Food Eng Rev (2015) 7:393–416
DOI 10.1007/s12393-014-9100-0
REVIEW ARTICLE
Designing Food Structure Using Microfluidics
F. Y. Ushikubo • D. R. B. Oliveira •
M. Michelon • R. L. Cunha
Received: 3 June 2014 / Accepted: 3 November 2014 / Published online: 19 December 2014
Ó Springer Science+Business Media New York 2014
Abstract Microfluidics is an emerging technology that can
be employed as a powerful tool for designing structures in the
food industry. Those structures can modify the texture and
flavor perception in a food product or can be used as carrying
vehicles for a wide range of bioactive compounds. Micro-
fluidic processes occur in strictly laminar flow, which is quite
interesting to process control. This results in particles with
more homogeneous size and shape, which improve the
properties of controlled release of active compounds and
their stability. Innumerable complex structures can be
designed, with single or multiple shells, one or more cores
inside the particles. In addition, self-assembled structures
can be formed in microfluidic devices. However, most of the
published works have fundamental character. Fundamental
studies are important to understand the physical phenomena
that occur at the microscale, in order to obtain successful
results in the design of microstructures. Especially in the case
of food-grade ingredients, more complex variables have to
be considered, such as their rheological and mass- and heat-
transport properties. In this review, the fundamentals of
microfluidics will be presented, such as the main forces and
dimensionless numbers that are involved in the microscale
processes and droplet formation regimes. In addition, the
most common microfluidic devices will be described, cov-
ering their geometries and materials. The review will also
present results from studies on structure design using mi-
crofluidics, including emulsion-based techniques for the
production of microparticles and strategies for the produc-
tion of self-assembled structures.
F. Y. Ushikubo  D. R. B. Oliveira  M. Michelon 
R. L. Cunha (&)
Faculty of Food Engineering, University of Campinas,
Campinas, SP 13.083-862, Brazil
e-mail: rosiane@fea.unicamp.br
Keywords Microfluidics  Food structure 
Encapsulation  Emulsion  Microparticle  Self-assembled
structure
Introduction
Microfluidics is defined as the science of designing, man-
ufacturing and operating processes and devices with small
amounts of fluids in laminar regime. Microfluidic devices
have dimensions ranging from a few millimeters to
micrometers, and they are characterized by exhibiting at
least one channel with dimension smaller than 1 mm [160].
The first applications of microfluidics started in the
beginning of the 1990s such as in blood rheology [64] and
chemical detection [83]. A decade later, the applications of
microfluidics expanded to a wide range of fields: chemis-
try, biology [120, 140], medical [155], agriculture and food
sciences [75, 98, 123] among others.
The use of microfluidic techniques allows the integra-
tion of procedures into planar chips or other small devices,
reducing reaction volumes and the associated cost of
chemical and biological experimentations by several orders
of magnitude, while simultaneously increasing perfor-
mance of the process [32, 91, 160]. The greatest advantage
of the application of microfluidic processes is the per-
spective of process intensification, which aims to develop
sustainable technologies with less financial demand and
increased production in terms of amplification process,
reducing costs and time for the implementation of the
laboratory to the industrial process [23, 153].
Several types of food structures may be obtained using
microfluidics devices: self-assembled structures [93],
emulsions [99, 100, 119, 170] and emulsion-based struc-
tures such as solid lipid microparticles [65, 129] and
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biopolymeric microbeads [38, 172]. The development of
methods to producing food structure has great importance
for the development of the food products, because they can
be used to modify the texture and flavor perception, to
mask undesirable taste/smell and to avoid oxidation of
compounds [111]. In addition, they can be used as encap-
sulation systems for oral administration with controlled
release of the bioactive and functional compounds, pro-
tecting against the action of enzymes and adverse condi-
tions of gastrointestinal tract such as ionic strength and acid
pH [82].
Production techniques of food structures with micro-
fluidic approach are able to overcome the hurdles inherent
of conventional methods, such as control of polydispersity
and particle size, and are still reported as more reproduc-
ible processes with highly controllable operational condi-
tions [34]. Moreover, particles or other food structures
obtained by microfluidics often dispense a subsequent
processing step for size reduction and homogenization such
as membrane extrusion, high-pressure homogenization or
microfluidization [22, 79]. Furthermore, the use of micro-
fluidic techniques is related to much faster reactions,
minimum size of devices, formation and control of a
defined interface between two phases due to strictly lami-
nar flow, low consumption and power dissipation and,
finally, relative low cost of production per device [19, 84,
123].
However, most of the published works in food pro-
cessing area still have a fundamental and exploratory
character. Moreover, a small number of studies are related
to the influence of interfacial phenomena and rheological
behavior of fluids on the generation and stability of the
structures [73, 102, 110, 139, 145]. One of the challenges
for implementation of microfluidic processes in the food
industry is the adjustment of the process conditions con-
sidering the fluid properties. Complex systems such as food
suspensions exhibit complex rheological properties that
may lead to the channels clogging, difficulties in the fluid
injection, flow stabilization or fluid flow breakup,
depending on process conditions employed. The develop-
ment of low-cost microfluidic devices that can operate at
high flow rates resulting in higher yields, as well as the use
of food-grade ingredients, remains as the major technology
challenges.
In this paper, the aim was to discuss the fundamentals of
microfluidics, such as the main forces and dimensionless
numbers that are involved in the microscale processes. In
addition, the most common microfluidic devices found in
the literature were described, covering their geometries and
materials. Recent literature was reviewed considering the
production of several types of food structures by micro-
fluidic routes, including single and multiple, emulsion-
based techniques for the production of particles and self-
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Food Eng Rev (2015) 7:393–416
assembled structures. At last, a brief review on the scaling
up of microfluidic systems was presented.
Microfluidics: Fundamentals
Dimensionless Numbers
Processes involving hydrodynamics can be described by a
large number of variables and properties that reveal the
dominating acting forces. The relation between these acting
forces is expressed by the dimensionless numbers, which
locates the system in the fluidic parameter space [125].
However, in microscale, the number of relevant parameters
is reduced, since the viscosity and interfacial tension are the
prevailing effects [15]. In microscale, the more relevant
dimensionless numbers are Reynolds, Weber, Capillary,
Péclet and the flow rate ratio. While Weber and Capillary
numbers characterize multiphase systems, Péclet number is
calculated for systems in which mass transfer occurs.
The Reynolds number (Re) expresses the ratio of inertial
to viscous forces in fluid flow: Re ¼ qUl=g, in which q is
the fluid density, U is the characteristic velocity, l is the
characteristic dimension of the channel and g is the fluid
viscosity. The flow regime in microfluidic devices is
mostly laminar (Re \ 2,100), considering that their char-
acteristic dimension is very small so that inertial effects are
normally irrelevant [16].
The Weber number (We) indicates the relative impor-
tance of inertial effects when compared to the interfacial
tension in a multiphase system: We ¼ U 2 ql=c;, where U is
the characteristic velocity, q represents the fluid density,
l is the characteristic dimension of the channel and c is the
interfacial tension. In droplet generation, We is usually
calculated regarding the dispersed phase to evaluate the
detachment forces.
The ratio of viscosity to interfacial tension is given by
the capillary number, Ca ¼ gU=c, where g is the fluid
viscosity, U is the characteristic velocity and c the inter-
facial tension. Ca is often calculated in multiphase systems
for the phase with the higher viscosity [15, 16].
The Péclet number (Pe) expresses the relative impor-
tance between diffusion and convection: Pe ¼ Ul=D,
where U is the characteristic velocity of the flow, l is the
characteristic length of the channel and D is the diffusion
coefficient of the particle/molecule of interest. This
dimensionless number is highly relevant for mixing of
miscible fluids [13].
In systems with mixing fluids, the flow rate ratio is
usually represented by the abbreviation FRR, and it is
calculated by the ratio of the aqueous to the organic phase
flow rates (Qa and Qo, respectively), which gives
FRR = Qa/Qo [14, 57, 95]. In systems with droplet
Food Eng Rev (2015) 7:393–416
generation, the flow rate ratio can be expressed as the
relation between the dispersed to the continuous phase flow
rates (Qd/Qc) [10, 33, 145] or as the ratio between the
continuous to the dispersed phase flow rates (Qc/Qd) [11,
102]. Since flow rate is the major operating condition at
microfluidic, this dimensionless number acquires a great
importance at microscale. Almost all works involving
droplets, bubbles, micro-/nanoparticles and self-assembled
structures relate this dimensionless number as the main
factor in obtaining structures with the desired sizes and
shapes [10, 46, 57, 145].
Further information about dimensionless numbers in
microfluidics can be found in Addae-Mensah et al. [7],
Atencia and Beebe [13], Gañán Calvo and Gordillo [39],
Garstecki et al. [40], Phapal and Sunthar [113] and Squires
and Quake [125].
Microdevice Geometries
Different geometries have been suggested to generate a
wide range of structures. For the droplets generation, there
are shear-induced geometries, such as those based on
capillaries assemblies and planar geometries, and interfa-
cial tension-induced one, which are the terrace geometry
and its variations. In the case of systems that involve mass
transfer, such as for the fabrication of self-assembled
structures, mostly planar cross-junction geometry has been
used.
In shear-induced geometries, droplets can be formed at
different regimes: squeezing, dripping or jetting. Squeezing
and dripping regimes occur at the tip of the tube orifice or
junction. The squeezing regime takes place when the
interfacial tension prevails over the shear forces, so the
droplet grows, until it almost blocks the cross section of the
channel. Then, the continuous phase is confined to a thin
film between the walls of the channel and the droplet,
increasing the pressure upstream of the droplet, resulting in
the detachment of the droplet neck [41]. In the dripping
regime, the droplet detaches when there is still room for the
continuous phase flow [121]. The jetting regime consists in
the formation of a long stream of the inner fluid where the
point of droplet detachment can vary, leading to a broader
