reaction of Jatropha curcas oil and ethanol for
the synthesis of biodiesel in three different micromixers, namely
a T-micromixer, a Cross-micromixer and a Double-T-micromixer.
For each type of device, the simulations investigated the fluid
mixing behavior at different Reynolds numbers and the oil con-
version efficiency for different Reynolds numbers and residence
times, respectively. The results showed that the T-micromixer,
Cross-micromixer and Double-T-micromixer achieved maximum
conversion efficiencies of 98.48%, 98.55% and 96.00%, respectively.
Tian et al. [64,65] developed a simple approach for the continu-
ous synthesis of high quality CdSe quantum dots (QDs) in which
the nucleation intensity of the QDs was enhanced by preheating
the Cd and Se precursors in an oil bath prior to their mixing in a
686 C.-Y. Lee, L.-M. Fu / Sensors and Actuators B 259 (2018) 677–702
Fig. 14. Microreaction system with multilayer passive micromixer used for polymerization of amino acid NCAs. (Reprinted from Ref. [132] with permission of Royal Society
of Chemistry.).
Fig. 15. Schematic illustration of fast polycondensation process in continuous-flow
microreactor with micromixer. (Reprinted from Ref. [134] with permission of John
Wiley and Sons.).
micromixer. It was shown that the preheating process enabled the
synthesis of CdSe QDs with a smaller size and a narrower size dis-
tribution. Similar microfluidic devices have also been proposed for
the synthesis of ginkgolide B, ZIF-8 and HRPIBs [66–68]. Table 2
presents a brief overview of the proposals presented in [69–88] for
the use of micromixers in chemical synthesis applications.
4. Chemical reactors [89–128]
Mixing is a highly important unit operation in process indus-
tries, and hence the academic study of mixing in chemical reactors
is of great practical significance. Micro-mixing works simultane-
ously with macro-mixing in the chemical reactors used in process
industries, and plays a key role in achieving the optimal selectivity
with respect to the desired products [89–93]. Micromixers also play
a critical role in determining the performance of the microreactors
used for the manipulation of reagents or catalyst concentrations in
the chemical processing field.
Schwarzer et al. [94–96] conducted numerical and experi-
mental investigations into the precipitation of barium sulfate
nanoparticles in a high capacity microfluidic T-mixer operating
in the high Reynolds number regime (Re = 200–15000) (Fig. 9).
The simulations were based on a population balance equation
and a global mixing model. The results provided many useful
insights into the micromixing, nucleation and growth stages of
the precipitation process. Moreover, a good general agreement
was observed between the predicted size of the precipitated par-
ticles and that observed experimentally. Kawanami et al. [97]
presented a microfluidic water-mediated reaction system based on
a step-by-step rapid mixing and heating approach for inducing the
Sonogashira coupling reaction without the need for organic sol-
vents or specific ligands (Fig. 10). It was shown that the desired
products could be obtained in quantitative yields within approx-
imately 4 s when using a ligandless PdCl2 catalyst in pure water
at 16 MPa and 250 ◦ C. Moreover, exceptionally high turnover fre-
quencies of up to 4.3 × 106 h−1 were observed. Notably, the desired
products remained on the surface of the aqueous solution, while
the catalyst was deposited as Pd0 . As a result, the products could
be easily isolated using either a phase separation or filtration tech-
nique.
Chen et al. [98] presented a microreactor with a split-and-
recombine (SAR) structure for the synthesis of imidazole-based
carbohydrate derivatives (Fig. 11). The SAR structure induced a
combined diffusion and chaotic advection effect, and therefore
enhanced both the mixing index and the reaction performance. The
experimental results showed that the proposed device achieved
a similar yield to that of a macroflask, but with a far faster syn-
thesis time. In a later study [99], the same group developed a
SAR ␮-reactor for mixing fluids at Reynolds numbers ranging from
Re = 0.01–100 and viscosities of  = 0.000855–0.186 kg m−1 s−1 . The
simulation results showed that the SAR structure induced a 3-
D rotational flow, which prompted an intense stretching of the
species contact interface and improved the mixing performance
as a result. The 3-D structure of the device enabled the two fluids
to generate sequential stretching and folding, increasing the inter-
facial area between two fluids and, thus, facilitating mixing [100].
Mozharov et al. [101] proposed an improved method for deriving
kinematic information about the reaction process in microfluidic
systems based on a step change in the flow rate and the applica-
tion of real-time noninvasive Raman spectrometry measurements
at the end of the flow line. Taking the Knoevenagel condensation
reaction for illustration purposes, it was shown that the proposed
system offered several important advantages over conventional
methods, including a fivefold reduction in the time required to
obtain the kinematic data and a tenfold reduction in the reagent
consumption.
Han et al. [102] performed CFD simulations based on a standard
engulfment (E) model and a finite-rate/eddy-dissipation (FR/ED)
model to investigate the micromixing performance of viscous fluids
in a stirred tank reactor fitted with a Rushton turbine. The valid-
ity of the numerical model was validated using experimental data
reported in the literature. The simulation results showed that the
micromixing performance and reaction rate both improved with a
higher agitation speed, a lower fluid viscosity, and a feeding loca-
tion closer to the discharge area of the rotating impeller. Duan et al.
[103] used a combined CFD and E-model approach to simulate the
micromixing effect in single-phase stirred tanks with parallel com-
petitive reaction systems. In the proposed model, the turbulence
kinetic energy and dissipation in the reaction zone were obtained
by solving the transport equations of the mixture fraction and its
variance. The predicted values of the segregation index were shown
 C.-Y. Lee, L.-M. Fu / Sensors and Actuators B 259 (2018) 677–702 687

Table 3
Summery of micromixer for microreactor applications.

