Chemical Engineering Science 66 (2011) 1463–1479

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Chemical Engineering Science

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

Nanoparticle synthesis in microreactors

Chun-Xia Zhao a,n, Lizhong He a, Shi Zhang Qiao b, Anton P.J. Middelberg a
a
The University of Queensland, Australian Institute for Bioengineering and Nanotechnology, Centre for Biomolecular Engineering, St Lucia, QLD 4072, Australia
b
The University of Queensland, Australian Institute for Bioengineering and Nanotechnology, ARC Centre of Excellence for Functional Nanomaterials, St Lucia, QLD 4072, Australia

a r t i c l e in fo abstracts

Article history: Nanoparticles have been a research focus for more than two decades. The advent of microfluidic
Received 30 June 2010 technology provides alternative strategies for the synthesis of nanoparticles in reactors having a
Received in revised form micrometer length scale. The integration of nanoparticle and microreactor technologies delivers
26 August 2010
enormous opportunity and impetus for the further development of novel materials and reactors. In this
Accepted 27 August 2010
article, recent achievements in the synthesis of nanoparticles in microfluidic reactors are reviewed. A
Available online 19 September 2010
variety of strategies for synthesizing nanoparticles are presented and compared, including continuous
Keywords: flow, gas–liquid segmented flow and droplet-based microreactors. Different categories of nanoparticles
Nanoparticles manufactured in microreactors are summarized to highlight the wide application of microfluidic
Microreactor
systems in the development of novel nanomaterials. The control of nanoparticle synthesis is also briefly
Continuous flow
discussed.
Segmented flow
Droplets & 2010 Elsevier Ltd. All rights reserved.
Emulsions

1. Introduction
Nanoparticles (NPs) have been widely used in diverse areas
such as electronics, energy, textiles, biotechnology and medicine,
bio-imaging, bio-sensing, and gene and drug delivery (Weng et al.,
2008). Increasing interest has been attracted to the synthesis and
study of nanoparticles over the past two decades. A variety of
synthetic methodologies for the preparation of NPs within a
narrow size distribution are available. These methods are
typically grouped into two main categories. The ‘‘top-down’’
approach involves the construction of nanoparticles from a much
larger solid by milling (Lam et al., 2000), attrition, etc., while the
‘‘bottom-up’’ approach involves the condensation of atoms or
molecular components in a gas or liquid phase. The latter
approach is generally considered to be far more promising due
to the higher level of control offered. Within the ‘‘bottom-up’’
paradigm, numerous kinds of nanoparticles have been produced
by liquid-phase synthesis, using a number of techniques such as
co-precipitation of sparingly soluble products by addition reac-
tion, exchange reaction, reduction reaction, oxidation or hydro-
lysis, etc. (Cushing et al., 2004), sol–gel processing (Trewyn et al.,
2007), microemulsions (Eastoe et al., 2006), and more recently
biomimetic synthesis (El Rassy et al., 2005; Kang et al., 2006).
Generally, these approaches use the traditional ‘‘beaker methods’’.
These methods lack precise control over the mixing, nucleation
and growth processes, and thus final particle size, size distribution,
n et al., 2005), colloids (Kohler et al., 2005), zeolites (El-Sayed et al.,
Corresponding author. Tel.: + 61 7 3346 4263; fax: + 61 7 3346 4197.
E-mail address: z.chunxia@uq.edu.au (C.-X. Zhao).
crystal structure, etc. Sufficient mixing and rapid mass transfer
can significantly improve these parameters, which in turn control
both the physical and chemical properties of NPs.
Microfluidic technologies offer a variety of advantages over
conventional technologies for the synthesis of nanoparticles (Marre
and Jensen, 2010). First of all, the intrinsic small volume of
microreactors allows the use of expensive or toxic chemicals
without necessitating large inventory and processing volumes.
Secondly, the large surface area to volume ratio of microreactors
offers enhanced heat and mass transfer in comparison with
conventional reactors. Thirdly, some reactions which are too fast
to be controlled in traditional reactors can be easily accomplished in
microreactors due to the massively reduced characteristic time of
the transport processes at the micrometer length scale, which may
become comparable to that of the chemical reaction. Moreover,
efficient mixing is a key advantage for preparing monodispersed
nanoparticles in microreactors, and microfluidic devices provide
potential for automating multi-step processes, such as combining
analysis, reactions and purification in a single microchip and
realizing the final ‘‘lab-on-chip’’ design. In all, microreactors offer
many paradigm-changing opportunities for exploring and develop-
ing novel nanoparticle synthesis routes. Therefore, nanoparticles
with a certain particle size, uniform size distribution, and desired
structure can be formed in a better controlled reaction in
microreactors (Jiang et al., 2004). Numerous researchers have
emphasised the synthesis of nanoparticles using microreactors, such
as for semiconductors (Taton et al., 2001; Karhanek et al., 2005;
Medintz et al., 2005), metals (Panyam and Labhasetwar, 2003; Yang
2005), and organic compounds (Veiseh et al., 2005).

0009-2509/$ - see front matter & 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ces.2010.08.039
1464 C.-X. Zhao et al. / Chemical Engineering Science 66 (2011) 1463–1479
In this article, we briefly review state-of-the-art research for the
synthesis of nanoparticles in microfluidic reactors. The detailed
synthesis strategies of nanoparticles or composites in microfluidic
devices are outlined first; some comparative examples of the use of
special designed approaches to produce nanomaterials are also
provided to enhance understanding of nanoparticle synthesis on the
microscale. Then, the categories of nanoparticles manufactured in
microreactors are introduced to highlight the hot areas for
nanoparticle synthesis research. The control of microfluidic pro-
cesses is also briefly discussed.
2. Microfluidic synthesis strategies of nanoparticles
Chemical reactions are by far the most widely used method for
the synthesis of nanoparticles in both bulk solutions and
microfluidics. Generally, two or more reactants participating in
the reactions are brought together and reacted. The products with
low solubility precipitate producing nanoparticles. During this
precipitation process, nucleation, growth, coarsening, and/or
agglomeration occur simultaneously in bulk reactions. Difficulties
in isolating these processes independently make it difficult to
fully understand and precisely control the nanoparticle formation
process, and thus the final nanoparticle products. Microreactors,
generally defined as reactors having micrometer length scale
fabricated by microtechnology and precision engineering, exhibit
significantly enhanced control over each single process indepen-
dently. Microreactors can be mainly grouped into two categories:
continuous flow microreactors and segmented flow microreac-
tors. The latter one can be further divided into two sub-groups:
gas–liquid (bubbles) segmented microfluidic reactors and liquid–
liquid segmented or droplet-based microfluidic reactors. These
different reactors are reviewed in this section.
2.1. Continuous flow microreactors
Presently, the synthesis of most nanoparticles is carried out in
batch operations. Continuous synthesis is believed to be one of the
most promising advantages of microreactor technology. Continuous
flow microreactors are generally more productive, and are able to
improve the homogeneity of reaction solutions which leads to a
more uniform product (Jahn et al., 2008). Decreasing flow channels
down to the micrometer scale allows facile change of experimental
conditions within microseconds, and the reaction volume is also
greatly reduced to microlitres (Boleininger et al., 2006). In addition,
the chemical composition of the mixture can be continuously varied,
as different reagents can be added along the reaction channel, in
Fig. 1. Schematic diagram of single tubing reactors for nanoparticle synthesis: (A) silica glass capillary for CdSe nanoparticles ((Nakamura et al., 2002a)—reproduced by
permission of The Royal Society of Chemistry); (B) multi-step continuous reactor for CdSe/ZnS nanocrystals ((Wang et al., 2004)—reproduced by permission of The Royal Society
of Chemistry).
contrast to droplet-based reactors (Chang et al., 2008), which allows
the connection of individual reactions in series into multi-step
reactions (Abou-Hassan et al., 2009a). An additional advantage of the
continuous synthesis platforms is that scale-up is straightforward
either by increasing the running time or by simply running reactions
in parallel, therefore shortening the development time from
laboratory to commercial production (Ying et al., 2008). Further-
more, a continuous process is energy efficient due to the elimination
of high energy consumption for repeated heat-up and cool-down in
batch systems, and minimizes overall process inventory. Continuous
flow microreactors, based on an internally connected microchannel
network, can be generally categorized into two groups: the simplest
capillary tubes constructed by mechanical assembly and more
sophisticated on-chip microchannel networks fabricated using, for
example, lithography developed for the microelectronics industry.
2.1.1. Capillary tubes
The capillary-tube microfluidic reactor is a kind of micro-
reactor that is scaled down from normal tube reactors to have a
flow crosssectional area with a dimension at the micron level.
Silica glass (Fig. 1A) (Nakamura et al., 2002a), stainless steel
(Ju et al., 2006) and polymers (PVC and PEEK) (Boleininger et al.,
2006) have all been used to fabricate reactors having microscale
internal dimensions, and represent the simplest microreactors for
the synthesis of nanoparticles. The microscale diameter of these
capillaries or tubes facilitates improved size and composition
control in the nanoparticle synthesis field, especially providing for
accurate temperature control. It has been shown that only 0.4 s
was needed for a 200 mm diameter channel to heat a liquid from
20 to 300 1C (Nakamura et al., 2002a). Therefore, with the single
tubing microreactors, the reaction temperature can be easily and
accurately controlled and altered with a water or oil bath, or an
oven, and temperature can range from below room temperature
to several hundred degrees. Furthermore, several tubes can be
connected in series enabling multi-step synthesis of core–shell
composite particles, starting with formation of a CdSe nanopar-
ticle core followed by coating of a ZnS layer in the second step
(Fig. 1B). Two oil baths supply separated temperature control for
nanoparticle nucleation and growth, which indicates the flex-
ibility of microcapillaries or tubes (Wang et al., 2004). Using
transparent tubes (glass or polymer) also facilitates direct
observation of particle formation and the occurrence of nanopar-
ticle aggregation inside the tube (Boleininger et al., 2006).
2.1.2. Coaxial flow microreactor
Capillary-tube microreactors provide some advantages over
other formats, such as simplicity, high flexibility, and ease of
 C.-X. Zhao et al. / Chemical Engineering Science 66 (2011) 1463–1479 1465