size distribution. In this regime, the droplets generation is
explained based on the principle of Rayleigh–Plateau
instability, where perturbations in the jet result in an
increase in Laplace pressure within the jet. When this
pressure is high, the jet becomes thin enough to break the
stream into droplets [147]. In dripping and jetting regimes,
droplets detachment occurs through a balance between
interfacial and viscous forces.
In the next sections, the details of each geometry will be
presented, describing their mechanism, advantages and
disadvantages.
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Capillary Devices
The capillary microfluidic devices are assemblies of
coaxial capillary tubes, where one is placed inside another
with a larger diameter (Fig. 1a, b). These devices are
widely used for droplets, vesicles and microparticles gen-
eration. For single emulsions, co-flow and flow-focusing
arrangements are commonly used. In the former, fluids
move in the same direction, so that the dispersed phase is
driven by the interior of the small diameter capillary while
the continuous phase flows between the capillaries
(Fig. 1a). In the latter, fluids are introduced from the two
ends of the external capillary in opposite directions
(Fig. 1b). Both phases flow into the narrow inner capillary,
and the continuous phases constrict the dispersed phase,
which breaks into droplets in a dripping or jetting regimes,
depending on the operating conditions [121]. One advan-
tage of the coaxial microcappilaries is that the droplets are
surrounded completely by the outer phase, which increases
the effects of interfacial forces between the two phases. On
the other hand, the process with coaxial microcappilaries is
difficult to scale up because of the intensive hand labor in
the fabrication and alignment of the tubes [34].
Planar Microfluidic Devices
The planar microfluidic devices are channels with rectan-
gular cross section produced with different techniques and
materials, which are chosen depending on the application.
These devices differ from each other according to the type
of junction between the channels. T-, Y- and cross-junc-
tions are the most common planar devices used for droplets
generation [5, 27, 41, 42, 117, 126, 127, 145, 159]. In the
case of the production of self-assembling structures, the
most utilized geometry is the cross-junction [14, 51, 54–58,
95, 115].
In T-junction devices (Fig. 2a), the fluids are inserted in
two perpendicular microchannels. These devices are lar-
Fig. 1 Schematic illustrations of a a co-flow and b a flow-focusing
microcapillary devices for making droplets (reprinted with permission
from Utada et al. [147]. Copyright 2007, Cambridge University Press)
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Fig. 2 Design of planar microfluidic devices. a T-junction; b Y-junction; c cross-junction
Fig. 3 Schematic mechanism
of the droplet formation in a
terrace-based microchannel
device (reprinted with
permission from Sugiura et al.
[129]. Copyright 2000,
Elsevier)
gely used because of the facility in the generation of
monodisperse droplets and bubbles in a wide range of flow
rates [133, 145]. Even at low Ca, in which the droplet
detachment is less favored, droplets are detached in the
squeezing regime [33, 41, 165]. In this geometry, the
droplet generation occurs in two steps: The first is related
to the droplet growth and the second is the droplet
detachment [126].
In Y-junction (Fig. 2b), the angle between the channels
is usually higher than 90°, which will influence the droplets
generation, due to the effect of shear imposed by the
continuous phase on the dispersed one. Differently to
T-junction, the droplet detachment mechanism in Y-junc-
tion is described by one single step [127, 128]. The simpler
mechanism results in a higher dependence of shear and
interfacial forces, as well as of the operation conditions in
the droplets size generated in Y-junction. However, since
this geometry depends directly on the balance between
shear forces and interfacial tension, no droplets can be
formed at low Ca [145].
Cross-junction microfluidic devices (Fig. 2c) present
four crossed perpendicular or oblique channels, where
usually the flow of the lateral channels constricts the main
channel fluid flow, in a technique known as hydrodynamic
flow focusing [123]. This arrangement is the most used for
self-assembled structures formation, such as liposomes,
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Food Eng Rev (2015) 7:393–416
due to a great control of molecules diffusion between two
fluids [54]. This type of geometry is also used for droplets
formation. Compared with T- or Y-junctions, in cross-
junction, a higher shear is imposed by the continuous phase
due the flow at both sides of the dispersed phase stream.
Thus, this configuration may lead the production of smaller
droplets. However, depending on operating conditions,
jetting regime with the generation of polydispersed drop-
lets can occur, since the mechanism of breakup is directly
controlled by the flow rate ratio of the fluids [102].
The planar geometries have the advantage of being
easily designed and produced, giving the possibility to
create more elaborated configurations. On the other hand,
unlike the capillary devices, in planar microchannels, the
fluids are limited by microdevice walls at the upper and
down surfaces of the chip, which decreases the interfacial
area between the two phases.
Terrace Geometry
The terrace-based geometry consists in droplets generation
through the forced passage of the dispersed phase in a
microchannel to a terrace area filled with a continuous
phase, which can be stagnant (Fig. 3). The shallow depth of
the terrace leads to a disk-shaped droplet with a high
Laplace pressure, which is thermodynamically unstable.
Food Eng Rev (2015) 7:393–416
When the droplet comes to the terrace edge, it moves
spontaneously to a deeper region (well) and assumes a
thermodynamically more favorable spherical shape.
Diversified designs based on terrace microchannels were
presented to improve and increase the throughput of the
droplet generation, like those with symmetric straight-
through microchannels [68] showing circular or rectangular
cross sections, or asymmetric channels [69, 70] with cir-
cular and rectangular sections in the upstream and down-
stream, respectively. The latter configuration allows the
droplets generation with good performance independently
of the properties of the phases [69].
In this type of geometry, only the interfacial force drives
the droplets formation, unlike capillary and planar micro-
fluidic devices. This mechanism results in a very smooth
droplet detachment and consequently in high energetic
efficiency [130]. Besides, the arrangement in arrays allows
increasing the droplets throughput [70]. On the other hand,
the fabrication costs of the device are higher than mostly
planar geometries and capillaries.
Materials and Methods of Manufacturing Microfluidic
Devices
The first microfluidic devices were produced using
expensive and time-consuming techniques such as photo-
lithography and etching in silicon and glass derived from
microelectronics systems [137]. These techniques enable
the creation of devices with dimensions as low as few
micrometers [61–63, 68]. Besides, with different combi-
nation of techniques, more elaborated structures are
obtained, such as microgrooves, straight-through micro-
channels and micronozzles [156].
Silicon microfluidic devices can be obtained by isotropic
or anisotropic wet etching or by dry etching, which can be
physical, chemical or physical–chemical [80, 101]. The
main advantages of wet etching are the high selectivity,
repeatability controllable etch rate and relatively planar
etching surface. Physical dry etching can be applied to
almost all materials, but presents slow etch rates and low
selectivity. Chemical dry etching is more similar to wet
etching with higher selectivity. Reactive ion etching (RIE)
[59], a physical–chemical dry etching, is one of the most
popular dry etching techniques, as it can result in high
aspect ratios of channels [101].
Etching can be classified as a direct technique. This
category also includes laser ablation, micromachining,
photolithography in deep resists and stereolithography [18,
67].
Laser ablation involves the material removal by
absorption of short-duration laser pulses in the UV or IR
regions that break bonds within the long-chain polymer
molecules. This technique allows the fabrication of
397
microdevices with a sort of polymers such as polystyrene
(PS), cellulose acetate (CA), poly(ethylene terephthalate)
(PET), polycarbonate (PC) and polymethylmethacrylate
(PMMA) [76, 118]. This technique is also applied to glass,
ceramic, silicon and metals. Structures can have with
dimensions as small as 6 lm [112].
Mechanical micromachining methods, such as sawing,
cutting, milling and turning, allow the fabrication of
structures of a wide range of materials with dimensions of
few tens of micrometers [18]. A special application is for
machining stainless steel. This material has the advantage
of being more resistant to alkalis and acids and higher
mechanical strength than silicon, but cannot be etched
because of its multicrystal property [143]. Both laser
ablation and micromachining methods are fast techniques,
but their drawback is that the surface roughness obtained is
greater than that obtained in replication techniques [156].
Photolithography in deep resists is the application of a
negative photoresist such as SU-8 by spin coating on the
substrate, the exposition of the coated substrate under UV
light, followed by the baking and development steps. The
region exposed to the UV light become rigid and insoluble,
while the non-exposed areas are removed in the develop-
ment step. The use of SU-8 enables the fabrication of
structures with high aspect ratios and fine control, with
feature size as low as 1 lm [67]. In contrast, among the
disadvantages of SU-8, there are the difficulty of process-
ing this material, its high internal stress and, after the
exposition to UV light, it becomes hard to remove from
structures [18].
The stereolithography technique consists in focusing a
directed UV beam in a photocuring liquid polymer, which
is cured and forms two-dimensional solid structures. By
stacking the layers, a three-dimensional structure is fabri-
cated [18, 101]. The advantage of this technique is that the
device can be fabricated with all inlet and outlet ports
incorporated in one structure, so that no bonding or con-
nectors are needed [156]. However, the buildup time is
very slow, in the range of several hours [18].
On the other hand, replication techniques use a single
master structure, fabricated with a direct technique, to
replicate polymer structures many times [18]. The repli-
cation technologies were adapted to the microscale to
produce polymer microdevices at lower cost. Among the
replication techniques, there are injection molding [90], hot
embossing [37] and soft lithography [91].
In injection molding, the molten polymer is injected at
high pressure into the cavity of the mold. In hot embossing,
the mold and the flat polymer are heated up above the glass
transition temperature and they are brought together at a
controlled force [18, 67, 156]. While hot embossing is a
simpler technique with lower setting up costs, injection
molding is more feasible for mass production with shorter
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cycle time [101]. The most common polymers used in both
techniques are PMMA, PC, polystyrene (PS) [7, 18] and