Ref. and First Year Micromixer type Flow rate Index (%) Objective Materials
author

[110] Choe 2008 SAR mixer (passive) 5–30 ␮L/min M: 97% Lithium–halogen n-BuLi, BN, NH4 Cl,
exchange reaction anthraquinone
[111] Ukita 2008 Filter mixer (passive) 5 or 10 kPa N/R Competition ELISA NP, enzyme- labeled
AP, microbeads
[112] Fang 2009 SAR mixer (passive) R = 0.01 M: 100% Boost fluid reaction C-PC, R-PE
[113] Ziegenba 2010 Grooved mixer Re = 2.2–9.5 M: 95% Liquid-sided mass CO2 , OH−
(passive) transport
[114] Hsu 2010 SAR mixer (passive) 3 mm/s M: 100% Au nanoparticles Au-NP, DNA
decorated with
oligonucleotide
[115] Ko 2011 Pillar and nozzle mixer Re = 66.5 M: 87.7% DNA ligation DH5a competent cells,
(passive) Hind III
[116] Yasukaw 2011 T-shaped mixer 1 mL/min Y: <60% Ethyl pyruvate Ethyl lactate,
(passive) production acetonitorile, VOCl3 , O2
[117] Chen 2011 SAR mixer (passive) Re = 1 M: >95% Chaos and FRET FAM, TAMRA
reaction
[118] Li 2012 Zigzag mixer (passive) Re = 248.3 M: 90% CL reaction CL, HRP
[119] Al 2012 Grooved mixer 1.68 to 6.72 mL/min M: 95% Fast exothermic and CO2 , NaOH
(passive) mass transfer reactions
[120] Guo 2013 Multi-T mixer (passive) Re = 396–9960 N/R Heat exchanger reactor BTB, Na2 HPO4
[121] Sudar 2013 Teardrop mixer Re < 100 N/R Aldol addition reactor DHA, FSA
(passive)
[122] Dong 2014 Micro-sieve mixer 10–30 mL/min M:99.9% Micro-sieve dispersion SiO2 , BaSO4
(passive) reactor
[123] Liu 2014 T-shaped mixer Re = 395–3161 M: ∼100% Micro-impinging KI, KIO3 , H3 BO3 , NaOH
(passive) stream reactors
[124] Mitic 2015 4-jet tangential mixer Re = 1000– 1500 M: >90% Mix liquids HPTS, HCl, NaOH
(passive) microreactor
[125] Dong 2015 Micro-sieve mixer 6–23 mm/s C: <10% Catalyst microreactor Cyclohexanone,
(passive) ammonia, TS-1
[126] Plouffe 2016 SZ mixer (passive) 0.8–32 mL/min M: 95% Mass transfer 4-NPA, NaOH
microreactor
[127] Watanab 2017 K-M mixer (passive) Re = 24 N/R Central collision-type ZIF-8, 2-MIM, Zn(NO3 )2
microreactor
[128] Grundtvi 2017 2- parallel streams N/R N/R Biocatalytic PEA, ACE, APH, ATA
mixer (active) microreactors

N/R: not report; C: Conversion efficiency; M: Mixing index; Y: Yield efficiency.

to be in good qualitative agreement with the experimental results
for various agitation speeds and feed locations.
Hossain et al. [104] produced monodisperse poly(N-vinyl-2-
pyrrolidone) (PVP)-stabilized Pt nanoparticles (PtNPs) using an
interdigital triangular micromixer. It was shown that the microflu-
idic mixing process suppressed the hydrolytic decomposition
of the BH4− ions by the PtNPs formed in the initial stage of
the reaction. As a result, the PtNP yield was higher than that
obtained using a conventional batch mixing approach. Zuidhof et al.
[105,106] performed the Beckmann rearrangement of cyclohex-
anone oxime to ε-caprolactam in a microreactor with an integrated
SAR micromixer. The microreactor consisted of a low-temperature
mixing zone (65 ◦ C) followed by a high-temperature reaction zone
(100–127 ◦ C) (Fig. 12). The specified temperature conditions were
shown to achieve a selectivity of 99%. By contrast, that reported
in the literature for a similar setup but with a uniform mixing and
reaction temperature in the range of 100–127 ◦ C was just 95%. It
was additionally shown that the microdroplet size ranged from
10–25 ␮m, while the residence time of the reactants was less than
40 s. Finally, the molar ratio of oleum to cyclohexanone oxime was
reduced to 0.8 from the industrial value of 1.2.
Plouffe et al. [107] examined the flow regimes and mass transfer
rates in the two-phase alkaline hydrolysis of 4-nitrophenyl acetate
given five different complex micro-reactors with different mixing
mechanisms (Fig. 13). It was found that in systems with a low inter-
facial tension, the flow structure changed from slug, to parallel,
and then to drop flow as the flow rate was increased. However,
in systems with a higher interfacial tension, parallel flow was not
observed. In general, the curvature-based reactors were found to
have a relatively poorer mixing performance since they induced
a parallel flow structure and therefore resulted in a lower inter-
phase mass transfer rate. Similar microfluidic devices for rapid
liquid–liquid reactions were also presented in [108,109]. Table 3
summarizes the proposals presented in [110–128] for the further
use of micromixers in microreactor applications.
5. Polymerization process [129–158]
Mixing in polymerization processes is an extremely important
issue since a non-uniform mixing inevitably degrades the proper-
ties of the final synthesized product. Micromixers [129,130] can be
employed either for the initial mixing of the reactant streams or the
mixing of the reactive solutions encountered in multi-stage block
copolymerization processes. Moreover, micromixers with specific
designs can be employed to promote gradients of functionalities
along the polymer backbone. In addition, when coupled with liv-
ing or controlled radical polymerization techniques, micromixers
allow for the synthesis of multi-block copolymers, whose over-
all polydispersity indices and average molecular weights depend
directly on the geometry and characteristic dimensions of the
microsystem [131].
Honda et al. [132] performed the continuous polymerization
of N-carboxy anhydrides in a microreaction system consisting
of a multilayer laminar passive micromixer and PTFE micro-
tubes (Fig. 14). The properties of the synthesized products were
compared with those obtained in a conventional batchwise pro-
cess. It was shown that the polymers produced in the proposed
microreaction system had a narrower molecular weight distri-
688 C.-Y. Lee, L.-M. Fu / Sensors and Actuators B 259 (2018) 677–702

Fig. 16. Schematic illustration of continuous flow reactor with HP-IMM micromixer for production of different end groups. (Reprinted from Ref. [137] with permission of
American Chemical Society.).

Fig. 17. (a) Sn(OTf)2 catalyzed continuous flow ring-opening polymerization in PTFE tubular microreactor with T-type micromixer, and (b) SEC of PCL with DPtarget = 10 at
80 ◦ C and DPtarget = 30 at 110 ◦ C in microreactor and batch reactor. (Reprinted from Ref. [139] with permission of Royal Society of Chemistry.).