manufacture and operation, and so on, but some problems
remain, including blockage of the channel, adhesion to the
channel surface, and a relatively high product polydispersity. A
microfluidic device assembled by coaxial dual tubes (Fig. 2A) was
developed in an attempt to resolve problems including clogging
and high polydispersity which exist in single-tubing microfluidic
reactors (Takagi et al., 2004). Titania nanoparticles with narrow
size distribution were prepared in this coaxial flow microreactor
by an annular laminar flow of two immiscible liquids: tetra-
isopropoxide (TTIP) in the inner tube and isopropanol/water in
the outer tube, and no precipitation of particles on the tube wall
was observed. A water–liquid paraffin two-phase segmented
coaxial dual-tube microfluidic device (Fig. 2B) has also been
reported for synthesizing ultrafine zeolite A crystals (Pan et al.,
2009). Inert solution (liquid paraffin) was used as a continuous
phase, and synthesis solution was used as the dispersed phase.
Thus, the synthesis solution was encased in continuous phase,
which avoids direct contact between the reaction mixture and the
wall of the microchannel. The outer tube was immersed in an oil
bath to control the synthesis temperature. Iron oxide nanoparti-
cles were synthesized in a coaxial flow microreactor with a size
less than 7 nm (Abou-Hassan et al., 2008). Goethite nanoparticles
have also been synthesized by separating the nucleation and
growth processes, a coaxial flow microreactor for nucleating the
primary particles thus avoiding clogging or precipitation on
the channel walls, and the single-tubing reactor for the growth
of the goethite nanoparticles (Abou-Hassan et al., 2009b).
Magnetic and fluorescent g-Fe2O3/SiO2 core/shell nanoparticles
have been synthesized in a continuous multi-step lab-on-chip
platform by connecting three coaxial flow microreactors in series
that enables sequential reactions (Abou-Hassan et al., 2009a).
2.1.3. 2-D micromixing based reactors
Owing to the absence of turbulence due to the low Reynolds
number in microscale channels, mixing is predominately by
molecular diffusion. Furthermore, the laminar flow leads to a broad
residence-time distribution, which causes wide particle size dis-
tributions. Therefore, maximizing the mixing in microfluidic reactors
is an extremely important objective. Rapid and tunable mixing in
microfluidics is particularly important for better control over the
process of nanoprecipitation. Three main structures – flow-focusing
(Fig. 3A), Y-shape (Fig. 3B) and T-type (Fig. 3C) microchannels – are
widely used. A hydrodynamic flow-focusing microchannel was used
to synthesize PLGA–PEG nanoparticles by rapidly mixing polymer-
acetonitrile solutions and water (Karnik et al., 2008). Two vertical
fluid streams mix with the central channel stream, and the narrow
width of the focused stream enables rapid mixing through diffusion.
Y-shaped microfluidic devices have been applied for making nano-
sized drug particles with the aim of enhancing the solubility of
poorly water soluble drugs (Ali et al., 2009a, 2009b). The molecules
were first dissolved in solvent and were then precipitated by adding
non-solvent. A narrow-sized nano-suspension composed of amor-
phous spherical particles with a mean particle size of 500764 nm
has been obtained with this approach (Ali et al., 2009b). A T-type
microchannel reactor has also been employed to prepare mono-
dispersed nanocrystals of barium sulfate and boehmite (Ying et al.,
2008). The T-type microchannel reactor provides a vortex chamber

Fig. 2. Schematic of microfluidic synthesis of nanoparticles using coaxial flow microreactors: (A) schematic of a microfluidic device assembled by coaxial dual tubes
(reprinted from (Takagi et al., 2004), Copyright (2008), with permission from Elsevier); (B) (a) general flowchart of the microfluidic system, (b) detailed illustration of the
coaxial dual pipe assembly (reprinted with permission from (Pan et al., 2009). Copyright 2009 American Chemical Society).