cyclic olefin copolymer (COC) [60, 108].
Soft lithography is one of the most common techniques
to fabricate planar microfluidic devices [91]. In this tech-
nique, a master structure is produced by photolithography.
An elastomer precursor with curing agent is poured into the
mold and cured, so the structure can be peeled off. The
most popular elastomer polymer is poly(dimethylsiloxane)
(PDMS), which offers optically transparency, non-toxicity
and flexibility [92]. Despite these advantages, PDMS is a
hydrophobic polymer that absorbs nonpolar organic sol-
vents [136] and hinders the production of stable O/W
emulsions [17]. Besides, its deformability leads to the
reduced control over the hydrodynamic field [22, 57]. To
circumvent the former problem, some techniques were
proposed to make the PDMS surface more hydrophilic:
oxygen plasma treatment [134], UV/UV–ozone treatments
[35], glass coating by sol–gel [1], layer-by-layer deposition
[17] and covalent surface modification via graft photopo-
lymerization [52].
Applications
Emulsions
Emulsions play an important role in food industry, in the
form of oil-in-water (O/W) emulsions, such as mayonnaise
and dressings, or as water-in-oil (W/O) emulsions, such as
butter and margarine. They can be used as a part of more
complex foods, such as in yogurts and processed cheeses,
or as a base to create new structures such as ice creams
[30]. Moreover, emulsions can also be employed in func-
tional applications, such as vehicles for bioactive com-
pounds [89].
Conventional methods of emulsification include high-
pressure homogenizers, colloid mills, high-speed mixers and
ultrasonic homogenizers [88]. Those methods do not allow a
precise control in the particle size distribution, resulting in
highly polydisperse emulsions. Furthermore, in order to
break up the droplets, high shear stress is applied in the sys-
tem, which can cause proteins denaturation, degradation or
loss of activity in thermo- or shear-sensible compounds.
As an alternative technology, microfluidic devices can be
applied to the production of individual droplets. As a result,
highly monodisperse emulsions are obtained through a
smoother process [121, 130]. The size of the droplets formed
in the microfluidic devices is in the range of tens of
micrometers, when obtained in terrace-based geometry
devices [131] and in a wider range from tens to hundreds of
micrometers in shear-based geometries, such as microcapil-
laries [78, 116] and planar geometries [103, 148].
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Food Eng Rev (2015) 7:393–416
Fig. 4 Basic concept for preparing double emulsions (W/O/W) using
T-shaped microchannels (reprinted with permission from Okushima
et al. [109]. Copyright 2004, American Chemical Society)
Several studies have focused in emulsions produced by
microdevices using food-grade ingredients, such O/W
emulsions stabilized by proteins [119, 170], or containing
edible oils with bioactive components [99, 100].
Furthermore, due to the high manipulating control pro-
vided by the microfluidic devices at laminar regime, more
elaborated structures can be created. One example is the
double or multiple emulsions, such as water-in-oil-in-water
(W/O/W) and oil-in-water-in-oil (O/W/O), which are
interesting structures for encapsulating hydrophilic and/or
hydrophobic compounds.
Double emulsions can be produced with two successive
T-junctions (Fig. 4). The desired number of internal
droplets can be introduced in the larger drop with the
adjustment of the internal and external droplets breakup
rates [109]. Moreover, the production of a double emulsion
with two different compositions in the internal phase can
be performed by the use of a cross-junction geometry in the
first step [107].
Multiple emulsions can be also formed in sequential
cross-junctions along a microchannel [2]. With alternate
wettability between the junctions, double, triple and up to
indefinitely order emulsions can be produced (Fig. 5). By
setting the jetting regime in the initial junctions and drip-
ping instability in the final junction, the jet is broken into
monosized drops at a constant rate [3]. This method is
specially useful to break up viscoelastic fluids [4], which
normally do not detach droplets easily. The viscoelastic
fluid is injected as the inner phase, and the intermediate
phase is a fluid that can be easily emulsified. With the
instability, the intermediate phase breaks up and so does
the inner phase. This method is quite interesting for the
food systems, because many of food-grade ingredients
show viscoelastic properties.
A method to produce multiple emulsions in a single step
consists in the use of two capillaries of circular cross
section disposed within a rectangular capillary [146]
(Fig. 6a). In this configuration, the internal phase is
Food Eng Rev (2015) 7:393–416
Fig. 5 Drop maker arrays used to produce multiple emulsions with
controlled order. Photomicrographs of a single, b double, c triple,
d quadruple and e quintuple emulsion drop maker arrays. The
pumped through the interior of one capillary, while the
intermediate phase flows through the external capillary in
the same direction. The external phase flows externally the
second capillary, in the opposite direction to the other flu-
ids. When the three fluids reach the collection tube, a double
emulsion is formed. By placing sequential capillaries,
indefinite ordered multiple emulsions can be produced [28]
(Fig. 6b). The number of internal droplets and the middle-
phase thickness are controlled by the ratio between the flow
rates of the phases. By adding one more microcapillary
parallel to the inner phase capillary, two different inner
phases can be injected into the larger droplet [6].
Fig. 6 a Microcapillary geometry for generating double emulsions
from coaxial jets. Schematic of the coaxial microcapillary fluidic
device (from Utada et al. [146]. Reprinted with permission from
399
multiple emulsions produced by the arrays are shown in the right. The
scale bars denote 100 lm (reprinted with permission from Abate and
Weitz [2]. Copyright 2009, Wiley–VCH)
Microparticles
Microparticles of several to hundreds of micrometers can
be generated based on the solidification of droplets of
single or multiple emulsions. They can be used as a vehicle
to transport a compound to a specific target. The solidifi-
cation of the droplets increases the system stability and
protects the compound from external agents (oxygen, light,
reacting environment). Moreover, the release of the com-
pound in the target site can be achieved by the exposition
of the microparticle to a specific condition (temperature,
pH, presence of enzymes). By the production of
AAAS). b Schematic diagram of the extended capillary microfluidic
device for generating triple emulsions (reprinted with permission
from Chu et al. [28]. Copyright 2007, WILEY–VCH)
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microparticles through microfluidics, the narrow particle
size distribution of droplets results in particles with more
homogeneous mechanical properties [36]. In the next sec-
tions, the main solidification methods to obtaining of food-
grade microparticles and some types of microparticles and
other flow-induced structures will be presented.
Solidification Methods
The crystallization of the oil phase is an interesting method
for the particle solidification in applications in which the
compound release occurs by the increase of the tempera-
ture. The lipid in the liquid state is injected into the
microfluidic device to generate the droplets and then is
crystallized by cooling to form solid particles [65, 129,
162] (Fig. 7). The bioactive compounds are released at the
melting temperature of the lipid. This temperature can be
adjusted by selecting the composition of lipids with dif-
ferent saturation degrees.
Another method is the fabrication of microgels, which
consists in generating biopolymer droplets in the micro-
fluidic device and subsequently inducing its gelation, inside
or outside the device. This is a very convenient method for
the encapsulation of food compounds, since several types
of food-grade ingredients, such as polysaccharides and
proteins, can be employed as the carrier material. Although
the polymerization of droplets into microbeads is exten-
sively studied in synthetic polymers systems, we focused
only in biopolymers due to their higher compatibility with
food products. A list of publications related to microgels
fabrication is presented in Table 1.
One of the most applied gelling methods is the ionic cross-
linking of charged polysaccharides. Examples of biopoly-
mers used in the ionic crosslinking method include sodium
alginate [26, 48, 77, 78, 116, 122, 132, 135, 163, 168, 172] and
low methoxyl pectin [38], which form gels in the presence of
a divalent ion such as Ca2? by binding to guluronic and
galacturonic acids, respectively. Other examples reported in
the literature are the ionic cross-linking of chitosan with Cu2?
[167] and carboxymethylcellulose with Fe3? [171].
Fig. 7 Microfluidic production
of solid fat microparticles
(reprinted with permission from
Kim et al. [66]. Copyright 2013,
American Chemical Society)
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Food Eng Rev (2015) 7:393–416
Although less frequently applied in food systems,
biopolymers can also gel through covalent cross-linking,
such as the gelation of gelatin with genipin [50] and
peroxidase-catalyzed gelation in chemically modified
gelatin [24].
Several methods to gel the biopolymer by ionic or
covalent cross-linking in microfluidic devices were pro-
posed: (1) coalescence of droplets, (2) in situ mixing, (3)
internal and (4) external gelation (Table 1). Each gelling
method is described in the following.
The gelation through the droplets coalescence is based
on the collision of one droplet containing the biopolymer
solution with a second droplet containing the cross-link-
ing ion [77, 122, 132] (Fig. 8a). In this method, no sur-
factant is used in the continuous oil phase, since the
coalescence of the droplets is desirable. The flow rate of
the cross-linking agent is set higher than that of the
biopolymer, in order to avoid the coalescence of bio-
polymer droplets. One of the disadvantages of this
method is the difficulty in producing well-defined and
homogeneous microbeads if gelation occurs before the
stabilization of the droplet after the coalescence [135],
resulting in higher particle size polydispersity, with
coefficient of variation (CV = standard deviation/average
size*100) up to 14 % [132], while other gelation methods
usually result in CV lower than 5 %. Furthermore, this
method is dependent on the probability of the droplets
collision, which makes it difficult to obtain 100 % suc-
cessful merging droplets.
In the ‘‘in situ mixing’’ method, microfluidic devices
with more than two inlet channels that encounter at the
junction allow the injection of the biopolymer and the
cross-linking agent solutions separately into the chip. The
two streams merge and form a droplet, which is rapidly
detached at the channel junction by the shear stress of the
oil continuous phase flow (Fig. 8b). A winding channel
after the droplet generation can improve the reagents
mixing [26, 38]. The drawback of this method is the
gelation of the biopolymer at the junction of the device.
Water or a solution with the encapsulating material can be
 Table 1 Studies related to biopolymer microgels produced with microfluidic devices
Gelling method Aqueous phase Oil phase Device material and Channel dimensions Operating conditions Particle average Reference
geometry size