bution than those produced in the batchwise process. Moreover,
the molecular weight of the synthesized products could be con-
trolled by adjusting the flow rates of the reactants injected into
the microreactor. Rosenfeld et al. [133] performed the continuous
nitroxide-mediated copolymerization of n-butyl acrylate (BA) and
styrene (S) in a two-stage process based on two serial microtube
reactors. For comparison purposes, the output flow from the first
reactor was mixed with the second monomer solution using two
different types of micromixer, namely a high pressure interdigi-
tal multilamination micromixer (HPIMM) and a simple T-junction
micromixer. The results showed that the use of the HPIMM led to
a narrower molecular weight distribution of the synthesized prod-
ucts (i.e., an improved control of the copolymerization reaction)
due to a more efficient mixing of the viscous n-butyl acrylate (BA)
and the liquid styrene prior to entering the second microreactor.
Kessleret et al. [134] performed the rapid polycondensation
of trialkoxysilanes to PSSQs in a continuous-flow microreactor
consisting of two syringe pumps, two preheating loops, a SAR
micromixer, and Mecanyl tubes of different lengths (1, 3, 6, 9 or
12 m) to adjust the residence time (Fig. 15). It was shown that
the molecular weight of the synthesized products increased from
1900–11,000 g/mol as the residence time increased. In other words,
the microreactor setup offered the possibility to synthesize PSSQs
with adjustable properties. Similar continuous flow microreac-
tion devices based on various types of micromixer design were
presented for rapid polymerization applications in [135–140]. Ton-
hauser et al. [136] synthesized end-functionalized polystyrenes
by living anionic polymerization in a microstructured reactor via
termination by acetal-protected functional epoxides. In the pro-
posed method, the monomer and indicator were mixed using a
high-pressure slit interdigital micromixer (HP-IMM) immersed in
a water bath with a predefined temperature. The reaction mix-
ture was then combined with the termination reagent (glycidyl
ether) in a simple T-junction micromixer. The end-functionalized
polymers were recovered within several seconds. Moreover, quan-
titative end-capping was confirmed in all cases by MALDI-ToF-MS
observations. In a later study by the same group [137], a continu-
ous flow reactor with a tangential four-way jet micromixing device
was used to synthesize living polymers with a predictable disper-
sity and a controlled molecular weight through a suitable control
of the total flow rate (Fig. 16).
Zhu et al. [139] presented a simple PTFE tubular microreactor
with a T-type micromixer (Fig. 17(a)) for the ring opening polymer-
ization of cyclic monomers using Stannous(II) trifluoromethane
sulfonate (Sn(OTf)2 ) as a catalyst. It was shown that under the
same reaction conditions, the continuous mode reactor resulted
in faster CL polymerization than that achieved in a conventional
batch mode operation (i.e., 90.1% vs. 81.8% monomer conversion
 C.-Y. Lee, L.-M. Fu / Sensors and Actuators B 259 (2018) 677–702 689

Fig. 18. (a) Photograph of suspension injection with T-shape micromixer, and (b) mixing effect of fluorescent slugs. (Reprinted from Ref. [165] with permission of Elsevier.).

Table 4
Summery of micromixer for polymerization process applications.

Ref. and First Year Micromixer type Flow rate Efficiency (%) Objective Materials
author

[138] Qiu 2016 T-junction mixer 40 mL/min C: 80% Acrylic acid polymerization K2S2O8, Acrylic acid
(passive)
[140] Nagaki 2004 IMM, SAR mixer 10 mL/min C: 80% Cation pool-initiated Vinyl Ethers, N- acrliminium
(passive) controlled polymerization ion
[141] Iwasaki 2005 T-shape mixer 0.2–1.0 mL/min Y: 34.2% Polymerization of BA, BMA, BA, BMA, MMA,VBz, St
(passive) MMA,VBz, and St
[142] Yasuhiro 2006 Y-shape mixer 2.5–5.0 mL/min C: 100% Bond forming reaction PA-PAT, (NH4 )2 PdCl4,
(passive) (PA-TAP-Pd)
[143] Iwasaki 2007 T-shape (passive) 0.17 mL/s C: 100% Cationic polymerization of CF3 SO3 H, 1,3-DPB
vinyl ethers
[144] Rosenfeld 2008 HIPMM, and slit plate 9.3–26.5 mL/min C: 98% Copolymerization of BA and St BA, St, Toluene, acetic
mixer (passive) anhydride
[145] Nagaki 2008 T-shape mixer (4, 2.0–3.0 mL/min Y: 100% Anionic polymerization THF, Me2 SiCl2 , s-BuLi
passive)
[146] Nagaki 2009 T-shape mixer (2, 3.0 mL/min C: 100% Anionic polymerization MMA, But MA, BuMa, s-BuLi
passive)
[147] Iida 2009 T-mixer (active) 0.5–10 mL/h C: 97% Anionic polymerization s-BuLi, NaOH, CaH2
[148] Nagaki 2010 T-shape mixer (3, 3.12–3.25 mL/min C: 99% Anionic polymerization MMA, But MA, BuMa, s-BuLi
passive)
[149] Nagaki 2011 T-shape mixer (2, 1.0–3.0 mL/min C: 100% Anionic polymerization MMA, But MA, BuMa, MeOH
passive)
[150] Nagaki 2012 T-shape mixer (4, 1.75–7.0 mL/min C: 100% Anionic polymerization LiCl, THF, alkyl methacrylates,
passive) tert-butyl acrylate
[151] Venden 2013 SOR-2 static mixer 1–3 mL/min C: 80% RATF polymerization THF, PnBuA, CPD-TTC, DoPAT
(passive)
[152] Méndez 2014 SAR and LLMR mixer 420 mL/min C: 30% Free-radical polymerization L-A75, L-331M80, L-JWEB50,
(passive) MEK
[153] Haven 2015 SOR-2 static mixer 2–5 mL/min Y: 14, 43% RATF polymerization nBA, EHA, AIBN, CPD-TTC,
(passive) DoPAT
[154] Zhang 2015 Zigzag-shape mixer 2.4 kPa N/R Interfacial polymerization TMC, POSS, PIP, JEFF
(passive)
[155] Nagaki 2015 T-shape mixer (3, 3–15 mL/min Y: 99% Cationic Polymerization 2,6-di-tert-butylpyri-dine,
passive) trimethyl(1-phenylv-
inyloxy)silane,
allyltrimethylsilane
[156] Tani 2016 T-shape mixer (2, 5 mL/min Y: 99% Cationic polymerization Cu-AAC
passive)
[157] Nagaki 2016 T-shape mixer (2, 10–30 mL/min Y: 100% Anionic polymerization s-BuLi, n-BuLi, THF, MeOH
passive)
[158] Ryu 2017 T-shape mixer 2, 6 mL/min N/R styrene radical polymerization Toluene, AIBN, styrene
(passive)

N/R: not report; C: Conversion efficiency; Y: Yield efficiency.