Fig. 3. Microreactors for nanoparticle precipitation: (A) flow focusing microchannel; (B) Y-shaped microchannel; and (C) T-type microchannel.
1466 C.-X. Zhao et al. / Chemical Engineering Science 66 (2011) 1463–1479
Fig. 4. Micro-mixer based microreactors: (A) flow-through microreactor for the
synthesis of gold nanoparticles (reprinted from (Wagner et al., 2008), Copyright
(2008), with permission from Elsevier); (B) micro flow-through synthesis of core–
shell nanoparticles (reproduced with permission from (Kohler et al., 2007)); (C)
Image of microfabricated reaction device ((Edel et al., 2002)—reproduced by
permission of The Royal Society of Chemistry).
Fig. 5. Microfluidic reactors using micro-electro-mechanical-system (MEMS) technology: (A) PDMS-based microfluidic control module consisting of microchannels, two
micro-pumps, a micro-valve and a micro-mixer (Reproduced with permission from Weng et al., 2008); (B) PDMS-based microfluidic system consisting of two micro-pumps, a
micro-valve and a double-loop rotary micromixer (with kind permission from Springer Science + Business Media (Lee et al., 2009)).
at the T-junction. With high flow velocity, the impinging of the two
reactants at the T-junction leads to chaotic flow. The turbulence
provides an efficient micromixing of the reactants, and monodis-
perse BaSO4 nanocrystals of 18 nm were prepared (Ying et al., 2008).
The size of barium sulfate is strongly dependent on the velocity of
the reactants in the channel, and high velocity is beneficial for
producing small particles. Static chip micro-mixers containing split
and recombine units based on Si/glass technology have been used
for the preparation of nanoparticles (Wagner et al., 2008). Fig. 4A
shows a mixer with eight split and combine units. Firstly in
micromixer I, tetrachloroaurate solution and buffer solution (potas-
sium carbonate) were mixed, and then in the second mixing step
water was added. After the second residence loop, the reducing
agent (NaBH4) was mixed with the other educts in micromixer III
(Fig. 4A). The fluid channels were designed through three planes
resulting in an efficient lamination of the inlet streams of liquids.
A microfluidic system consisting of a two-step static micromixer,
which was also constructed based on the split and recombine
principle, a residence loop, and a T-connector, has been utilized for
the preparation of AuAg core–shell nanoparticles (Fig. 4B) (Kohler
et al., 2007). The conditions of local transport and mixing by inter-
diffusion depend strongly on the flow rate and the local geometry.
Another fast micromixer (Fig. 4C), developed by Bessoth et al.
(1999), contained two inlet flows, which were split into a series of
separate multichannel streams (16 partial flows). After mixing, the
channels were sequentially combined in a reverse network until all
partial flows were united in one outlet channel. The entire mixing
volume for the micromixer was less than 600 nl (Edel et al., 2002).
A complete reactor system can also be made by integrating other
units around the micromixer by using micro-electro-mechanical-
system (MEMS) technology. A MEMS-based microreactor has been
designed for the synthesis of gold nanoparticles. It integrated a
microfluidic control module (micro-pumps, a micro-mixer, and a
micro-valve) and a micro-temperature control module (micro-
heaters and a micro-temperature sensor) on a single chip (Fig. 5A).
Peristaltic pneumatic micro-pumps and a micro-valve were em-
ployed to drive and to control the sample fluids, and a single-loop
micro-mixer was used to mix the samples. When the micro-mixer
was activated, the fluid was moved clockwise and was then mixed.
Furthermore, micro-heaters and a micro-temperature sensor were
also integrated for temperature control. With this approach,
hexagonal gold nanoparticles without observable aggregation were
successfully synthesized, with the reaction time significantly
reduced from 30 min (traditional flask methods) to 5 min (Weng
et al., 2008). A double-loop rotary micromixer has also been
developed for controlling the fluids in either the clockwise or
counterclockwise directions to enhance mixing efficiency (Fig. 5B)
(Lee et al., 2009). It allows for a rapid and effective approach to
accelerate and to automate the synthesis of iron oxide nanoparticles.
 C.-X. Zhao et al. / Chemical Engineering Science 66 (2011) 1463–1479
2.2. Gas–liquid segmented microfluidic reactors
There are two approaches to enhance mixing in microreactors.
The first one is passive mixing, as described above, which depends
on the complexity of the channel structures. The other is active
mixing, which utilizes segmentation to improve mixing (Khan and
Jensen, 2007). Either liquid–liquid or gas–liquid segmented flow
reactor can be used for this purpose (Gunther et al., 2005;
Gunther and Jensen, 2006). Gas–liquid segmented flow reactors
are attractive due to the simple separation process of the gas from
the liquid. In addition, compared with continuous flow micro-
reactors, which have a wider residence time distribution (RTD)
and thus a wide particle size distribution due to the parabolic
velocity profile (Fig. 6A (a)), segmented flow microreactors can
narrow the RTD by carrying out reactions in segmented liquid
slugs, and segmenting gas is used to create recirculation and thus
enhance mixing within an individual liquid slug (Fig. 6A (b)).
In addition to enhanced mixing, another advantage of gas–
liquid segmented microfluidic reactors is that small liquid
reacting entities can be separated from each other by gas bubbles,
thus reducing axial dispersion. These two effects collectively
provide a well-defined residence time for a microreactor. The
narrowed residence time, in turn, reduces particle size poly-
dispersity. It has been proved experimentally that segmentation
of a reaction solution by N2 bubbles is effective for narrowing the
particle diameter of CdSe nanocrystals in capillary microreactors
(Nakamura et al., 2002a). A narrow size distribution of silica
particles, which is difficult or impossible to produce in a
conventional laminar flow reactor, has been generated by using
gas–liquid microfluidic reactors (Khan et al., 2004).
The gas–liquid segmented flow reactor can be constructed in
different ways, and typical designs are compared in Fig. 6B–D.
Fig. 6. Segmented gas–liquid flow microreactors: (A) (a) schematic of parabolic
velocity profile in continuous flow microreactors, (b) schematic of the flow pattern
in segmented flow microreactors; (B) straight channel (reprinted with permission
from (Khan et al., 2004). Copyright 2004 American Chemical Society); (C) With
four inlets (reprinted with permission from Khan et al. (2004). Copyright 2004
American Chemical Society); (D) Meandering channels ((Gunther et al., 2004)—re-
produced by permission of The Royal Society of Chemistry).
1467
Fig. 6B consists of two liquid inlets (L1 and L2) followed by a gas-
injection nozzle (G) and an outlet (O). In the design of Fig. 6C,
micromixing is accomplished by first introducing four streams of
liquid into a long micromixing section, followed by gas injection
to create slugs to increase recirculation and mixing during the
aging process (Khan et al., 2004). Both Fig. 6B and C use straight
channels although they differ in the design of inlets. As an
alternative to straight channels, the design in Fig. 6D consists of
meandering channels (Gunther et al., 2004). These meandering
channels can further enhance radial mixing through periodically
switching recirculation patterns across the centre of channels.
Although gas–liquid micromixing greatly enhances micromixing
performance, careful operation and very low throughput are
usually required to achieve stability of the special flow pattern
(Ying et al., 2008).
Recently, different channel designs have been compared by
Fries and von Rohr (2009a, 2009b). Changes of channel geometry
(radius of the bend, turning angle and channel diameters) can
decrease mixing time by a factor of 8 (Fries and von Rohr, 2009b).
Even solely changing the inlet design can alter liquid slug or
bubble length by a factor of 4 (Fries and von Rohr, 2009a). The
velocity profile is symmetric in a straight channel, while it
becomes asymmetric when a meandering configuration is
adopted.
Residence time distribution (RTD) is a critical parameter in
determining performance of a gas–liquid segmented reactor,
particularly for the size distribution of nanoparticles (Gunther
et al., 2004; Gunther and Jensen, 2006). It is thus important to
experimentally characterize and/or theoretically predict RTD.
Trachsel et al. (2005) has compared RTD of a continuous flow