Ionic cross-linking (1) 1.5 % sodium alginate Soybean oil Silicon micronozzle 30 lm inner width, 60 lm Qoil: 200 and 1,000 mL/s, Qalginate: 5 mL/ 77.4–216 lm Sugiura
(coalescence) in buffered solution array outer width and 15 lm h, QCaCl2 : 100 mL/h et al.
(2) 0.1 M CaCl2 in 0.14 M nozzle height [132]
NaCl solution
(1) 2 % w/w sodium Soybean oil PDMS, two cross- 50–200 lm width, 40 lm Qoil-in-alginate: 100 lL/h, Qalginate: 2 lL/h, Spheres: 21.7 lm Liu et al.
alginate junctions (droplets height QCaCl2 : 30 lL/h, Qoil-in-CaCl2 : 50 lL/h diameter, Disks: [77]
formation), one (spherical beads) 24.1 lm height,
Food Eng Rev (2015) 7:393–416

(2) 2 % w/w CaCl2

T-junction (fusion 41.3 lm
channel) diameter
(1) 1.5 % w/w sodium Edible oil PDMS, oblique flow 50 lm height, junction: Qoil: 6–96 lL/min, Qalginate: 2 lL/min, 104–167 lm Shintaku
alginate focusing 50 lm width, collecting QCaCl2 : 6 lL/min (spherical beads) et al.
(2) 0.1 M CaCl2 channel: 200 lm width [122]
Ionic cross-linking (1) 0.5–2 % w/w sodium 0.2–2 % w/w Span PDMS, 3 inlets 90 lm width and height Qoil = 1–5 lL/min (from graph), 60–90 lm Choi et al.
(in situ mixing) alginate 80 in hexadecane T-junction Qalginate ? QCaCl2 = 0.6–2 lL/min [26]
(2) 20 mM CaCl2 (droplet formation)
(1) 5 % w/w pectin or 4 % 2 % Span 80 in PDMS, 5 inlets oblique 100 lm width, 78 lm Qoil = 1.5–2 mL/h, 40–100 lm Fang and
w/w alginate Mineral oil flow-focusing height Qbiopolymer = QCaCl2 = 0.03–0.05 mL/ Cathala
(2) water h, Qwater: 0.07–0.08 mL/h [38]
(3) 1 % w/w CaCl2
Ionic cross-linking 2 % w/w sodium alginate 3 % w/w Span 80 PDMS, oblique flow (not informed) Qoil: 10.5–16.6 mL/h, Qalginate?CaCO3: 60–110 lm Zhang et al.
(internal gelation) with 0.1 %w/w CaCO3 and 5 % w/w focusing 0.7–0.8 mL/h [172]
acetic acid in
soybean oil
2 % w/w sodium alginate 2 % w/w lecithin in PDMS, T-junction Dispersed and continuous Qoil: 200–600 lL/h, Qalginate?CaCO3: 20 94–139 lm Tan and
in RPMI solution with corn oil with phases channels: 50 lm lL/h Takeuchi
CaCO3 nanoparticles acetic acid (0.67 and 150 lm width, [135]
(1.14 and 2.27 mg/mL) and 2.68 lL/ml channel height: 48 lm
oil)
2 % w/v sodium alginate 0.5 % v/v acetic acid Stainless steel manifold Inlet channel cross- (not informed) 80–400 lm Workman
with 0.5 % w/v CaCO3 in sunflower oil with HPLC sectional area: 500 lm2 et al.
connectors in cross- [163]
junction
2 % w/w sodium alginate, (i) 8 % w/v PGPR in Microcapillary Injection tube tip: 60 lm Qinner = 300 lL/h, Qmiddle = 400 lL/h, Hollow capsules: Liu et al.
1.5 g/L CaCO3, 1 % w/w Soybean oil (outer Qouter: 4,000 lL/h 383 lm (inner [78]
Pluronic and 30 mmol/L phase) diameter), 467
PAG (middle phase) (ii) 1:1 v/v soybean lm (outer)
oil ? benzyl
benzoate (inner
phase)
401