for 40 min). Furthermore, the continuous mode reactor suppressed
inter/intramolecular transesterification due to its high mixing and
mass/heat transfer efficiency, and therefore resulted in a narrower
molecular weight distribution (Fig. 17(b)). Table 4 summarizes the
applications of micromixers for polymerization processes reported
in [138–158].
6. Extraction and purification processes [159–191]
Extraction using microfluidic devices is generally applied to
solvent extraction, also known as liquid–liquid extraction. The
extraction process consists of two steps, namely the formation
of a dispersion followed by phase separation. The main parame-
ter governing the extraction process is mass transport across the
690 C.-Y. Lee, L.-M. Fu / Sensors and Actuators B 259 (2018) 677–702
Fig. 19. Schematic illustration of active microfluidic T-mixer for DNA digestion and
restriction. (Reprinted from Ref. [171] with permission of AIP Publishing LLC.).
phase boundary. Consequently, efficient micromixers are essential
in improving the extraction performance [159–162].
Mae et al. [163] presented two SAR micromixers (YM-1 and
YM-2) for the rapid aqueous extraction of phenol from dodecane.
It was shown that both micromixers enabled the production of
soap-free emulsions after very short contact times. In addition,
the emulsion droplet size reduced with an increasing total flow
rate or decreasing oil concentration. The two micromixers achieved
maximum emulsion production rates of 5 L/h (YM-1) and 20 L/h
(YM-2), respectively. It was therefore concluded that both devices
had the potential for application in large-scale industrial plants.
Sprogies et al. [164] evaluated the performance of seven differ-
ent micromixers when applied to the extraction of iodine from an
aqueous solution into n-hexane. The results showed that a mul-
tilamination mixer achieved a better extraction efficiency than a
T-junction mixer (i.e., 0.75 and 0.5, respectively). However, the
extraction efficiency was still significantly lower than that achieved
by a nozzle mixer and SAR mixer (i.e., 0.9 and 0.95, respectively).
Ufer et al. [165] investigated the potential for using suspended
catalyst particles in two-phase slug flow to perform the hydro-
genation of m-nitrotoluene with aqueous potassium formate in a
T-shaped micromixer (Fig. 18). The particle behavior was observed
in various biphasic liquid–liquid systems using a fluorescence illu-
mination technique. In general, the results showed that silicon
dioxide or aluminum oxide particles suspended in the aqueous
phase followed the flow streamlines within the mixer almost
exactly, while carbon-based particles suspended in continuous
Fig. 20. (a) Schematic illustration of assembled device, (b) particle trapping in laminar flow and chaotic flow, and (c) three different micromixer geometries. (Reprinted from
Ref. [177] with permission of American Chemical Society.).
organic phase tended to form a cap around the rear end of the
aqueous slug. Malsche et al. [166] investigated the liquid–liquid
extraction performance of three different mesoflow reactors. For
each mixer, the mass transfer rate and extraction performance were
evaluated using a fluorescence observation method. The LTF-MX
mixer was found to provide the highest extraction performance
at high flow rates, while the vortex-reactor was found to offer a
superior performance at intermediate flow rates. In a later study
[167], the same group combined a continuous flow reactor with
a self-built settler to perform the separation of Co/Ni with cyanex
272. It was shown that the use of the settler resulted in a signif-
icant reduction in the total residence time in both a single-stage
setup and a multi-stage setup. Furthermore, it was shown that the
useful volume of the proposed system was much higher than that
of a conventional mixer-settler system (i.e., a phase-separation-
volume-to equilibrium-volume ratio of 1:2 as opposed to 4:8 for a
conventional system).
The quality of processes such as polymerase chain reaction (PCR)
is fundamentally dependent on the sample condition. Thus, to
improve the detection accuracy of pathogens (for example), purifi-
cation of the DNA sample is first required before the PCR process can
be performed. Furthermore, a higher sample concentration is also
beneficial in improving the detection sensitivity. Consequently,
various micromixers based on a filtering or trapping concept have
been proposed for controlling the buffer concentration or generat-
ing chaotic advection [168–170].
Lin et al. [171,172] presented an integrated microfluidic chip for
rapid DNA digestion and time-resolved capillary electrophoresis
(CE) analysis. The chip comprised two gel-filled chambers for DNA
enrichment and purification, respectively, an active microfluidic
T-mixer for DNA/restriction enzyme mixing (Fig. 19), a serpen-
tine channel for DNA digestion reaction, and a CE channel for
on-line CE analysis. The time-resolved electropherograms showed
that the device was capable of concentrating and analyzing Фx-
174 DNA samples comprising 11 fragments within 24 min. Similar
DNA digestion microfluidic devices based on three different types
of passive micromixer (namely, zigzag, spiral and split-and-merge
(SAM)) were proposed in [173–175].
Lee et al. [176] presented a serpentine chaotic micromixer for
DNA purification purposes, in which fluid twisting and flattening
mixing effects were induced in two channels arranged perpendic-
ularly to one another. The effects of the microchannel geometry
on the mixing performance were systematically explored using
two Tris-HCl buffer solutions with and without fluorescein label-
ing, respectively. Moreover, the DNA purification performance was
confirmed using a sample obtained by dissolving a single hair
root in DNA extraction solution. The results showed that the pro-
posed micromixer greatly simplified the DNA preparation process
compared to traditional methods. Lee and Voldman [177] investi-
gated the performance of three different micromixer designs (i.e.,
 C.-Y. Lee, L.-M. Fu / Sensors and Actuators B 259 (2018) 677–702 691

Fig. 21. Schematic illustrations of single-chamber micromixing and PCR. (Reprinted from Ref. [205] with permission of American Chemical Society.).

Fig. 22. (a) Schematic view of lab-on-a-disc concept, (b) microfluidic chambers for loading LAMP reagent, mixing, metering, sealing, isothermal amplification, detection and
temperature sensing, (c) Salmonella detection processing steps. (Reprinted from Ref. [209] with permission of Elsevier.).

a groove micromixer (SGM), a herringbone micromixer (HM), and
a staggered herringbone micromixer (SHM)) in enhancing the par-
ticle trapping efficiency of DEP-based microconcentrators (Fig. 20).
The results showed that chaotic mixing helped expose more par-
ticles to the DEP field than non-chaotic mixing, and therefore
enhanced the trapping efficiency. Overall, the SHM mixer was
found to provide the optimal performance; with a trapping effi-
ciency around 50% higher than that obtained using a straight and
smooth channel. Table 5 summarizes the proposals presented in
[160–191] for the use of micromixers in extraction and purification
processes.
7. Biological analysis processes [192–231]
Micromixers have been employed in many biological analyti-
cal processes, including stem cell differentiation, cell culturing, cell
lysis, immune response analysis, cancer metastasis, and DNA analy-
sis [192–203]. Micromixers are commonly incorporated within LOC
devices, which integrate several functional miniaturized devices
(including micropumps, microvalves and micro-reaction cham-
bers) to accomplish the complete assay of bio-materials on a single
microfluidic platform. Micromixers also play a key role in PCR or
loop-mediated isothermal amplification (LAMP) devices in the bio-
logical and biochemical engineering fields [204–212].
692 C.-Y. Lee, L.-M. Fu / Sensors and Actuators B 259 (2018) 677–702

Table 5
Summery of micromixer for extraction and purification process applications.