microreactor and gas–liquid segmented reactor, and found the
latter one can significantly narrow RTD. Different tracers such as
colored dyes, fluorescent species or pH indicators can be injected
to the system to characterize mixing and determine RTD. Details
of characterization methods can be found in a recent review
article (Aubin et al., 2010). Mixing can also be analyzed using
numerical simulation as recently carried out by Fries and von
Rohr (2009b).
2.3. Droplet-based microreactors
Multiphase microfluidic flow has made significant advances in
the past decade. Owing to advantages including large interfacial
area, efficient mixing and fast mass transfer, well controlled
droplet or plug flows have been widely used in nanoparticle
synthesis (Mantzaris, 2005). Moreover, the encapsulation of
reactions in segmented droplets or plugs can also protect the
nanoparticles from contact with microchannel walls, and thus
avoid undesired blocking or contamination of channels (Poe et al.,
2006; Song et al., 2008a). The self-recirculation flow in the
segmented droplets can also intensify mixing and eliminate axial
dispersion (Burns and Ramshaw, 2001; Schabas et al., 2008).
Microfluidic droplet techniques have been widely developed and
provide an approach able to improve mixing efficiency and
provide better control over the concentration of reagents.
Depending on the microstructure of the emulsion droplets,
synthesis of nanoparticles in microreactors can be characterized
as single-emulsion based, double-emulsion based or coalescence
based.
2.3.1. Single-emulsion based methods
A single-step reaction can be achieved in microfluidic channels
by encapsulating reagents within droplets or plugs (Song et al.,
2003). For example, BaSO4 nanoparticles have been synthesized in
a controlled two-phase flow in a T-junction microchannel device.
1468 C.-X. Zhao et al. / Chemical Engineering Science 66 (2011) 1463–1479
Droplets of barium chloride aqueous solution were formed by
cross-flowing rupture in butyl alcohol, hexyl alcohol, or octyl
alcohol solutions with sulfuric acid. The reaction of sulfuric acid
with barium chloride took place at the droplet interface. The
turbid dispersed aqueous phase indicated the chemical reaction
occurred on the aqueous side of the interface and the produced
particles remained in the dispersed aqueous side (Li et al., 2008).
The nanoparticle size varies greatly with flow pattern and droplet
size even at the same initial concentration. As an alternative, two
aqueous reagent streams can be converged into droplets through
a short segment of channel where the streams initially flow
laminarly alongside each other (labeled R1 and R2 in Fig. 7A)
(Shestopalov et al., 2004). To prevent these two reagents from
mixing before the droplet formed in the water-immiscible
solvent, an inert stream was introduced between them (labeled
S in Fig. 7A). Winding channels then induced rapid mixing by
chaotic advection. After mixing, the droplets were allowed to
react while flowing through a serpentine section of the channel
(labeled ‘‘reaction 1’’ in Fig. 7A). Reaction times could be
controlled by adjusting flow rates or by designing and fabricating
networks with different lengths of channel between junctions. For
synthesizing nanoparticles in droplets at high temperature, a
serpentine flow-focusing glass microreactor with a step increase
in channel height (Fig. 7B) has been designed. Cadmium and
selenium precursors flowing in octadecane droplets through a
high-temperature (240–300 1C) reaction zone produced high-
quality CdSe nanocrystals (Chan et al., 2005). A novel approach for
designing a microfluidic reactor for the high-temperature synth-
esis of semiconductor nanocrystals was developed by Winterton
et al. (2008) using a two-phase flow profile consisting of nanoliter
Fig. 7. Droplet-based microreactors for synthesizing nanoparticles: (A) micro-
graph of a microfluidic device for performing droplet-based two-step synthesis
((Shestopalov et al., 2004)—reproduced by permission of The Royal Society of
Chemistry); (B) microreactor channel design with droplet jet injector (reprinted
with permission from Chan et al. (2005). Copyright 2005 American Chemical
Society); (C) schematic layout of conceptual microfluidic reactor design (with kind
permission from Springer Science + Business Media (Winterton et al., 2008).
droplets of organic solvents in perfluorinated polyether. The flow
channels of the reactor were configured to spiral in and out of a
series of reaction coins contained within each reactor unit
(Fig. 7C). The size and operating temperature of each coin can
be independently controlled to permit the temperature profile of
the reactor to be tuned to the requirements of the synthesis,
allowing the nucleation and growth stages to be temporally and
spatially separated (Winterton et al., 2008). Taken together, these
studies illustrate the range of syntheses that can be conducted by
combining two-phase flows with specified geometric designs in
microreactors.
To perform a multi-step nanoparticle synthesis with this droplet-
based microfluidic method, additional reagent must be added to the
droplets. This addition can be accomplished by merging one stream
of droplets with a second stream of droplets from R3 (Fig. 7A) (Song
et al., 2003). The resulting droplets were mixed as they flowed
through a winding section of channel. Similarly, additional streams
can be added further downstream. The amount of reagent added to
droplets could be adjusted by changing the flow rate of the
additional reagent streams (Shestopalov et al., 2004). At a low total
flow velocity (67 mm/s), the aqueous stream immediately coalesced
with the initial droplet and injected solution into the droplet. At a
critical higher flow velocity (133 mm/s), the aqueous stream R3
formed a visible interface with the droplet, and the droplet coalesced
with the reagent stream just downstream of the junction. At even
higher total flow velocities, the aqueous stream R3 formed an
interface with the initial droplet, but the interface never broke
(Shestopalov et al., 2004). CdS/CdSe core–shell particles can be
synthesized by infusing a stream of Na2Se through the quench inlet
(Shestopalov et al., 2004).
As an alternative to reaction within the bulk of the droplet
proper, emulsion droplets have also been used as soft templates to
make microspheres, microcapsules and microgels. A number of
approaches have been utilized to solidify droplets, such as using
ultraviolet (UV) or thermal energy by carrying UV or thermal curable
polymers, solvent evaporation or diffusion-induced self-assembly,
gelation, interfacial reaction, and so on. A series of self-assembling
water-in-oil (W/O) emulsions consisting of aqueous Na-alginates
were formed in a cross-junction microchannel, and then dripped
into a solution of 20% calcium salt to form Ca-alginate microspheres
by gelation (Fig. 8A) (Huang et al., 2006). Furthermore, gold
nanoparticles as a model drug can be encapsulated at an excellent
level of entrapment efficiency. PLGA microspheres have been made
using oil droplets of chloroform containing poly(DL-lactide-co-
glycolide) (PLGA) and CdSe/ZnS QDs in a poly(vinyl alcohol) (PVA)
and chitosan (CS) aqueous solution in a microfluidic cross-junction,
and solvent evaporation was used to solidify the droplets (Fig. 8B)
(Chang et al., 2007). The removal of chloroform induces cross-linking
of the PLGA matrix and leads to shrinkage of the microspheres.
Microfluidic-based synthesis of non-spherical magnetic hydrogel
microparticles with different morphology (spheres, disks and plugs)
have been synthesized in a T-junction channel via UV-initiated
photopolymerization (Fig. 8C) (Hwang et al., 2008). Microcapsules
have also been produced through interfacial radical polymerization
under UV irradiation using water droplet containing N-isopropyla-
crylamide (NIPAM) monomer and cross-linker as templates in a
flow-focusing microchannel, with the oil phase containing the
photoinitiator as the continuous phase (Fig. 8D) (Choi et al., 2008).
With the poly-NIPAM (PNIPAM) layer at the interface becoming
thicker, the polymerization rate becomes slower due to slowed
diffusion of free radicals into the aqueous phase. When no radical
diffuses across, the interfacial polymerization ceases and hollow
microcapsules with a shell of membrane were obtained. Mesopor-
ous silica microspheres have also been synthesized by an one-step
in situ rapid solvent diffusion-induced self-assembly of droplets
containing ethanol-rich silicate precursor within a cross-junction
 C.-X. Zhao et al. / Chemical Engineering Science 66 (2011) 1463–1479 1469