123
 Table 1 continued
402

Gelling method Aqueous phase Oil phase Device material and Channel dimensions Operating conditions Particle average Reference
geometry size

123
Ionic cross-linking (1) 3 % w/v sodium Sunflower seed oil PMMA, cross-junction Collecting channel: 600 Qoil: 0.8 mL/min, Qalginate: 50–2,000 lm Huang et al.
(external gelation) alginate lm 0.08 mL/min [49]
(2) 20 % CaCl2 (collecting
reservoir)
0.8 % w/w j-carrageenan 0.25 % w/w CaI2 in PDMS, oblique flow At junction: 130 lm Qoil: 0.35 mL/h, Qcarrageenan: Not informed Zhang et al.
undecanol with focusing width, 110 lm height 0.03 mL/h [171]
Span 80
1 % w/w 0.25 % w/w PDMS, oblique flow At junction: 130 lm Qoil: 0.25 mL/h, QCMC: Not informed Zhang et al.
Carboxymethylcellulose Fe(NO3)3 in focusing width, 110 lm height 0.03 mL/h [171]
undecanol with
Span 80
2 % w/w sodium alginate 0.5 % w/w CaI2 in PDMS, oblique flow At junction: 130 lm Qoil: 0.2–15 mL/h, Qalginate: 30–230 lm Zhang et al.
undecanol with focusing width, 110 lm height 0.3–0.7 mL/h [171]
Span 80
2 % w/w sodium alginate 2 % w/w calcium PDMS, oblique flow Not informed Qoil: 15.6–17.2 mL/h, Qalginate: 50–70 lm Zhang et al.
acetate and 3 % focusing 0.6–0.7 mL/ [172]
w/w Span 80 in
soybean oil
(1) 3 % w/w chitosan Sunflower seed oil PMMA, cross-junction 200 lm Qoil: 0.1 = 1.0 mL/min, Qchitosan: 100–800 lm Yang et al.
(2) 20 % CuSO4 solution 0.001–0.1 mL/min [167]
(injected after droplet
formation)
(1) 1.5 % w/v sodium Span 80 in sunflower PMMA, T-junction 200 lm width, 1.5 mm Qoil: 0.5–1.2 mL/min, Qalginate: 70–220 lm Yeh et al.
alginate seed oil height 0.001–0.05 mL/min [168]
(2) 20 % w/v CaCl2
(collecting reservoir)
(1) 2 % w/v sodium 8 % w/v PGPR in Glass Microcapillary Injection tube tip: 20–40 Qinner: 60–800 lL/h, Qmiddle: Core and shell: Ren et al.
alginate (middle phase) soybean oil (inner lm 400–4,000 lL/h, 117–173 lm [116]
(2) 10 % w/v CaCl2 and outer phase) Qouter and QCaCl2 : 2,000–14,000 lL/h (inner diameter);
(injected in collecting 250–255 lm
tube) (outer)
(1) 1.5 % w/w sodium (1) 5 % w/w Span Glass Microcapillary Injection tube tip: 50 lm Qoil: 1,800 lL/h, Qalginate: 30 lL/h Varied shapes (size Hu et al.
alginate 80 in n-decanol not informed) [48]
(2) 15 % w/w barium or (2) 5 % w/w Span
calcium acetate in and 1.5 % w/w
glycerol/water mixture CaCl2 in n-decanol
(collecting reservoir) (collecting
reservoir)
Chemical cross-linking (1) 1 % w/v gelatin and Sunflower seed oil PMMA, cross-junction, Collecting channel: 600 Qoil: 0.4–1.4 mL/min, Qalginate: 130–580 lm Huang et al.
(external gelation) 2 % w/v genipin lm 0.01–0.07 mL/min [50]
(2) 10 % w/v genipin
(collecting reservoir)
Food Eng Rev (2015) 7:393–416
 Table 1 continued
Gelling method Aqueous phase Oil phase Device material and Channel dimensions Operating conditions Particle average Reference
geometry size

Temperature 5 % w/w gelatin pH 7.4 5 % w/w TGCR in Silicon microchannel Channel: 16 lm width, Temulsification = 40 °C, Tcollect = 25 °C, 31.6 lm Iwamoto
iso-octane plate (terrace 11 lm height Tcool = 5 °C et al. [53]
geometry)
1.75 % w/w j-carrageenan Sunflower seed oil Glass Microcapillary inner capillary: 0.1 mm Qbiopolymer: 6.25 and 250 lL/min, Qoil: Elongated particle: Walther
inner diameter, outer 1–100 mL/min, 300–440 lm. et al.
capillary: 1 mm inner Temulsification = 100 °C, Toil = 54 °C, [157]
diameter. Tcool = room
Food Eng Rev (2015) 7:393–416

Agarose solution 3 % w/w Span 80 in PDMS or polyurethane, 30 and 60 lm heigh Temulsification = 37 °C Disks: 50–250 lm Xu et al.
hexadecane flow-focusing device diameter [164]
2–5 % w/w agarose 1.5 % w/w Span 80 PDMS, sequential 60 lm height, 60–100 lm Qoil: 0.05–04 mL/h, Qagarose: 95–100 lm Wang et al.
in mineral oil T-junctions width 0.025–0.2 mL/h (first junction) (supplementary [158]
Temulsification = 37 °C, Tcool = 2 °C material)
Temperature ? chemical 2 % w/v agarose in DMSO 0.5–1 % w/w PDMS, oblique flow- 130 lm height, 80 lm Qagarose ? Qgelatin ? Qperoxide = 0.6 mL/ 105–175 lm Chau et al.
cross-linking 1 % w/v chemically triblock copolymer focusing device width h, Qperoxide = 0.2 mL/h, [24]
modified gelatin surfactant in Qoil = 0.6–24 mL/h
fluorinated oil Temulsification = 37 °C, Tcool = 4 °C
5 mM hydrogel peroxide
Solvent extraction 4 % w/w chitosan in 2 % 2 % w/w Span 80 in Cylindrical Teflon Teflon capillary: 500 lm, Qoil: 5–2,000 lL/min, Qchitosan: 3–100 100–700 lm Xu et al.
w/w acetic acid aqueous 30 % w/w capillary and microneedle: 160 lm lL/min [166]
solution triotylamine in microneedle inserted (injection)
octyl alcohol in a cross-shaped
PMMA plate

TGCR tetraglycerine-condensed ricinoleic acid ester, PAG diphenyliodonium nitrate, PGPR polyglycerol polyricinoleate, HPLC high-performance liquid chromatography, DMSO dimethyl
sulfoxide
403