Ref. and First Year Micromixer type Flow rate Index (%) Objective Materials
author

[160] Gürsel 2016 Inline mixer (passive) 10–50 mL/min E: 100% Liquid–liquid Toluene–water–
extraction acetone, acetate–
water–acetone
[161] Azimi 2017 T-type mixer (passive) Re = 75 E: 88.4% Liquid-liquid mass Fe3 O4
transfer
[172] Fu 2007 Doulbe-T mixer 150 V/cm, 5 Hz M: 98% DNA digestion -DNA, Eco RI enzyme
(active)
[173] Kefala 2015 Zigzag, aspiral, SAM Re = 0.5 M: 92% DNA digestion Endonuclease, 635-bp
mixer (passive) DNA
[174] Kastania 2016 Zigzag mixer (passive) 1, 10 mL/min R: 96% DNA purification Salmonella cell, DNA
M: 95%
[175] Tserepi 2014 Zigzag mixer (passive) 3 ␮L/min M: 100% DNA digestion 273-bp DNA, enzyme
Re = 0.208
[178] Kuo 2015 fishbone filtration 0.02 ␮L/s N/R Extraction of human Whole blood, plasma
mixer (passive) plasma
[179] Azimi 2015 Y-type mixer (passive) 5–20 ␮L/min E: >45% Liquid–liquid mass Fe3 O4 , n-butanol
transfer
T: >70%
[180] Domíng 2016 Multilamination, 30 mL/h N/R Supercritical fluid Ethanol, scCO2
T-type mixer (passive) extraction
[181] Shih 2016 Multi-channel mixer 400 ␮L/min E: 100% R: 83–110% Solid phase extraction Mn, Co, Ni, Cu, Pb
(passive)
[182] Jafari 2016 Twisted mixer Re = 77–460 E: 60–100% Liquid–liquid Cu(II),D2EHPA
(passive) extraction
[183] Kakavan 2016 T mixer with PJ, PJC, Re = 181 E: 77.8% (PMN) Liquid-liquid mass 1-octanol, propionic
PJN, PMC, PMN transfer acid
(passive)
[184] Rahimi 2017 CPJ, Y mixer (passive) 0.75–6 ␮L/min R0 : >95% Liquid-liquid mass Fe3 O4 , Cu (II), D2EHPA
transfer
[185] Peng 2017 Y-type mixer (passive) 20–80 ␮L/min E: ∼80% Solid phase extraction Cr(III),Cr(VI)
[186] Domíng- 2017 Multilamination, 25 ␮L/min R: >85% Supercritical fluid Ethanol, scCO2
uez T-type mixer (passive) extraction
[187] Ji 2007 Planar spiral mixer Re < 1 N/R DNA purification DNA from human
(passive) blood
[188] Morales 2010 Vortex mixer (passive) 0.4–2 ␮L/min R: >92% Phenol extraction BSA, 0.1–10-kb DNA
[189] Tai 2011 Membrane- type mixer 0.34 ␮L/s M: 96.7% Sample pretreatment ␤-actin gene, cDNA,
(active) and hybridization mRNA
[190] Chen 2013 Groove-shape mixer 1.67–8.36 ␮L/min A: 100% Sample amplification -DNA, 99-bp DNA
(passive)
[191] Hellé 2015 Thermomixer (active) 0.3–1.0 mL/h E: 90.7% Liquid–liquid Uranium(VI), Aliquat
extraction

N/R: not report; A: Amplification efficiency; E: Extraction efficiency; M: Mixing index.

R: Recovery efficiency; R0 : removal efficiency; T: Mass transfer efficiency.

Kim et al. [205] presented a simple approach for perform-
ing micromixing and biochemical reactions on a single platform
without the need for pumps by using natural convection to mix
the species and capillarity regulation to achieve sample transport
(Fig. 21). The feasibility of the proposed device was demon-
strated by performing the PCR amplification of an influenza viral
DNA fragment. The proposed microfluidic system was reported
to have several important advantages over conventional PCR sys-
tems, including a faster thermal response, a smaller number of
microfluidic device components, and a pumpless operation, which
resulted in a shorter idle time, a simpler and cheaper fabrication
process, and a manual operation. Sayad et al. [209] presented a
centrifugal microfluidic CD-based device for the LAMP detection
of foodborne Salmonella. The CD platform was designed to per-
form all of the steps required to complete the pathogen detection
process, including LAMP reagent loading, mixing, metering, seal-
ing, isothermal amplification, heating and detection (Fig. 22). The
experimental results showed that the device had a detection limit of
5 × 10–3 ng/␮L when tested on tomatoes spiked with Salmonella.
Moreover, the entire process from sample preparation to detection
was completed within 70 min in a fully automated manner.
The detection and quantification of proteins is indispensable
in fundamental research and clinical diagnosis [213]. Lee et al.
[214,215] presented an integrated microfluidic chip (Fig. 23)
consisting of pneumatic micropumps, an active vortex-type
micromixer, a pneumatic micro-injector and several microvalves
for performing the entire C-reactive protein (CRP) detection pro-
tocol [214,215]. The micromixer performed the mixing of the
reagents and biosamples using a driving frequency of 8 Hz and an
applied pressure of 20 psi. The results showed that the integrated
microfluidic system was capable of automatically completing the
entire protocol within 30 min with a detection limit of 0.0125 mg/L.
Furthermore, it was shown that the CRP concentrations obtained
for clinical samples of human serum were in good agreement with
those obtained using a conventional benchtop system.
Circulating tumor cells (CTCs) in the blood of cancer patients is
an important indicator of disease progression and survival. How-
ever, due to the rarity of CTCs in the bloodstream, they must first
be enriched before molecular and cellular analyses can be per-
formed for clinical purposes [203]. Many integrated micromixers
have been proposed to facilitate the perturbation, lysis, separa-
tion, isolation and detection of cells [216–221]. For example, Lin
et al. [216] presented an integrated microfluidic device in which the
CTSs were continuously coated with anti-epithelial cell adhesion
molecule-conjugated beads using a Taylor–Gortler vortex microflu-
idic mixer (Fig. 24). The feasibility of the labeling system was
demonstrated using two different breast cancer cells. The coat-
ing efficiency achieved using 3-mm beads was found to be very
 C.-Y. Lee, L.-M. Fu / Sensors and Actuators B 259 (2018) 677–702 693

Fig. 23. (a) Photograph showing detailed components of integrated microfluidic chip (Reprinted from Ref. [214] with permission of Elsevier.), and (b) schematic illustration
of active vortex-type micromixer. (Reprinted from Ref. [215] with permission of Elsevier.).