Fig. 8. Microparticle synthesis using droplet templating microreactors: (A) schematic of monodispersed Na-alginate microemulsions generator in a cross-junction
microchannel ((Huang et al., 2006)—reproduced by permission of The Royal Society of Chemistry); (B) schematic drawing of the formation of microgels in a microchannel
cross-junction (Reproduced with permission from Chang et al. (2007)); (C) schematic diagram of the T-junction microfluidic channel with aluminium reflectors for spherical
and non-spherical magnetic hydrogel synthesis: sphere, disk, and plug ((Hwang et al., 2008)—reproduced by permission of The Royal Society of Chemistry); (D) schematic
illustration of the synthesis of ordered mesoporous silica particles using microfluidic diffusion-induced self-assembly (Copyright Wiley-VCH Verlag GmbH & Co. KGaA.
Reproduced with permission from (Lee et al., 2008)); (E) schematic diagram of flow-focusing microfluidic device used to synthesize monodisperse thermo-sensitive hollow
microcapsules ((Choi et al., 2008)—reproduced by permission of The Royal Society of Chemistry); (F) schematic diagram of a microfluidic reactor for fabrication of hollow
titania microspheres ((Gong et al., 2009b)—reproduced by permission of The Royal Society of Chemistry).

microchannel (Fig. 8E) (Lee et al., 2008). Hollow titania microspheres
have been fabricated in a flow-focusing microreactor by using
precursor dissolved in hexadecane as the continuous phase, and
water in glycerol as the dispersed phase (Fig. 8F) (Gong et al.,
2009b). Hydrolysis starts around the droplets as soon as the droplet
is formed. The carrier fluid (paraffin+butanol) introduced from inlet
3 was designed to gradually dissolve the hexadecane, which allowed
the butanol to absorb water from droplets, and thus ensures further
hydrolysis. After that, a quench step was introduced to cease the
hydrolysis reaction. This approach provides another strategy for
using the droplets as a soft template by containing precursor
solution in the continuous phase. More examples, including the use
of droplet templates to prepare Janus or ternary particles,
functionalized microspheres, microcapsules and microgels will be
presented in Sections 3.5 and 3.6.
2.3.2. Double-emulsion based methods
Several microfluidic approaches are available to prepare double
or multiple emulsions. Microfluidic devices with two consecutive
T-junctions (Okushima et al., 2004; Nisisako et al., 2005), or two
flow-focusing regions (Seo et al., 2007; Chen et al., 2009b;
Hennequin et al., 2009), with local surface modification, were
designed for the formation of double emulsions. A coaxial micro-
capillary device has also been developed by Utada et al. (2005) to
produce double emulsions; Chu et al. (2007) reported an alternative
1470 C.-X. Zhao et al. / Chemical Engineering Science 66 (2011) 1463–1479
Fig. 9. Double emulsion templating microreactors: (A) schematic picture and
photograph (inset) of the microfluidic flow-focusing device for the core/shell double
emulsion (Copyright Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced with
permission from (Gong et al., 2009a)); (B) scheme of the PDMS device for forming
double emulsion droplets consisting of the hydrophobic monomer core with
magnetic material (black) that is encapsulated by a hydrophilic monomer droplet
(white) suspended in fluorocarbon oil (gray) (Copyright Wiley-VCH Verlag GmbH &
Co. KGaA. Reproduced with permission from Chen et al. (2009a)).
microcapillary technique. Microfluidic devices in combination with
pneumatically controlled moving-wall structures have also been
presented to generate double emulsions (Lin et al., 2008a, 2008b;
Lao et al., 2009). Core/shell microspheres comprising an inner core of
aspirin solution and an outer shell of high molecular weight
chitosan, embedded with magnetic nanoparticles, were fabricated
in a flow-focusing microchannel using a double emulsion template
(Fig. 9A) (Gong et al., 2009a). The outermost chitosan layer
composed of magnetite particles was dehydrated by dewetting
(Gong et al., 2009a). Double emulsions (O/W/O), produced in a
double flow-focusing microchannel spatially patterned with a
sol–gel layer functionalized with photoreactive silanes, were applied
to form magnetic hydrogel particles with uniform anisotropic
features (Fig. 9B) (Chen et al., 2009a). The aqueous outer droplet
shell and the inner hydrophobic ferrofluid were polymerized by UV
exposure and thermal cross-linking, respectively (Chen et al., 2009a).
2.3.3. Coalescence based reactors
Instead of encapsulating all the reagents in one droplet, or one
regent in the droplet and another in the continuous phase,
there is still another way that two droplets containing different
reagents can be contacted and coalesced to initiate the reaction. The
concept of fusing droplets has been shown previously (Song et al.,
2003; Tan et al., 2004), but controlled droplet fusion, especially
for the fusion of same-sized droplets, is still a challenge due to the
difficulty in manipulating droplets under relatively high flow
velocities. Microfluidic technology capable of controlling and
manipulating single droplet in a precise manner offers a promising
approach for controlling droplet coalescence. Monodisperse sodium
alginate microparticles with diverse shapes (such as plugs,
disks, microspheres, rods, and threads) were produced using this
coalescence-based approach by the control of the microchannel
geometric confinement and liquid-phase flow rates (Liu et al., 2006).
Two individual flow-focusing sections were used to generate sodium
alginate and CaCl2 droplets, followed by fusing them in a circular
expansion chamber to initiate the reaction (Fig. 10A) (Liu et al., 2006).
A circular expansion chamber was also applied for fusing the droplets
from the main and branch channels (Fig. 10B), where CaCl2 meets,
and then coalesces with, alginate droplets. High (93%) droplet
fusion occurred in this chamber (Zhao et al., 2009). A double
T-junction microreactor with tapered chamber was designed to
generate alternating droplets (Fig. 10C). The alternating droplet
generation was the result of a ‘‘push–pull’’ mechanism. By adjusting
the relative flow rates in the two reagent inlet channels, the device
allowed continuous alternating droplet formation with droplet ratios
from 1:5 to 5:1. The tapered chamber was designed to generate a
velocity gradient and allow droplet approach and drainage of the oil
film between droplets. The channel width reduction between the
tapered channel and the outlet channel increased the flow pressure to
promote film rupture and facilitate droplet fusion. Both surface-
tension driven mixing and picoliter droplet volume expedited mixing
speed and efficiency. This facilitated the chemical reaction taking
place in each fused droplet and prevents aggregation. Therefore,
nanoparticles and small reactant size distributions were achieved
(Hung et al., 2006). A micromixer was used for the coalescence of
0.01 M BaCl2 and 0.01 M (NH4)2SO4 droplets, and BaSO4 nanoparticles
with an average diameter of 15 nm were produced (Su et al., 2007).
2.4. Comparison of different microfluidic approaches
Continuous flow microreactors have been used to rapidly grow
and characterize inorganic nanocrystals (Nakamura et al., 2002a;
Chan et al., 2003; Yen et al., 2003; Wang et al., 2004). High tempera-
tures, caustic precursors, and rapid kinetics involved in the synthesis
of semiconductor nanocrystals pose a big challenge for microfluidic
techniques (Yen et al., 2003). Capillary or tube microfluidic reactors
with their unique characteristics such as simplicity, robust materials
(such as steel, silica glass, or strong polymers) and high temperature
adaptability can meet the stringent demands, so have attracted
attention for the synthesis of semiconductor nanocrystals. However,
some inherent disadvantages, such as the particle size distribution
broadened by the velocity and residence time distributions inherent
to microfluidic laminar flow (Yen et al., 2003), the contamination of
channel walls due to the deposition of nanoparticles, clogging
(Shestopalov et al., 2004) and so on, urge microfluidic scientists to
develop new strategies. Segmented flow microreactors consist of
two distinct types which can use either bubbles or liquid drops to
produce segments. In a gas–liquid segmented reactor, inert gas
bubbles are produced to enhance mixing by creating recirculation
within a liquid slug while decreasing axial dispersion by separate
liquid slugs from each other. The reduced RTD significantly
narrows the nanoparticle size distribution (Gunther et al., 2004).
This gas–liquid based technique offers a distinguishing advantage,
e.g. easy separation of gas from liquid, but still suffers from
deposition or clogging since the nanoparticles produced may contact
the channel wall. In contrast, the liquid–liquid segmented flow
approach encapsulates the precursor solution in liquid droplets, so
that they do not interact with channel walls, and thus contamination
or clogging can be completely avoided. Furthermore, these droplets
can be precisely controlled and manipulated in microfluidic reactors,
such as through droplet formation, separation, fusion and so on.
Alternatively, using droplet templating technology for manufactur-
ing microspheres, microcapsules and microgels has been intensively
investigated in recent years, and hybrid microparticles functiona-
lized with nanoparticles such as magnetic nanoparticles, quantum
dots or drugs provide great potential in a vast range of applications.
 C.-X. Zhao et al. / Chemical Engineering Science 66 (2011) 1463–1479 1471