123
404
Fig. 8 Schematic of the microfluidic production of alginate micro-
gels by a coalescence of biopolymer and cross-linking agent droplets
(reprinted with permission from Shintaku et al. [122]. Copyright
2007, Springer), b in situ mixture (reprinted with permission from
Choi et al. [26]. Copyright 2007, Springer), c internal gelation
(reprinted with permission from Zhang et al. [172]. Copyright 2007,
WILEY–VCH), d external gelation adding the crosslinking agent
injected between the biopolymer and the cross-linking
agent solutions to avoid their contact at the junction [38].
The internal gelation of the microgels consists in the
generation of biopolymer droplets containing the cross-
linking agent that initially is in an inactive form. A reaction
initiator present in the continuous phase diffuses through
the droplets and activates the cross-linking agent, initiating
the gelling reaction (Fig. 8c). An extensively studied sys-
tem is composed of alginate and CaCO3 in the dispersed
phase and oil with acetic acid in the continuous phase [135,
163, 172]. With the droplet formation, the acid diffuses
into the droplet, decreases its pH and releases the Ca2? ion,
according to the reaction: CaCO3 ? 2H? ? CaH-
CO3? ? H? ? Ca2? ? H2O ? CO2 :. Thus, the ion
Ca2? can bind to the guluronic acids of alginate and the
microgels are formed.
123
Food Eng Rev (2015) 7:393–416
downstream (reprinted with permission from Ren et al. [116].
Copyright 2010, Elsevier), e external gelation adding the crosslinking
agent off-chip (reprinted with permission from Huang et al. [50].
Copyright 2009, from Elsevier) and f external gelation adding the
crosslinking agent in the continuous phase (reprinted with permission
from Zhang et al. [172]. Copyright 2007, WILEY–VCH)
A drawback of this method is that it results in weak gels
with low stability [172]. In addition, channel clogging can
occur due to the rapid acidification and gelation of the
alginate at the channel junction. This problem can be
overcome by the injection of an additional flow of pure oil
near the junction to avoid the gelation before the droplet
formation [163]. A different strategy that avoids channel
clogging is to add a photoacid generator with the biopoly-
mer and the CaCO3 nanoparticles dispersion. After the
droplets generation, UV radiation is applied to release the
Ca2? ions from CaCO3 and react with the alginate [78].
The ionic cross-linking can also be carried out through
external gelation. In this method, the cross-linking agent is
added after the droplet generation. There are different strategies
to make the cross-linking agent reach the biopolymer. A cross-
linking agent aqueous solution can be added downstream after
Food Eng Rev (2015) 7:393–416
the droplet formation, so the biopolymers react with the cross-
linking ion at the interface of the oil and aqueous stream
(Fig. 8d) [116, 167]. Another strategy is the off-chip ionic
cross-linking, that is, the biopolymer droplets are formed in the
oil phase and are collected in a cross-linking agent solution in
the collecting reservoir (Fig. 8e) [49, 50, 168]. The droplets
tend to sink to the aqueous phase because of their higher den-
sity. In a different approach, the cross-linking agent is solubi-
lized in the continuous phase, so after the droplets are formed,
the agent diffuses into the droplet, resulting in the gelation
reaction (Fig. 8f) [172]. In this method, the cross-linking agent
has to be partially soluble in both dispersed and continuous
phases. A suitable crosslinking agent for this method is calcium
acetate, which diffuses efficiently in alginate solution, resulting
in stable microgels with narrow size distribution [172].
Moreover, biopolymer gelation induced by temperature
can be used to generate microbeads without a cross-linking
agent. The biopolymer solution is injected in the microde-
vice at a temperature higher than its gelation point. After the
droplets formation, they are cooled below that point. This
method is applicable, for example, for gelatin [53], since it
presents random coil configuration at 35–40 °C, and below
this temperature range, collagen-like triple helices and
hydrogen bond cross-links are formed [71, 87], resulting in
thermoreversible microgels. Some polysaccharides, such as
j-carrageenan [157] and agarose [24, 158, 164], can also
form gel by cooling, helix formation and stabilization
through hydrogen bonds [12, 87]. One drawback of this
technique is the temperature control along microfluidic
device, which is critical due to its small dimensions and the
large temperature gradient [144]. Since the temperature
affects the viscosity of the solutions, this is a very important
variable to achieve the repeatability of the process.
In the case of pH-sensitive biopolymers, such as chito-
san, their gelation could be achieved by the change in pH
[166]. In this method, an acidic solution containing the
Fig. 9 a Core–shell particles with the shell consisting of a resolid-
ified lipid and the core formed by an aqueous solution. Electron
microscopy image of a cracked lipid shell. The scale bars denote
100 lm (reprinted with permission from Windbergs et al. [162].
Copyright 2013, American Chemical Society). b CLSM images of
monodisperse core–shell Ca-alginate microcapsules loaded with
405
biopolymer is dispersed in a continuous organic phase
containing an extractant. With the acid diffusion to the
organic phase, the biopolymer gels are formed.
Types of Microparticles and Other Flow-Induced
Structures
In this section, some configurations of microparticles that are
reported in the literature are described. Although some of
them use non-food-grade ingredients, they show the possi-
bilities to be explored in the future of the food industry. The
simplest structures, microbeads are formed by the production
of a single emulsion, in which the dispersed phase is solidified.
As discussed in the solidification methods, solid fat micro-
particles can be obtained through the oil crystallization in O/W
emulsions [65, 129], while biopolymer microbeads are
formed based on W/O emulsion [26, 38, 132, 135, 172].
Moreover, microcapsules can be obtained by the for-
mation of a double emulsion and subsequently solidifica-
tion of the middle phase, resulting in the formation of a
shell [146]. Microcapsules may be a hollow shell, which is
formed based on an air-in-oil-in-water (A/O/W) bubble–
emulsion system [72] or a shell–core carrier, which is a
capsule (shell) filled in with a solid or liquid (core), based
on the solidification of the intermediate phase of a W/O/W
or O/W/O double emulsion (Fig. 9a, b) [78, 116, 162].
Shell–core microcapsules are interesting structures to load
both hydrophobic and hydrophilic drugs.
Janus particles, which are composed by two hemi-
spheres with different compositions, could be an interesting
application in the controlled release of more than one
bioactive compound at different targets by specific enzy-
matic hydrolysis (Fig. 9c) [85]. The formation of such
structures is based on the injection of two inner phases in
separately channels into the continuous phase. The solu-
tions that compose the inner phase should be miscible in
BSA-FITC molecules (reprinted from Liu et al. [78]. Copyright
2013, Elsevier). c Fluorescence confocal microscopy images for FA-
alginate/Bodipy-pectin hetero Janus microbeads. Scale bar 100 lm
(reprinted with permission from Marquis et al. [85]. Copyright 2013
American Chemical Society)
123
406
each other, so they form a single drop. As soon as they
merge, the droplet is detached and solidified. Since the
droplet is formed at laminar regime inside the microdevice,
the mixing rate of the solutions is not high. Therefore, a
heterogeneous structure is obtained.
In addition, there are structures other than particles that
can be produced by microfluidic methods. Microfibers,
which can be exploited for modifying food texture and, at the
same time, for compounds encapsulation, can be obtained
through the confinement of a biopolymer solution flow by an
outer phase in a planar cross-junction or microcapillary
geometry. The outer phase contains the gelling agent,
resulting in the gelling of the biopolymer in the form of a
continuous microfiber [29, 169]. The diameter of the fibers is
controlled by the ratio of the inner to outer phases flow rates.
Furthermore, foams are formed in microfluidic devices by
the injection of air bubbles in a solution [8, 124]. Foams are
interesting structures that modify the texture and rheology of
the products, resulting in a change in their appearance and
mouthfeel [21]. Different sensorial characteristics can be
obtained by controlling the microbubble size through the
solution flow rate, air pressure and solution viscosity.
Self-assembled Structures
Self-assembled structures consist in the arrangement in dif-
ferent configurations of surfactant molecules under certain
conditions of concentration and system polarity. Microfluidic
technologies have recently been developed for the production
Fig. 10 Schematic diagram of the hypothesized mechanism for
liposome formation in a planar microfluidic hydrodynamic focusing
device. The central stream is composed of the phospholipid dispersion
123
Food Eng Rev (2015) 7:393–416
of self-assembled structures, either as adaptation of traditional
methods or totally innovative techniques [154]. The small
dimensions of microchannel enable rapid and uniform mass
transfer that can dramatically improve self-assembly yield and
size distribution. In addition, the possibilities of solvent
recycling and integration of separation techniques are ideal to
reduce cost effective of the production of self-assembled
structures [22, 23]. Particles formed using microfluidics by
self-assembly include among others conventional liposomes,
niosomes and polymersomes.
Liposomes
Liposomes can be used as nanocarrier systems for the
protection and delivery of bioactive compounds [96, 97] or
modifying the texture of food components, developing new
tastes and sensations [25]. Liposomes are formed by polar
lipids, usually phospholipids. Phospholipids have the
capacity of self-organization in bilayers or lamellae in
aqueous media, exposing their hydrophilic heads, hiding
their hydrophobic tails and forming flat structures. These
structures close on themselves forming vesicles of spheri-
cal shell type to achieve thermodynamic stability [81, 115].
The production of liposomes by the microfluidic
approach is based on the hydrodynamic flow-focusing
method in microfluidic devices with cross-shaped geome-
try. According to Fig. 10, the formation of liposomes by
this method is achieved by introducing an organic disper-
sion containing phospholipids through a central channel
in ethanol, which is hydrodynamically compressed by the two
adjacent aqueous streams (adapted with permission from Balbino
et al. [14]. Copyright 2013, Elsevier)
 Table 2 Experimental data compiled of the self-assembly structures production in a microfluidic hydrodynamic focusing devices
Structure Organic phase Aqueous Characteristics of device FRR range Average Reference
phase diameter
Compounds Solvent Device Width/depth Intersection
material angle