Fig. 24. (a) Schematic illustration showing size amplification of cells on chip, (b) microscopic image of silicon mold used to fabricate micromixer microchannel, and (c)
photograph of Taylor–Gortler vortex microchip. Note that all of the channels have the same mixing zone, composed of 20 consecutive wavy ducts. (Reprinted from Ref. [216]
with permission of Elsevier.).

different in each case. Thus, it was inferred that the labeling sys-
tem had good antigen-antibody specificity. Moreover, the device
showed a high-throughput performance with a treatment time
of just 11.25 min for a 7.5 mL blood sample and a flow rate of
600 mL/min.
Bioterrorism and bio-warfare have emerged as major concerns
in recent years. Cho et al. [222] developed an integrated microflu-
idic device for performing the bio-barcode assay-based detection of
biological agents, including botulinum toxin A. The device incorpo-
rated micropumping actuation for sample loading, passive mixing
to induce MM–biological agent–PM complexes [223], magnetic
separation to purify the target–probe complexes, and ␮CE to ana-
lyze the barcode DNAs (Fig. 25). The device was shown to have a
high sensitivity and a total response time of just 30 min.
Many microfluidic devices have been proposed for virus and
bacteria detection and evaluation purposes [224–229]. Lee et al.
[225] presented an integrated microfluidic system based on virus-
bound magnetic bead complexes for the rapid diagnosis of dengue
virus. The device comprised two micropumps, a pneumatic four-
membrane-type micromixer, a microcoil array and a sample
purification chamber. The device permitted the simultaneous
detection of IgG and IgM in two different detection chambers. The
experimental results showed that the proposed device achieved a
detection time of just 30 min (around 8 times faster than a con-
ventional benchtop method). Moreover, the detection limit was
found to be 21 pg (around 38 times better than that of a traditional
method). Zhang et al. [227] developed a microfluidic mixer-based
method for determining the inactivation kinetics of Escherichia coli
in chlorine solutions. The mixer incorporated three different mixing
designs, namely Y-junction, Dean vortex, and chaotic, to accurately
determine the reaction time and control the chlorine concentration
(Fig. 26). It was shown that the device enabled the pathogen inac-
tivation kinetics to be assessed in less than 1 s. Table 6 presents a
brief review of the other main applications of micromixers in the
biological analysis field reported in [193–231].
8. Droplet/emulsion and other processes [232–260]
Microfluidic droplet (or emulsion) devices are designed to
enable chemical reactions to be carried out inside microdroplets
with a volume on the order of a few microliters or less. Gener-
ally speaking, the microfluidic droplets or emulsions are formed
and suspended in an immiscible phase such as oil, water in oil, or
water/oil/water. Micromixing is then achieved by means of chaotic
694 C.-Y. Lee, L.-M. Fu / Sensors and Actuators B 259 (2018) 677–702

Fig. 25. (a) Schematic illustration of biobarcode assay based biological agent detection, (b) photograph of assembled micro device for micropumping, passive mixing,
magnetic separation, and ␮CE, and (c) photograph of assembled micro device showing sample and probe inlets, micropump and passive mixer. (Reprinted from Ref. [222]
with permission of Royal Society of Chemistry.).

Fig. 26. (a) Schematic illustration of microfluidic mixer that simulates instant cross-contamination and sanitization scenarios, and (b) photograph of sample microfluidic
device used to simulate pathogen survival scenarios. (Reprinted from Ref. [227] with permission of Elsevier.).

advection induced by either droplet motion or the channel shape
[232–245].
Yeh et al. [236] presented a gradient-microfluidic droplet gen-
erator consisting of J-junction block passive micromixers and
flow-focusing devices to generate droplets with four different sizes
and concentrations. It was shown that the size of the droplets
could be precisely controlled by adjusting the relative flow rates
of the water phase and oil phase, respectively. The feasibility of the
proposed platform was demonstrated by generating Ca-alginate
microcapsules with different concentrations of BSA for drug release
purposes. In a later study [237], the same group developed a similar
microfluidic droplet generator to produce water droplets with 11
different trypan blue concentrations. The water droplets were then
used to encapsulate magnetic Fe3 O4 nanoparticles for potential
use in the drug delivery or pharmaceutical fields. The experimen-
tal results showed that the chitosan emulsions had a coefficient of
variation of less than 10% and a microparticle size of 44–83 ␮m.
Turbulent flow provides an effective means of achieving homo-
geneous mixing. However, generating turbulent flow in microscale
channels presents a major challenge. Accordingly, You et al. [242]
fabricated a Y-shaped turbulence microfluidic mixer in which the
bonding strength between the PDMS and glass substrates was
enhanced via a chemical surface treatment process using epoxy
and amino functional groups to form a doubly-crosslinked nanoad-
hesive (DCNA) layer (Fig. 27). The improved bonding strength
provided by the DCNA allowed the mixer to be operated with water
flow rates as high as 40 mL/min (corresponding to a Reynolds num-
ber of Re = 4423). Notably, the high flow rate enabled a yield of
as much as 10 mg of emulsion to be obtained within one minute.
The corresponding throughput (4.0 × 106 droplets per second) was
thus far higher than that obtained using conventional droplet
microfluidic devices with a typical throughput of just a few tens
of thousands.
Lee et al. [243] developed a magnetic droplet microfluidic sys-
tem in which the mixing performance was enhanced by means of
acoustic excitation (Fig. 28(a)). The experimental results obtained
using droplets of methylene blue and glycerol (5 wt%) showed
that a fully mixed condition could be achieved within 60 s when
acoustic excitation was applied, whereas the droplets remained
unmixed in the absence of excitation. In addition, it was shown
that droplets of a different size were excited at different acous-
tic frequencies. As a result, the device offered the possibility for a
selective mixing performance. Samiei et al. [246] presented an elec-
trohydrodynamic (EHD) technique for performing the rapid mixing
of stationary droplets on digital microfluidic platforms by apply-
ing a high frequency AC voltage to induce circulation zones within
 C.-Y. Lee, L.-M. Fu / Sensors and Actuators B 259 (2018) 677–702 695

Fig. 27. (a) Experimental setup for measuring pressure drop along microfluidic channel, and (b) intensity profiles, corresponding snapshot images, and simulated concen-
tration contour images at inlet and outlet. (Reprinted from Ref. [242] with permission of Royal Society of Chemistry.).

Table 6
Summery of micromixer for biological analytical process applications.