Fig. 10. Coalescence based microreactors: (A) (a) schematic diagram of the microfluidic device pattern; the microfluidic device includes (b) one flow-focusing channel for
generating the sodium alginate droplets and (c) another flow-focusing channel for generating CaCl2 droplets; (d, e) fusion channels with two circular expansion chambers
(reprinted with permission from Liu et al. (2006). Copyright 2006 American Chemical Society); (B) schematic diagram of the device used for the synthesis process:
(a) magnified photograph of the droplet formation; (b) the device used for the generation of magnetic-alginate JPs; (c–f) the gelation induced by CaCl2 solution in the fusion
chamber ((Zhao et al., 2009)—reproduced by permission of The Royal Society of Chemistry); (C) schematic diagram of the microchannel pattern for the droplet fusion
((Hung et al., 2006)—reproduced by permission of The Royal Society of Chemistry).

3. Categories of nanoparticles prepared in microreactors
3.1. Metallic or inorganic nanoparticles
Metallic or inorganic nanoparticles show different chemical,
physical, optical and thermal properties when compared with
bulk solids, due to the relatively larger amount of high-energy
surface and the nanometer-scale mean free path of electrons in
metals. The effects of surface diffusion of atoms can also be magnified
as the relative time for a surface-exposed atom to move from one
side of a particle to another is greatly reduced by the smaller length
scales involved. Varied wet chemical methods have been used for the
synthesis of metallic or inorganic nanoparticles, including co-pre-
cipitation, sol–gel processing, microemulsions, hydrothermal and
solvothermal processing, templated synthesis, and biomimetic
synthesis. This section reviews approaches for different metallic
and inorganic nanoparticle synthesis in microfluidic devices.
3.1.1. Semiconductor (CdS, CdSe and CdSe/ZnS)
Semiconductor nanoparticles have many potential and estab-
lished applications in areas including electronics, optics, chemical
catalysis and solar energy conversion due to their unique
properties, which rely in particular on particle size as well as
crystal shape and structure. Therefore, increasing efforts have
been made to produce nanoparticles with well-defined size and
desired crystal structure (Hines and Guyot-Sionnest, 1996).
Continuous-flow microreactors, especially capillary or tube
microreactors, in combination with precise temperature control,
have been widely used to synthesize inorganic nanocrystals
(Nakamura et al., 2002a; Chan et al., 2003; Yen et al., 2003; Wang
et al., 2004).
The CdSe nanocrystal is one of the most intensively studied
semiconductors because of potential applications including as
fluorescence tags and in optical memory and electronic devices.
CdSe nanocrystals are often prepared in a surfactant, like trioctyl
phosphine (TOP) and its oxide (trioctyl phosphine oxide, TOPO), at
high temperature (250–350 1C). This method can produce high
quality CdSe nanocrystals, but usually a small batch (about
5–50 mL) (Peng and Peng, 2001) is required to ensure adequate
control of reaction conditions. High quality CdSe nanocrystals
have been synthesized continuously in microcapillaries of fused
silica (Nakamura et al., 2002a, 2002b), glass capillaries (Nakamura
et al., 2002a), and in a droplet-based 2-D glass microreactor (Chan
et al., 2005). CdS nanocrystalline semiconductors have been
prepared in a 2-D micro-mixing-based reactor (Fig. 4C) developed
by Bessoth et al. (1999). To increase the relatively low quantum
yield of fluorescence, a surface-capping layer of, e.g. ZnS or CdS
can be deposited on the CdSe nanocrystals (Talapin et al., 2001). In
addition, ZnS-capped CdSe is useful as a fluorescent biological
label (Bruchez et al., 1998). The fluorescence properties of
ZnS-capped CdSe are determined by the ZnS shell thickness.
1472 C.-X. Zhao et al. / Chemical Engineering Science 66 (2011) 1463–1479
ZnS-capped CdSe nanocrystals with a quantum yield (QY) of over
50% and a narrow size distribution have been produced using the
commercial single-molecular precursor (diethyldithiocarbamic
acid zinc salt, [(C2H5)2NCSS]2Zn) of ZnS in a fused silica capillary
microreactor (Wang et al., 2005). Highly luminescent CdSe/ZnS
NCs having QY up to 70% and a narrow particle size of 30 nm were
synthesized by firstly mixing CdSe and ZnS precursors in
a convective micromixer, followed by flow through a heated
PTFE capillary for the final coating process (Luan et al., 2008).
An on-line detector system was developed to optimize the
synthesis of CdSe nanoparticles, and it was found that tempera-
ture, reaction time and the concentration of reaction additive are
important parameters controlling properties of CdSe nanoparti-
cles (Toyota et al., 2010).
3.1.2. Gold/silver
Noble metal nanoparticles are interesting materials for medical
applications (Yguerabide and Yguerabide, 1998). Size control of
gold nanoparticles plays a crucial role due to the critical interplay
between biology and physics at the nanoscale level; for example,
the uptake of gold nanoparticles into mammalian cells is shape
dependent (Chithrani et al., 2006). Shape is also important in
purely physical applications, for example in optics, where rod-
shaped nanoparticles often have superior optical properties due to
the optical antenna effect (Link and El-Sayed, 2000; Mohamed
et al., 2000; Sonnichsen et al., 2002). In all cases, the availability of
dispersed nanoparticles lacking significant aggregation is an
essential pre-requisite for practical application. Until now, the
chemical reduction method is still one of the most popular
methods used to produce a large quantity of dispersed nanopar-
ticles of diameter less than 10 nm (Henglein, 1993). Among the
available shape-controlled synthesis processes, the formation of
hexagonal gold nanoplates has attracted considerable interest (Sun
and Xia, 2002). Gold and silver nanoparticles with size between 4
and 7 nm were prepared by reduction of metal salt solutions
(tetrachloroaurate solution HAuCl4 or silver nitrate AgNO3) with
borohydride (NaBH4) in a static chip micro-mixer, manufactured
using Si/glass technology, and containing eight split and recombine
units at room temperature (Wagner et al., 2008). A micro-electro-
mechanical-system, integrating micro-mixer, micro-pumps, a
micro-valve, micro-heaters and a micro-temperature sensor, was
designed to synthesize hexagonal gold nanoparticles. Mixing and
heating time for gold salts and reducing agents are important
factors influencing the final products (Weng et al., 2008). A mixing-
based reactor possessing eight split and recombine units was
designed to facilitate efficient mixing for the synthesis of gold
nanoparticles, and elevated pH (around 9.5) and modified hydro-
phobic surface was tested to reduce reactor fouling as a result of
the uncontrolled deposition of gold particles (Wagner and Kohler,
2005). Transparent PVC tubing was used to prepare gold nanorods,
which showed no visible particle aggregation on the walls. PEEK
capillaries were used to make silver rods. Tests with other tubing
materials showed clogging and particle aggregation on the walls
(Boleininger et al., 2006). These continuous microreactors allow the
reproducible and controlled synthesis of noble nanoparticles,
although the fundamentals physical processes still require elucida-
tion. Recently, anisotropic gold nanoparticles have been prepared
by a droplet-based microfluidic approach which prevents contact
of nanocrystals with channel walls (Duraiswamy and Khan, 2009).
This method also enables fine-tuning particle shapes from sphere
to rod structure.
3.1.3. TiO2
Titania nanoparticles and microspheres are of particular
interest owing to their diversified applications including in
photocatalysts (Oregan and Gratzel, 1991; Joo et al., 2005),
photovoltaic materials, paint pigments, dye-sensitised solar cells
(Oregan and Gratzel, 1991; Jiu et al., 2006), sensors (Zhu et al.,
2002), and so on. Typical applications in photocatalytic reactions
and photovoltaic efficiencies require low material density, high
surface area, and high light-trapping and conversion efficiency
(Kasuga et al., 1998). TiO2 nanorods have been synthesized in a
two-input/one-output Y-shaped microfluidic chip (Cottam et al.,
2007) placed in an oven at 90 1C. The use of an oven rather than a
more conventional hot plate provided improved thermal stability
and reproducibility. Compared to the technically demanding and
time consuming methods including layer-by-layer polyelectro-
lyte-mediated deposition, colloidal-particle templating or spray-
drying (Caruso et al., 1998; Jiang et al., 2001; Zhu et al., 2003) for
the preparation of hollow titania microspheres, an alternative
approach using a metal alkoxide as a precursor and emulsion
droplets as soft templates was implemented in a facile manner in
microreactors by controlling water diffusion, which initiates the
hydrolysis on water droplets (Gong et al., 2009b).
3.1.4. Magnetic nanoparticles (iron oxide/cobalt)
Magnetic nanoparticles are finding increasing practical and
research application in areas including biomedical imaging
(Nishibiraki et al., 2005; Hong et al., 2008), bio-sensing and
diagnosis (Pankhurst et al., 2003), biological sample labeling and
sorting (Bulte et al., 2001; Lehmann et al., 2006; Pipper et al.,
2007) and controlled drug delivery (Alexiou et al., 2000). For
biological or biomedical applications, particle size, the nature of
surface coatings (Wang et al., 2007) and the need for dispersed
nanoparticles lacking significant aggregation are again important
factors determining scope for practical application. Of the
available preparation techniques including co-precipitation
(Cheng et al., 2005), thermal decomposition (Huh et al., 2005),
laser ablation (Chen et al., 2004), and microscale encapsulation
(Shchukin et al., 2003), the co-precipitation method is still one of
the most common methods used to produce magnetic nanopar-
ticles due to its simplicity. Cobalt nanoparticles with three
polymorphs (face-centered cubic (fcc), hexagonally close packed
(hcp), and epsilon (h) phases) have been produced in a micro-
fluidic process (Song et al., 2006). Amorphous cobalt (Song et al.,
2009b) and cobalt samarium (Song and Henry, 2009a) nanopar-
ticles with stable crystal structures and magnetic properties have
also been synthesized in microreactors by using elevated reaction
temperatures followed by rapid quenching of the colloids to
reduced temperatures.
3.1.5. Others
Zeolite A with a small size and narrow size distribution has been
prepared in a single-phase stainless steel microchannel reactor (Ju
et al., 2006). A two-phase segmented microfluidic device using
coaxial dual tubes (Pan et al., 2009) was developed to solve
problems which occur in single-phase microfluidic reactors, such
as blockage of the channel, the need for long aging times, and the
broad particle size distribution that results. Zeolite NaA with
different particle sizes and particle size distributions could be
synthesized in the microchannel reactor by adjusting the aging time,
the crystallization temperature and the residence time in the
microreactor. Barium sulphate, widely used as packing materials
and as an additive in paints, coatings and plastics, has been
produced in a large-scale micro-porous tube-in-tube microchannel
reactor (MTMCR) (Wang et al., 2009). The throughput can be up to
9 L/min, and the production capacity was greatly increased
compared to typical microreactors operating at 4–100 mL/min.
Palladium nanoparticles have been prepared using a glass
capillary microfluidic reactor system (Torigoe et al., 2010).
 C.-X. Zhao et al. / Chemical Engineering Science 66 (2011) 1463–1479
The synthesized nanoparticles were stabilized by poly(benzyl ether)
Dendron ligand. The Pd nanoparticles prepared from the micro-
fluidic system has a monodisperse particle size (3.170.2 nm),
which could not be achieved using a conventional batch reactor.
The synthesis of doped nanoparticles has been an important
topic due to their novel optical and electronic properties different
from those of bulk materials (Kane et al., 1999; Norris et al., 2001).
The synthesis of doped nanoparticles by a chemical route is
complex. Many parameters influence the synthesis and in
particular nanoparticle growth, and nanoparticles readily undergo