Liposomes DMPC and cholesterol Isopropanol Phosphate- Silicon and 42–64 lm Oblique 10–60 50–150 nm Jahn et al.
(5 mM) buffered borosilicate 100 lm (*angle [55]
saline glass 45°)
EPC and cholesterol Ethanol Phosphate- Glass Circular section Oblique 8–12 66.27–189.9 nm Huang et al.
Food Eng Rev (2015) 7:393–416

(3.84 mM) buffered (*1 mm) (*angle [51]

saline 45°)
DMPC and cholesterol Isopropanol Phosphate- Silicon and 42–65 lm Oblique 6–36 54–156 nm Jahn et al.
(5 mM) buffered borosilicate 120 lm (angle 45°) [57]
saline glass
Silicon and 10 lm Perpendicular 12–48 60–142 nm
borosilicate 36 lm
glass
DPPC (6.25 mM) Isopropanol Phosphate- Silicon and 21 lm Perpendicular 10–25 82–130 nm Hong et al.
buffered borosilicate 39 lm [45]
saline glass
DLPC, DMPC, DPPC, DSPC Isopropanol Phosphate- Silicon and 65 lm Perpendicular 9–49 *62 nm Zook and
and cholesterol (5 mM) buffered borosilicate *260 lm Vreeland
saline glass [173]
DMPE and cholesterol (5 mM) Isopropanol Phosphate- PDMS and 200 lm Perpendicular 2–7 *100– Wi et al.
buffered glass 50 lm *500 nm [161]
saline
DSPC and DSPE-PEG5000 (1.92 mM) PFP Phosphate- PDMS and 12–45 lm Oblique Not 360 nm–11 lm Martz et al.
buffered glass 200 lm (*angle informed [86]
saline 45°)
Asolectin from soybean, oleic acid and Ethanol Glycerol and PDMS 30–50 lm Oblique Not *500 nm Davies
cholesterol (*6.41 mM) deionized 40–60 lm (*angle informed et al. [31]
water 45°)
POPC and DMPC (2–20 mM) Isopropanol Phosphate- Glass 220 lm Perpendicular 4–40 *50–*160 nm Mijajlovic
buffered 50 lm et al. [95]
saline
EPC, DOPE and DOTAP (8–92 mM) Ethanol Deionized PDMS and 140 lm Perpendicular 8–18 85.8–508 nm Balbino
water glass 100 lm et al. [14]
DMPC, DMPE-PEG5000, DMPE- Ethanol Aqueous Cyclic olefin 190 lm Oblique 40–100 *80–110 nm Hood et al.
PEG2000, DSPE-PEG2000 and buffer 270 lm (*angle [47]
cholesterol (20 mM) 45°)
DMPC, DPPC, DOPC and HSPC Ethanol Ultrapure Glass Circular Axial flow 10–100 *50–*250 nm Phapal and
(*15.6 mM) water section (500 lm) focusing Sunthar
[113]
407

123
 Table 2 continued
408

Structure Organic phase Aqueous Characteristics of device FRR range Average Reference
phase diameter

123
Compounds Solvent Device Width/depth Intersection
material angle

Niosomes Span 20, Span 60 and Span 80 and Isopropanol Phosphate- Silicon and 65 lm Oblique 15–50 54–84 nm Lo et al.
cholesterol (5 mM) buffered borosilicate 120 lm (*angle [79]
saline glass 45°)
PDMS and 400 lm Perpendicular 15–50 272–*560 nm
glass 56 lm
Polymersomes P2VP-b-PO (0.5–1 g/L) Ethanol Water PDMS 30–70 lm Perpendicular 0.25–4 40 nm–2 lm Thiele et al.
70 lm [141]
PMPC-b-PDPA (5 g/L) Phosphate- Phosphate- PDMS and 100 lm Oblique 1–6 75–275 nm Brown et al.
buffered buffered glass Not informed (*angle [20]
saline saline 45°)
PB-b-PEO (4 g/L) THF Water Glassy carbon 45 lm Not informed 1 29–46 nm Thiermann
200 lm et al.
[142]
Stainless steel Not informed Not informed 1 25–49 nm
400 lm
HSPC hydrogenated soy phosphatidylcholine, EPC natural egg phosphatidylcholine, PS L-a-phosphatidylserine, DOPC 1,2-dioleoyl-sn-glycero-3-phosphocholine, P2VP-b-PO poly[2-
vinylpyridine]-b-poly[ethylene oxide], PMPC-b-PDPA poly[2-(methacryloyloxyethyl phosphorylcholine)]-b-poly[2-(diisopropylaminoethyl methacrylate], PB-b-PEO poly[butadiene]-b-
poly[ethylene oxide], POPC 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, DMPC 1,2-dimyristoyl-sn-glycero-3-phosphocholine, DMPE 1,2-dimyristoyl-sn-glycero-3-phosphoethanola-
mine, DOPE 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, DLPC 1,2-dilauroyl-sn-glycero-3-phosphocholine, DSPC 1,2-distearoyl-sn-glycero-3-phosphocholine, DPPC 1,2-dipalmitoyl-
sn-glycero-3-phosphocholine, DPPE 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, DOTAP 1,2-dioleoyl-3-trimethylammonium-propane, DSPE-PEG5000 1,2-distearoyl-sn-glycero-3-
phosphoethanolamine-N [methoxy-(polyethylene glycol)-5000], DMPE-PEG5000 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N [methoxy-(polyethylene glycol)-5000], DMPE-
PEG2000 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N [methoxy-(polyethylene glycol)-2000], DSPE-PEG2000 1,2-distearoyl-sn-glycero-3-phosphoethanolamine- N [methoxy-
(polyethylene glycol)-2000], Span 20 sorbitan monolaurate, Span 60 sorbitan monostearate, Span 80 sorbitan monooleate, PFP perfluoropentane, THF tetrahydrofuran
Food Eng Rev (2015) 7:393–416
Food Eng Rev (2015) 7:393–416
and subsequent compression of this dispersion by two
adjacent aqueous streams. The hydrodynamic flow focus-
ing of the lipid dispersion causes the controlled diffusion of
organic solvent into the aqueous phase. As a result, water
molecules will replace the organic molecules around the
phospholipids causing a change in the solubility of the
system. This fact triggers the self-organization of phos-
pholipids in bilayer fragments and subsequently in spher-
ical unilamellar vesicles [14, 51, 54–58, 95, 115].
Experimental data compiled from the literature of self-
assembled structures production in a microfluidic hydro-
dynamic flow-focusing devices are given in Table 2. Many
of the studies mention only the composition of the system
and the FRR range used in the experiments, but do not
present further details evaluating the effect of the geome-
try, the dimensions and configurations of the channels
(width and depth of the rectangular cross section and angle
of intersection of the side channels relative to the central
one) and the manufacturing materials on the average
hydrodynamic diameter and polydispersity index of the
self-assembled structures.
Several studies show that the size of the liposomes
obtained by hydrodynamic flow-focusing is practically
constant when the flow in the microchannel is between 30
and 200 lL/min, if the FRR is kept constant. A reduction in
FRR will cause an increase in the width of organic stream,
providing a central zone with a high concentration of
Fig. 11 Scale-up of production with a 16-channel module.
a Schematic of the microchannels on a chip. Labels ‘‘b’’ and ‘‘w’’
specify the inlet positions for black and white isobornyl acrylate,
respectively. The aqueous phase is infused from the inner 16 inlets,
arranged circularly, b schematic of internal structure of the holder
409
organic solvent. A higher concentration of the solvent can
stabilize the phospholipids bilayer fragments and allows
greater aggregation, resulting in large liposomes with a
wide particle size distribution. On the other hand,
increasing the value of FRR, the organic solvent will be
more diluted because the organic stream is hydrodynami-
cally focused into a thin jet. The reduced concentration of
organic solvent limits the formation of phospholipids
bilayer fragments, resulting in smaller liposomes with more
homogeneous size distribution [55–57].
Although there is little discussion about the influence of
dimensions and configurations of the planar microfluidic
devices on liposomes production, some studies express the
results as a function of these parameters. Jahn et al. [57]
studied the influence of the dimensions of the microfluidic
hydrodynamic focusing device using microchannel with
different widths, depths and intersection angles between
the lateral and central channels. Balbino et al. [14] studied
the continuous production of liposomes employing micro-
fluidic devices with one or two parallel hydrodynamic
focusing. The results of both studies showed that in general
the dimensions and geometry of the devices do not sig-
nificantly affect the size and polydispersity of liposomes.
However, since the devices with large dimensions are
easier to fabricate and operate, achieving higher flow rates,
they are generally associated with higher-throughput per-
formance compared with smaller devices [22].
with a glass chip (side view), c top view of the formation of biphasic
droplets in the module, d magnified view of the co-flow geometries
and e magnified view of the outlet port in the center of the chip
(reprinted with permission from Nisisako et al. [106]. Copyright
2006, WILEY–VCH)
123
410 Food Eng Rev (2015) 7:393–416