Ref. and First Year Micromixer type Flow rate Index (%) Objective Materials
author

[193] Chen 2007 Filtration mixer 1–25 ␮L/min M: ∼90% Cell separation, lysis and DNA Whole blood.
(passive) purification
[194] Huh 2007 Actuated mixer (active) 1.96 Hz M: ∼90% Cell disruption Escherichia coli
[196] Nason 2011 Zig-zag shaped mixer 0.3–3 ␮L/min M: 79.4% Drug screening SaOS-2 cell
(passive)
[197] Wang 2012 Ribcage mixer 0.05 mL/h M: ∼100% Protein concentration Bovine serum albumin (BSA)
(passive) measurements
[198] Balbino 2013 Vortex mixer (passive) 140 mm/s N/R Produce pDNA/CL complexes. Plasmid DNA, cationic
liposome
[199] Lin 2014 Bubble-driven mixer 25–400 mL/h M: 90% Bladder cancer biomarker Bladder cancer
(active) detection
[200] Aguirre 2015 Trapezoid type mixer Re = 11 B:2% v/v blood Incubation and separation MCF7 breast cancer cell
(passive) cancer cell
[203] Lee 2017 Multivortex mixer 400 ␮L/min R: 90.63% Isolation of circulating tumor MCF-7 cell
(passive) cells
M: ∼80%
D: ∼99%
[206] Choi 2012 Multi-layer mixer 12 ␮L/min N/R PCR-microarray system 11 types genes
(passive) (100-bp ∼ 290-bp)
[208] Geissler 2014 Air stream mixer Re ∼100 M: ∼90% DNA hybridization assays L. monocytogenes, P. ramorum
(passive) and V. dahlia DNA
[211] Louns- 2013 Serpentine mixer 10 ␮L/min A: 6-fold PCR system ␤-globin, gelsolin genes
bury (passive)
[213] Li 2013 Dual-focusing mixer 35 kPa M: 93% DNA–protein interaction G-quadruplex, SSBP
(passive)
[215] Yang 2015 Vortex-type mixer 300 ␮L/min M: > 96% (7 Hz) C-reactive protein C-reactive protein
(active) measurement
[217] Rajabi 2014 SAR and SHM mixer 2000 ␮L/min CL: 100% Cell perturbation, lysis, and CHO cell
(passive) separation
[218] Femmer 2015 SHM mixer (passive) Re = 10 N/R Gas-liquid contact oxygenation Red blood cell
device
[220] Cosen- 2015 3-SERP mixer (passive) Re = 0.1 M: 93% Red blood cell lysis Red blood cell
tino
[223] Gao 2015 Acoustic mixer 125–150 Hz B: >50% Antibody-antigen binding Antibody-antigen
(passive) assay
[226] Wang 2013 USCC mixer (passive) Re > 80 M: >80% Bacteria detection and Escherichia coli
quantification
[229] Petkovic 2017 Rotary mixer (active) Re = 0.02 N/R Detection of Hendra virus Hendra virus
[230] Jung 2011 Serpentine 3D mixer 3.8–100 ␮L/h CP: 100% Multiplex pathogen detection 3 bacteria cells, barcode DNA
(passive)
[231] Liu 2016 3D U-type mixer 0.21 ␮L/min M: >90% Analysis of biomacromolecules G-quadruplex
(passive) folding kinetics

N/R: not report; A: Amplification efficiency; B: Binding efficiency; CL: Cell lysis efficiency.
CP: Cell capture efficiency; D: Depletion efficiency; M: Mixing index; R: Recovery efficiency.

the droplets, thereby prompting a rapid mixing of their contents
(Fig. 28(b)). It was reported that the proposed platform had sev-
eral key advantages over conventional mixing methods, including
a shorter mixing time, a lower number of electrodes (and hence a
smaller size), and a stationary operation (i.e., a reduced risk of cross
contamination and surface bio-fouling).
In addition to the critical roles played by micromixers in the
chemical and biological applications described above, micromixers
can also be used to perform important functions such as microflu-
idic switching; nanocomplex, oxidation and adduct formation;
velocity measurement; supercritical fluid fractionation; and so on
[247–253]. Bezagu et al. [248] presented a rapid active mixer based
696 C.-Y. Lee, L.-M. Fu / Sensors and Actuators B 259 (2018) 677–702

Fig. 28. (a) Schematic illustrations of magnetic droplet manipulation system actuated by magnetic actuation and acoustic excitation (Reprinted from Ref. [243] with permis-
sion of Elsevier.), and (b) schematic illustrations of electrohydrodynamic mixing in open DMF and closed DMF systems. (Reprinted from Ref. [246] with permission of Royal
Society of Chemistry.).

Fig. 29. Ultrasound-induced vaporization of a perfluorocarbon phase for efficient mixing in microfluidic channels. (Reprinted from Ref. [248] with permission of Royal Society
of Chemistry.).

on the localized vaporization of a perfluorocarbon stream sand-
wiched between two fluid streams at the focal zone of an ultrasound
transducer (Fig. 29). It was shown that a thorough mixing of the
PFC stream with the adjacent fluid streams was achieved within
approximately 100 ms after the application of an acoustic pulse.
Moreover, laminar flow was re-established within approximately
the same time scale; thereby enabling the PFC phase and mixed
phase to be easily separated at the outlets of the mixing channel.
Van den Brink et al. [251] developed a microfluidic electrochem-
ical cell with an integrated passive gradient rotation micromixer for
the oxidation and adduct formation of xenobiotics. The micromixer
was designed specifically to mix liquids in the shallow channels
required for thin-layer electrochemical flow cells. Moreover, its
operating principle was based on a rotation of the concentration
gradient over the entire channel height. The gradient rotation mixer
enabled the reactive oxidation products to be mixed with additional
reagents within seconds after they were generated and with an
efficiency of ∼80% (i.e., ∼8-fold higher than that achieved in a typ-
ical T-junction mixer). Table 7 presents a brief review of the other
main proposals for the use of micromixers for droplet/emulsion and
other processes reported in [234–260].
9. Conclusions
Micromixers continue to receive significant attention in the
research community due to the tremendous advantages they bring
to the fields of chemical, biological, medical and environmental
analysis. Since the year 2000, more than 2300 papers focusing
on the topic of micromixers have been published. Furthermore,
these papers have been the subject of more than 40000 citations
(January 2010–June 2017: ISI Web of Science). Of these papers,
around 20%–25% relate to the applications of micromixing tech-
 C.-Y. Lee, L.-M. Fu / Sensors and Actuators B 259 (2018) 677–702 697

Table 7
Summery of micromixer for droplet/emulsion and other process applications.