‘‘self-purification’’, an intrinsic mechanism through which impu-
rities are expelled (Erwin et al., 2005; Dalpian and Chelikowsky,
2006). Water soluble 1-thioglycerol-capped Mn-doped ZnS nano-
crystalline semiconductor nanoparticles (TG-capped ZnS:Mn)
have been synthesized by mixing a solution of Zn and Mn
precursors (0.016 M ZnCl2, 0.004 M MnCl2, 0.02 M of 1-thiogly-
cerol) with 0.02 M Na2S in a microfluidic reactor (Singh et al.,
2008). Mn was successfully doped in a ZnS semiconductor at
room temperature as well as at 80 1C.
3.2. Core–shell particles
Core–shell materials offer two categories of advantages over
uniform particles. Firstly, varied electronic, photonic and chemical
properties can be formed with tailored structure and composition.
Secondly, a robust shell provides a protective, biocompatible or
inert surface with desired hydrophobicity. Typical particle cores
can be polymeric, inorganic (e.g., silica) or metallic (e.g., gold)
with size between 2 and 10 mm. Spherical gold-core–silver-shell
nanoparticles have been formed in a two-step procedure in a
microreaction system with a two-step static micromixer and a
T-connector, and a second outer polymer layer can be formed
even if the polymer solutions were added in an early stage of
particle formation (Kohler et al., 2007). Fluorescent silica-coated
magnetic nanoparticles have been prepared in a coaxial flow
based multi-step microreactor system (Abou-Hassan et al.,
2009a). The silica shell protects the inner nanoparticle and offers
a biocompatible and hydrophobic surface, while the g-Fe2O3
nanoparticles offer the possibility of targeting using, for example,
directed magnetic fields. Moreover, incorporation of chromo-
phores in the silica shell provides magnetic and luminescent
core–shell nanocomposites with applications as contrast agents
for molecular imaging. A continuous-flow microreactor has been
used for the preparation of titania-silica core–shell particles by
multi-step addition and rapid mixing of small amounts of coating
reactant (Khan and Jensen, 2007). Core–shell microspheres,
comprising an inner core of aspirin solution and an outer shell
of high molecular weight chitosan, embedded with magnetic
nanoparticles, were also fabricated in a double-emulsion tem-
plated flow-focusing microreactor (Gong et al., 2009a).
3.3. Self-assembly of quantum dots
Hierarchical colloids self-assembled from nanoparticles pre-
sent some specific and unique properties (Alivisatos, 1996; Boal
et al., 2000; Lin et al., 2003). Microreactors offer immense
potential for the controlled self-assembly of nanoparticles into
higher-order structures. Blends of block copolymer-stabilized CdS
quantum dots (QDs) with external polystyrene (PS) brush layers
(PS-CdS) and polystyrene-block-poly-(acrylic acid) (PS-b-PAA)
stabilizing chains co-dissolved in dimethylformamide (DMF) can
self-organize into mesoscale spherical assemblies termed ‘‘quan-
tum dot compound micelles’’ (QDCMs) (Yusuf et al., 2007) in a
single-phase flow-focusing microchannel. A gas–liquid microflui-
dic reactor has been applied to induce QDCM formation via water
1473
addition and self-assembly (Schabas et al., 2008). Compared to the
single-phase flow-focusing microfluidic reactor, mixing was
greatly enhanced by chaotic advection within the sinusoidal
mixing channel. However, the polydispersities of QDCM were not
improved, and it was discovered that the mean sizes and
polydispersities of the assemblies, immediately following self-
assembly, were largely governed by the steady-state water
content, regardless of very different mixing times. Furthermore,
mean QDCM sizes and polydispersities were both significantly
decreased in the post-formation channel by tunable processing of
the assemblies due to shear-induced particle breakup within the
recirculating flow fields of the liquid plugs (Schabas et al., 2008).
It was further demonstrated that QDCM size can be tuned in the
range of 40–140 nm (Wang et al., 2010). However, shear-induced
particle breakup was limited to a common minimum particle size
around 40 nm (Wang et al., 2010). These observations underline
the importance of microfluidic control, offering a mechanism to
separate and individually control complex reaction steps.
3.4. Polymer nanoparticles
Compared with the breadth of activity at the intersection of
inorganic nanoparticles and microfluidics, relatively little has
been done for the synthesis of organic nanoparticles. The
synthesis of biodegradable poly(lactic-co-glycolic acid)-b-poly-
(ethylene glycol) (PLGA–PEG) polymeric nanoparticles has been
achieved in a hydrodynamic flow-focusing microchannel by
nanoprecipitation (Karnik et al., 2008). Particle size, polydisper-
sity and drug loading can be varied by flow rates, polymer
composition, and polymer concentration (Karnik et al., 2008). A
nano-suspension of hydrocortisone, a practically water insoluble
drug, was prepared by controlled precipitation using a micro-
fluidic technique (Ali et al., 2009b). An axisymmetric flow-
focusing microchip was utilized to synthesize cross-linked
alginate microparticles and nanoparticles using aqueous alginate
droplets as templates, followed by the shrinkage of the drops due
to the water diffusion to the continuous phase (Rondeau and
Cooper-White, 2008). In the case of very low alginate concentra-
tion (0.001–0.005%), biopolymer nanoparticles of sizes ranging
from 10 to 300 nm were generated. Considering the high potential
of polymer nanoparticles to provide new drug delivery vehicles, it
is likely that microfluidics will find increasing use for their
controlled synthesis.
3.5. Janus or ternary particles
Janus particles (JPs), particles with at least two physically or
chemically different surfaces, have attracted increasing interest
due to the dual-functionalized optical, electronic, and sensor
devices (Perro et al., 2005) and their surfactant-like behavior near
interfaces. The production of Janus particles can be achieved by a
wide variety of approaches, such as a selective masking (Takei and
Shimizu, 1997), colloidal crystallization (Velev et al., 2000),
microcontact printing (Cayre et al., 2003), electrical jetting (Roh
et al., 2005), controlled coalescence of two distinct droplets
followed by solidification of the merged phases (Millman et al.,
2005), phase separation (Gu et al., 2004), and through template-
directed self-assembly (Yin et al., 2001). Janus and ternary
polymer particles with sharp interfaces have been synthesized
in a flow-focusing microfluidic device by employing the breakup
of two or three parallel largely immiscible liquids into droplets,
followed by UV irradiation (Nie et al., 2006). Monodisperse hybrid
Janus microspheres (HJM) having organic and inorganic parts
have been prepared in a simple cross-flowing microfluidic device
using merged perfluoroplyether (PFPE) (the organic phase) and
1474 C.-X. Zhao et al. / Chemical Engineering Science 66 (2011) 1463–1479
hydrolytic allylhydridopolycarbosilane (AHPCS) (the inorganic
phase) droplets (Prasad et al., 2009). Dumbbell like hybrid Janus
microspheres were formed after UV curing, with two distinctive
regions: a hydrophobic hemisphere (PFPE) having a smooth
surface and a relatively hydrophilic region (AHPCS) with a rough,
porous surface. Furthermore, HJM can be converted into SiC-based
ceramic hemispheres through the removal of the organic portion
and etching off the silica shell. The incorporation of magnetic
nanoparticles into the inorganic part shows the feasibility of the
forced assembly of HJM in an applied magnetic field (Prasad et al.,
2009). Biocompatible calcium alginate Janus particles with one
magnetic hemisphere and one hemisphere for cell encapsulation
have also been fabricated in a microfluidic device (Zhao et al.,
2009). The magnetic hemisphere can be manipulated by a
magnetic field, while the other hemisphere can be used as a
carrier of cells or bioactives.
3.6. Microcapsules/microgels/microspheres and related hybrid
materials
Microcapsules, microgels and microspheres are attractive
materials due to their wide application in drug delivery and in
cell, protein and enzyme immobilization. To solidify the interface
or the whole droplet, there are several methods including
photopolymerization, hydrolysis, dewetting and chemical reac-
tion. Microcapsules with rigid walls consisting of cross-linked
polyelectrolyte and metal nanoparticles were synthesized first by
formation of a sacrificial dextran-based microgel in a simple
tubing-needle-based microfluidic setup, with subsequent layer-
by-layer coating by negatively charged platinum nanoparticles
(PtNPs) and a positively charged diazoresin (DAR), finally
removing hydrogels by hydrolyzation (Gokmen et al., 2009).
Furthermore, microcapsules with stimuli-sensitive properties
offer greater versatility for triggered release controlled by
external stimuli such as pH, temperature, electric or magnetic
fields (Ibarz et al., 2001; Kataoka et al., 2001; Liu and Eisenberg,
2003; Ma et al., 2006). Thermo-sensitive poly(N-isopropylacryla-
mide) (PNIPAM) microcapsules have been prepared by radical
polymerization of monodisperse aqueous droplets containing
monomer and cross-linker at the interface under UV irradiation
in a simple flow-focusing microfluidic device (Choi et al., 2008).
Poly(NIPAM) microgels were generated in a capillary microfluidic
device made of three separate capillary tubes (Kim et al., 2007).
Ca-alginate microspheres were produced in a cross-junction
microchannel and gold nanoparticles, as a model drug, could be
encapsulated inside the microspheres (Huang et al., 2006).
Monodisperse mesoporous silica microspheres have been gener-
ated in a microfluidic flow-focusing device using emulsion
droplets containing silica precursor and surfactants as templates,
and the evaporation of the solvent in droplets leads to the
solidification of silica and micellization of the surfactant (Carroll
et al., 2008). Well-ordered 2D hexagonal mesoporous silica
microspheres with corrugated surface were synthesized using a
one-step ‘‘microfluidic diffusion-induced self-assembly’’ method
within a T-shape flow-focusing microchannel (Lee et al., 2008).
Hollow microspheres with CdS–TiO2 hybrid shells were prepared
by including luminescent CdS nanoparticles in the oil phase with
titania precursor in a coflowing microfluidic device made of two
coaxial microcapillaries (Eun et al., 2009).
To further expand their applications, microcapsules, microgels
and microspheres have been functionalized with additional
desirable properties (Rogach et al., 2000; Zhang et al., 2004; Pich
et al., 2006) by incorporating magnetic nanoparticles, quantum
dots, etc. Polycaprolactone (PCL) microcapsules encapsulating the
anticancer drug tamoxifen, Fe3O4 nanoparticles (NPs) and CdTe
quantum dots (QDs), potential candidates for a smart drug
delivery system, were prepared in a microchannel cross-junction
by a facile and one-pot method (Yang et al., 2009). Magnetic
hydrogels have been produced in a flow focusing microchip
using double emulsions as templates. These hydrogel particles
show excellent rotational control by an external magnetic field
(Chen et al., 2009a). Furthermore, hydrogels with uniformly
encapsulated magnetic nanoparticles exhibit superparamagnetic
behavior, which is desirable in most biological applications
(Hwang et al., 2008). PLGA microcapsules encapsulating CdSe/
ZnS QDs, developed in a cross-junction microfluidic system,
provide amplified and reproducible signals for fluorescence-based
bioanalysis (Chang et al., 2007), which can also be converted to
PLGA microspheres by solvent evaporation (Chang et al., 2007).
4. Control of microfluidic process for synthesizing
nanoparticles
4.1. Control of nanoparticle size, size distribution and shape
Microfluidic reactors can control the reaction more precisely
than bulk batch reactors which exhibit relatively poor mixing and
mass transfer performance. Compared to bulk batch reactors,
continuous flow microreactors can develop nanoparticles with a
smaller mean particle size and narrower particle size distribution
(Ju et al., 2006). For CdSe nanocrystals in a single silica glass
capillary microreactor, longer reaction times and higher reaction
temperatures yielded larger particles (Nakamura et al., 2002a).
The particle size distribution was relatively broad due to the
velocity and residence time distributions (Yen et al., 2003). For