Niosomes Polymersomes

Niosomes are synthetic membrane vesicles produced by
self-assembly of nonionic surfactants that do not dissociate
at neutral pH. Their structure, properties and production
procedure are similar to those of conventional liposomes.
Niosomes can encapsulate hydrophilic molecules in their
inner aqueous core and partition hydrophobic ones into
their bilayer membrane [22, 79]. Microfluidic methods can
be used to produce niosomes with precise control of the
particles size and polydispersity. Lo et al. [79] used planar
microfluidic hydrodynamic flow-focusing devices manu-
factured with different materials for niosomes production,
following the concept proposed by Jahn et al. [54]. The
results demonstrated the potential of microfluidics for the
production of synthetic membrane vesicles of 54 nm size
with low polydispersity through self-assembly of nonionic
surfactants (Table 2).
Polymersomes, also referred to as polymeric vesicles, are
spherical vesicles formed by the self-assembled amphi-
philic block copolymers in aqueous environment. The
preparation methods of polymersomes include similar
techniques as those used to obtain liposomes and niosomes
[74, 141, 142]. The production of polymersomes occurs
through two different microfluidic approaches. The first is
based on the mixing technique using a planar microfluidic
hydrodynamic flow-focusing devices, consisting of per-
pendicularly crossed microchannels to focus an ethanolic
block copolymer solution into a stream of water [20, 141].
Some results obtained by this technique are given in
Table 2. The second technique is based on the formation of
W/O/W double emulsion using a capillary device. This
method relies on the evaporation of the solvent of the
double emulsion stabilized by the copolymer. As the

Fig. 12 Common layouts of

microfluidic channels for
distribution of fluids from a
single manifold into multiple
parallel drop generation units.
In each the device consists of 8
drop generation units (cross-
junctions). The abbreviations
CP, DP and E denote the inlets
of continuous and dispersed
phase fluid and the outlet of
emulsion product, respectively
(adopted from Tetradis-Meris
et al. [138]. Reprinted with
permission from [156].
Copyright 2013, Elsevier)

123
Food Eng Rev (2015) 7:393–416 411

solvent evaporates, the polymer self-assembles into a Therefore, the number of inlet channels increases by a
vesicular structure [9, 22, 43, 66]. factor of 2 between two consecutive branching levels. The
ladder-type structure has two main feed channels, one for
the dispersed phase and one for the continuous phase, and
Perspective for Application in Food Industries: Large- smaller channels branching off them [138, 156]. One
Scale Production hundred and eighty integrated drop generation units with
cross-junctions (20 9 20 lm) arranged in 9 parallel lines,
The overall market for microfluidics-based products was each line with 20 cross-junctions, and connected using an
valued at nearly $5.1 billion in 2011 and $5.6 billion in the ladder-type architecture, were used to produce W/O
2012, and the total in market revenues is expected to reach emulsions with a droplet diameter of 21 lm with droplet
nearly $10.3 billion in 2017 considering an annual growth diameter variations of less than 5 % [138].
rate of 13 % [94]. On the other hand, the current micro- Based on the terrace geometry, the edge-based droplet
fluidic technologies have to overcome some limitations to generation (EDGE) device (Fig. 13) was designed to form
make its applications potentially viable in the food multiple droplets at the edge of a shallow but rather wide
industry. rectangular plateau [149–151]. A 1.5 9 1.5 cm chip
The feasibility challenges include the precise control of
heat and mass transfer functions inside the microfluidic
channels and consequently their effects on the properties of
food structures. Another limiting factor is the requirement
of specialized facilities, such as a clean room for micro-
fluidic device fabrication. Consequently, high manufac-
turing costs of devices remain a hurdle for the microfluidic
technology and its application in the food industries [98].
Recently, more versatile and easy microfabrication meth-
ods that do not require a clean room facility have been
suggested in order to reduce the production costs [114].
Besides, the microfluidic technologies are still limited
by its low throughput. For practical use in food industry
where an annual throughput of many tons is generally
required, the scale-up can be done by the massive parall-
elization of devices, where several identical microfluidic
devices are subjected to the same process [44]. This type of
scale-up occurs without the need for larger equipment
design, reducing costs and time of implementation study to
industrial scale [104].
Parallel microfluidic devices in one-, two-, and three-
dimensional arrays have so far been coupled with a single
set of pumps so as to increase the throughput of emulsions
and might be used for others food structures [105]. An
approach consists in a planar microfluidic chip droplet
generator with microchannels circularly integrated, and a
support holder with concentric multiple annular channels
that supply each fluid evenly into the channels (Fig. 11).
With this strategy, simple O/W emulsion composed by
90.7-lm-mean-diameter droplets was produced with 2.2 %
coefficient of variation at a throughput of 180 mL h-1
[104–106].
Two layouts that allow to distribute fluids from a single
manifold to parallelized planar microfluidic microchannels Fig. 13 a Design of the EDGE microchip, where the dark channel
guides the to-be-dispersed phase, the gray ‘‘twisting road’’ is the
are the tree-type and the ladder-type multiple parallel drop
continuous phase channel and the rectangular areas in between are the
generation units (Fig. 12) [138]. The tree-type network has droplet formation units and b drawing of one droplet formation
one inlet for each phase at the zeroth branching level and parallelized unit (reprinted with permission from van Dijke et al.
2m inlet channels for each phase at the mth branching level. [150]. Copyright 2010, Elsevier)

123
412
composed by 196 plateaus (200 9 500 9 1.2 lm) is able
to produce up to 300,000 droplets per second per chip
[152].
Summary and Outlook
In the last decade, several strategies were presented to
produce different food structures, taking advantage of the
highly controlled hydrodynamics conditions of the micro-
fluidic devices. It has been proposed many devices geom-
etries, materials and fabrication methods. For successful
results, the knowledge of the fluid dynamics in the micro-
scale is essential. Thus, many studies have been published
aiming to explore the fundamentals of the microfluidics.
The operating conditions, mainly the ratio between the flow
rates, and the physical properties of the fluids such as the
viscosity and interfacial tension are determinant for
manipulating the size and shape of the structures.
The most promising application of food structure gen-
erated by microfluidic methods is the encapsulation of
bioactive compounds for controlled release. Single and
multiple emulsions, emulsion-template microparticles and
self-assembled nanoparticles with low size polydispersity
can be generated to load hydrophilic and/or hydrophobic
compounds. However, more studies are needed regarding
the stability of these structures in the final product as well
as in the gastrointestinal environment.
For the future of the food industry, some of the chal-
lenges regarding the use of microfluidics are the creation of
stable and responsive structures using only food-grade
ingredients, the production of devices that operate at high
throughput resulting in high yield for the production at
industrial scale.
Acknowledgments The authors would like to thank CNPq
(479459/2012-6, 140283/2013-7, 140270/2014-0 and 305477/2012-9)
and FAPESP (2011/06.083-0 and 2010/16.708-4) for their financial
support.
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