Ref. and First author Year Micromixer type Flow rate Index or size Objective Materials

[234] Furtaw 2009 Serpentine mixer 1–3 ␮L/min Ei: 35-fold Liquid–liquid droplet Ag colloids, PBS solution
(passive) process
[235] Matsu- yama 2010 Orifice-shaped mixer 3–45 L/h D: 5–30 ␮m Emulsification process Cyclic dimethyl silicon,
(passive) aqueous solution
[238] Ribeiro- Costa 2009 LTCC mixer (passive) 1.1–2.2 L/h Ee: 61–75% Emulsion/solvent BSA, PLGA
evaporation process
[239] Matsu- yama 2011 K-JET mixer (passive) 3–50 L/h D:10–100 ␮m Emulsification process Cyclic silicone, PVA, gel
capsule
[240] Montillet 2013 T-shape mixer Re: 5–23(O), D: <10 ␮m Emulsification process Sunflower oil,
(passive) 30–163(W) demineralized water
[241] Maillot 2014 Serpentine mixer 33–165 mm/s N/R Microfluidic droplet BSA, PVB
(passive) process
[244] Chen 2017 Laminar mixer Po = 500 mbar M: 98% Microfluidic droplet AcPHF6, ThT, orange G
(passive) process
Pw = 440 mbar D: ∼100 ␮m
[245] Larrea 2017 Slit-interdigital mixer 36–54 mL/min Ee: 100% Emulsification process SiO2 , Au, PLGA
(passive)
[247] Abadi 2013 SAR mixer (passive) 40 ␮L/min M: 85% Measured pH HCl, NaOH
[249] Bohr 2017 3D circular mixer 36 mL/min PDI: 0.3 Nanoconplex PDDA, PSS
(passive) production
[250] Santillo 2012 Turbulent vortex mixer 20 mL/min Mean size 60 nm Nanoparticle MoS2
(passive) precipitation
[252] Ergin 2015 Magnetic mixer 0–70 mm/s N/R Micro PIV Nile-red fluorescent,
(active) ␥-Fe2 O3
[254] Guo 2011 Serpentine mixer 30–80 ␮L/h D: 1–1.3 nL Microfluidic droplet Soybean oil, HgCl2 , Hg(II)
(passive) process
[255] Giuffrida 2015 Serpentine mixer 0.2–1 ␮L/min D: 20 nL Microfluidic droplet- K562 cell, miR-201, dNTPs,
(passive) ICSDP process RNaseOUT
[256] Ochs 2015 Serpentine mixer 0–67 psi N/R DNA synthesis in GGA compatible DNA,
(passive) droplet process
[257] Jin 2015 Bumpy mixer (passive) 100–500 ␮L/h D: ∼70 ␮m Microfluidic droplet Mineral oil, PBS, cell,
process
[258] Qu 2017 Heating mixer (active) 0.5 W, 1.56 GHz M: ∼100% Microfluidic droplet DMOS, xylene
process
Y: 60%
D: 20 ␮L
[259] Akbari 2017 3 spiral mixers 50–3000 ␮L/h D: 10–60 ␮m Cell micro- PEG-4-NH2 , PEG-4-NHS,
(passive) 3.1 MHz encapsulation process MDA-MB231 cell
[260] Bokharaei 2017 Laminar jet mixer 0.05–1 ␮L/min Ee: 96% Protein drug delivery BSA, PLLA
(passive) process
D: 20–30 ␮m

N/R: not report; Ee: Encapsulation efficiency; Ei: Enhancement intensity; D: Droplet diameter (size).
M: Mixing index; PDI: Polydispersity index; R: Production Recovered; Y: Yield efficiency.

nology, while the remainder concern the fundamental element

Fig. 30. Statistical breakdown of published literature in micromixing field by appli-
cation type.
development or enhanced micromixing performance of micromix-
ers. Fig. 30 presents a simple statistical breakdown of the published
research (from 2004 to 2017, but mostly in the past ten years)
covered in this review in terms of their related applications. As
shown, the main application fields include chemical reactors (18%),
biological analysis (17%) and chemical synthesis (16%).
Recent years have witnessed a persistent trend toward the
development of ␮TAS or LOC devices with integrated micromixers.
As described earlier in this review, micromixers can be classified as
either passive or active; depending on the manner in which species
mixing is performed. Passive micromixers contain no moving parts
and require no energy input other than the pressure head used to
drive the fluid flows at a constant rate. As a result, they are eas-
ily fabricated, designed and integrated in LOC devices. By contrast,
active microfluidic mixers stir or agitate the fluid flow using some
form of external energy supply. Thus, they tend to be bulkier than
passive mixers and less easily integrated in LOC devices. Conse-
quently, of the studies reviewed in this article, around 90% consider
passive micromixers.
Overall, the results presented in this review confirm the impor-
tance of micromixing technology for applications in the chemical,
biological, medical, environmental analysis, and chemical indus-
tries. While significant advances in micromixing technology have
been made in recent years, it seems likely that micromixing will
698 C.-Y. Lee, L.-M. Fu / Sensors and Actuators B 259 (2018) 677–702
continue to thrive as an active research field for years (if not
decades) to come as microfluidic and micro-electro-mechanical
systems (MEMS) technologies continue to evolve and progress.
Acknowledgements
The authors would like to thank the Ministry of Science and
Technology of Taiwan for the financial support of this study
under Grant Nos. MOST 103-2320-B- 020-001- MY3, MOST 103-
2221-E-020-025-MY3, MOST 106-2314-B-020 −002 −MY3, MOST
106-2221-E-020 −019 −MY3, MOST 106-2622-B-020-001 −CC2,
and 106TFDA-A-103.
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Biographies
Chia-Yen Lee received his BS and MS degrees in Department of Mechanical Engi-
neering from National Taiwan University, Taiwan in 1991 and 1993, respectively. He
received his PhD degree in Department of Engineering Science from National Cheng
Kung University, Taiwan in 2004. Before he studied for his PhD degree, he worked
as an engineer, an assistant manager and a section head in TECO, York and DiCon for
3, 1 and 2 years, respectively. He is currently an professor in the Graduate Institute
of Materials Engineering at National Pingtung University of Science and Technol-
ogy. His research interests lie on microfluidics, micro-sensors and applications of
nano-materials to micro-sensors.
Lung-Ming Fu received M.S. and Ph.D. degrees in Engineering Science from National
Cheng Kung University (NCKU), Taiwan, in 1997 and 2001. He had his postdoc
training in Department of Engineering Science at NCKU during 2002–2003. He is
currently a distinguished professor in the Graduate Institute of Materials Engi-
neering at National Pingtung University of Science and Technology. His research
interests are in Microfluidic systems, MEMS fabrication technologies, Micro-sensor
and Computational fluid dynamics.