drug nanoprecipitation using microfluidic reactors, artificial
neural networks (ANNs) have been employed to relate variables
including saturation levels of prednisolone, solvent and antisol-
vent flow rates, microreactor inlet angles and internal diameters
to particle size. The antisolvent flow rate was found to have a
dominant role in determining final particle size (Ali et al., 2009a),
while the flow rate of prednisolone solution has an opposite
effect. Sharper inlet angles (101 and 251) resulted in slightly
smaller particle sizes, underlining the sometimes subtle effect of
geometry. Gas bubbles introduced in continuous microreactor
flows can reduce nanoparticle size distribution by preventing
mixing between segments and by reducing the residence time
distribution (Nakamura et al., 2002a; Gunther et al., 2004). A
micro-porous tube-in-tube microchannel reactor (MTMCR) with a
high throughput (9 L/min) has been designed to synthesize
barium sulphate nanoparticles (Wang et al., 2009). Increasing
the total flow rate and phase concentrations and decreasing the
micropore size decreased the average particle size, while the flow
rate of the dispersed phase and mixing distance had little effect on
particle size (Wang et al., 2009). Shear-induced particle breakup
can also be used to control particle size (Wang et al., 2010). A
water–liquid paraffin two-phase segmented microfluidic device
assembled by coaxial dual tubes produced ultrafine zeolite A
crystals with narrow particle size distribution (Pan et al., 2009).
Droplet-based two phase flow microreactors can further
eliminate the dispersion-induced broadening of particle size
distributions. The flow of drops or plugs can provide high mixing
efficiency, which is very important in particle size control
(Mantzaris, 2005). The segmented droplets experienced a self-
recirculation flow due to the shear interaction with the carrier
fluid, resulting in intensification of the mixing and the elimination
of axial dispersion (Burns and Ramshaw, 2001; Schabas et al.,
2008). Thus, the reaction time could be reduced and the residence
time distribution of the solution in microchannels is narrower,
leading to narrower particle size distribution of the final products.
 C.-X. Zhao et al. / Chemical Engineering Science 66 (2011) 1463–1479
If the two-phase flow has different flow patterns or different
droplet sizes, nanoparticle size will vary greatly even at the same
initial concentration. This phenomenon suggests that big droplet
size is beneficial to nucleation rather than growth (Li et al., 2008).
At the drop generating stage, there is a strong inner circulatory
flow inside drops because of the action of shear force of the
continuous phase, and the mass transfer speed inside the drops is
very high. The mass transfer during the droplet formation stage
can contribute at least 30% of the total mass transfer (Xu et al.,
2008). Nucleation mainly takes place at this stage, and the extent
of chemical reaction may be significant. After droplet formation,
when the droplets travel along the mcirochannel, very weak inner
circulatory flow occurs, so the mass transfer just provides
material for particle growth. Noting these factors, it is apparent
that a bigger drop requires a relatively longer time for its
formation. Therefore, the nucleation stage lasts longer and
consumes proportionally more of the reactants. The materials
left for the later growth stage are consequently reduced, as is the
final particle size (Li et al., 2008).
The shape of nanoparticles is of interest for different applica-
tions, as noted earlier. It has been noted that the Au/Ag ratio
affects particle shape; at lower Au/Ag ratios and at higher Au/Ag
ratios, single spherical particles and larger aggregates of them
form preferentially. However, at Au/Ag ratios between 0.6 and 0.8,
a star-like particle with four regular branches can be generated.
Furthermore, adding silver salt after complete reduction of
tetrachloroaurate produces spherical core–shell particles (Kohler
et al., 2007). Such observations again highlight the need for
precise control over the contact of different phases during
nanoparticle formation if controlled and uniform properties are
to be obtained.
4.2. Control of crystal structure
In contrast to the control of particle size and shape, the control
of nanoparticles with desired crystal structure is less investigated.
However, the control of crystal structure is very important due to
the considerable influence that it has on the physical and
chemical properties of nanoparticles, especially when several
possible stable crystal structures are separated with only a small
energy difference. For example, at least three alternative crystal
structures are known for cobalt nanoparticles (Song et al., 2006).
Several conventional approaches, such as thermal annealing (Sun
and Murray, 1999; Nie et al., 2003), pressure-induced phase
transition (Calvo and Doye, 2004), and surfactant-induced phase
transition (Lin et al., 1999; Wilcoxon and Provencio, 1999) have
been attempted to deliver a chosen crystal structure. Microfluidic
technology provides enhanced control over the crystal structure
of nanoparticles through precise design of microreactors and
manipulation of the particle formation process. Temperature has a
great influence on the formation of crystalline structure. CdS
particles synthesized at room temperature in aqueous solutions
are not very crystalline (Shestopalov et al., 2004). Fine crystal
structures of cobalt nanoparticles were investigated by changing
the microfluidic kinetics at room temperature. High energy inputs
through sonication, elevated flow rate, or higher microreactor
temperature result in shorter inter atomic distance whereas low
kinetic energy (low flow rate, lower temperature) leads to longer
atomic distance (Song et al., 2008b). At high kinetic energy levels
Co nanoparticles form with mainly fcc structure, while at low
kinetic energy levels and short growth time, Co nanoparticles
have mainly hcp structures. At even lower energy levels but with
long growth time, the crystal structure shifts to the metastable
phase, or h structure (Song et al., 2006). Stable amorphous cobalt
(Song et al., 2009b) and cobalt samarium (Song and Henry, 2009a)
1475
nanoparticles can be formed in situ by the rapid cooling rates
possible in microfluidic processing. Nucleation and growth of
nanoparticles can be revealed in situ by combining a fast mixing
stopped-flow device with time-resolved small angle X-ray
scattering (SAXS) (Abecassis et al., 2007; Polte et al., 2010).
Abecassis et al. (2007) used synchrotron SAXS to assess gold
nanoparticle formation at a time resolution of 200 ms, showing
that nucleation rate can be increased by an order of magnitude by
replacing an alkanoic acid ligand with an alkylamine ligand. A
recent study by Polte et al. (2010) demonstrated that it is possible
to use a conventional in-house SAXS set-up to study nanoparticle
formation.
4.3. Control of surface chemistry of nanoparticles
Appropriate surface chemistry of nanoparticles is required to
either stabilize them in solution or to add functionality. One
advantage of microfluidic system is that it is possible to synthesis
nanoparticles and to functionalize them in the same microreactor
in a single step. Kikkeri et al. (2010) have recently prepared QDs
with surfaces functionalized with carbohydrates. This enables QDs
to specifically interact with lectins through carbohydrate–lectin
recognition. Valencia et al. (2010) have self-assembled lipid
molecules onto polymeric and quantum dot nanoparticles during
their preparation step. The lipids at nanoparticle surface enhance
stability of nanoparticles against aggregation even in the presence
of high salt concentration.
5. Discussion and concluding comments
Nanoparticles have been attracting interest in the past two
decades, and the emergence of microfluidic technologies provides
a wide variety of novel strategies for synthesizing particles at the
nanometer or micrometer length scale. Microfluidics can facilitate
the manufacture of materials with specially designed structures
and unique functions, such as core–shell, Janus and hybrid
capsule or microgel particles. The development of these micro-
fluidic processes offers novel methods and knowledge for
improving the properties of nanoparticles including particle size,
size distribution, and physical, chemical or biological properties
under a more mild and controllable environment.
This review has presented recent achievements in the synth-
esis of nanoparticles in microreactors. Parallel advances in
techniques for preparing nanoparticles and manufacturing micro-
fluidic devices offer great opportunities for developing novel
methods and knowledge in nanomaterials. Two main strategies
have been discussed for synthesizing nanoparticles in micro-
reactors, including continuous flow and segmented flow ap-
proaches. Continuous flow microreactors exhibit a number of
advantages, such as simple operation, high throughput, easy
control, high temperature adaptability, and so on. But some
inherent disadvantages, including wide size distribution due to
poor mixing, clogging or cross-contamination due to the direct
contact with channel walls, limit their application. Segmented
flow or droplet-based approaches can overcome the problems
existing in continuous flow type reactors and also offer some
advantages including large interfacial area, efficient mixing and
fast mass transfer, but still suffer various difficulties in some
situations, such as imprecise control of droplet coalescence
containing certain reactants to initiate the reaction, instability of
droplets, the difficulty of achieving multi-step reactions, and so
on. In the case of using droplet templating to manufacture
microspheres, capsules and gels, a vast diversity of routes have
been developed and many novel functional materials have
attracted increasing interest.
1476 C.-X. Zhao et al. / Chemical Engineering Science 66 (2011) 1463–1479
Nanoparticles of different categories have been reviewed
including semiconductor nanocrystals, noble nanoparticles
(gold or silver), TiO2 and magnetic nanoparticles. Much research
work has been focused on the proof-of-concept preparation of
nanoparticles. However, there is considerable scope for optimiza-
tion with regard to nanoparticle quality, functionality and yield.
Other specially designed particles with distinct structures such as
core–shell, Janus or ternary, hybrid particles or capsules encap-
sulating nanoparticles have also attracted a lot of interest.
The use of microfluidic reactors for generating nanoparticles
represents a novel and exciting bottom-up approach, which is still
at a very early stage of maturity. There are a few directions which
we consider important to advance the field:
(i) integration of particles separation with particle preparation.
Microchannels have already been used to continuously
separate particles based on flow fraction principle (Takagi
et al., 2005). A smart design may make it possible to integrate
particle preparation and separation in a single step, simplify-
ing particle production;
(ii) the development of on-line detection system to characterize
particle formation in real time, thus shortening the time to
optimize synthesis conditions (Polte et al., 2010);
(iii) the utilization of environmentally friendly reagents such as
biosurfactants in the production process (Kumar et al., 2010),
and;
(iv) scale-up strategies to realise large-scale processes for micro-
fluidic nanoparticle manufacture, making production prac-
tical for industrial application.
Nevertheless, the combination of nanoparticle and microfluidic
technologies provides a unique opportunity to fully exploit the
potential of microfluidic technology and to expand our knowledge
of nanoparticle synthesis, through precise control of the reaction
environment. Considering the rapid advancements that are
occurring in both fields, the expansion of knowledge at the
intersection will inevitably lead to new and exciting insights, and
the expanded application of microfluidics for the generation of
conventional and novel nanomaterials.
Acknowledgements
Financial support from the Australian Research Council (Grants
DP0771910 and DP1093056) is gratefully acknowledged. L.H.
acknowledges receipt of an AINSE Research Fellowship.
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