Continuous-flow lithography for high-throughput microparticle synthesis

ArticleinNature Materials 5(5):365-9 · June 2006with89 Reads
Impact Factor: 36.50 · DOI: 10.1038/nmat1617 · Source: PubMed

Precisely shaped polymeric particles and structures are widely used for applications in photonic materials, MEMS, biomaterials and self-assembly. Current approaches for particle synthesis are either batch processes or flow-through microfluidic schemes that are based on two-phase systems, limiting the throughput, shape and functionality of the particles. We report a one-phase method that combines the advantages of microscope projection photolithography and microfluidics to continuously form morphologically complex or multifunctional particles down to the colloidal length scale. Exploiting the inhibition of free-radical polymerization near PDMS surfaces, we are able to repeatedly pattern and flow rows of particles in less than 0.1 s, affording a throughput of near 100 particles per second using the simplest of device designs. Polymerization was also carried out across laminar, co-flowing streams to generate Janus particles containing different chemistries, whose relative proportions could be easily tuned. This new high-throughput technique offers unprecedented control over particle size, shape and anisotropy.


Available from: Daniel Pregibon, Jan 30, 2014
Continuous-flow lithography for
high-throughput m icroparticle synthesis
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Published online: 9 April 2006; doi:10.1038/nmat1617
recisely shaped polymeric particles and structures are
widely used for applications in photonic materials
and self-assembly
. Current
approaches for particle synthesis are either batch processes
or flow-through microfluidic schemes
that are based
on two-phase systems, limiting the throughput, shape and
functionality of the particles. We report a one-phase method
that combines the advantages of microscope projection
and microfluidics to continuously form
morphologically complex or multifunctional particles down
to the colloidal length scale. Exploiting the inhibition of
free-radical polymerization nea r PDMS surfaces, we are able to
repeatedly pattern and flow rows of particles in less than 0.1 s,
aording a throughput of near 100 particles per second using the
simplest of device designs. Polymerization was also carried out
across laminar, co-flowing streams to generate Janus particles
containing dierent chemistries, whose relative proportions
could be easily tuned. This new high-throughput technique oers
unprecedented control over particle size, shape and anisotropy.
Previous work on making particles in microfluidic devices
wasbasedonthebreako of droplets in two-phase flows at
a T-junction
or in flow-focusing geometries
surface-tension eects, such techniques have been restricted to
generating particles that are spheres, deformations of spheres
(rods, ellipsoids or discs) or cylinders
. Additionally, these
techniques are limited to making one particle at a time, and
require phase-separating chemistries (immiscible fluids) that are
also surface-compatible with the microfluidic devices used.
There is a tremendous need to generate monodisperse particles
with a greater diversity of shapes and w ith complex chemistries
Such particles can serve as new building blocks in self-assembled
structures, where it is known that the complexity of structures
greatly increases with anisotropic interactions
. These interactions
can be purely steric or arise due to spatially segregated surface
chemistries on a particle. Simulations show that many exotic
structures can be created with anisotropic interactions, but a
technology to synthesize a comprehensive particle library is
. Furthermore, microparticles can act as surfactants, and
their assembly depends subtly on their morphology
of particle suspensions is also very sensitive to particle shape, and
is important in the design of bullet-resistant f abrics
consumer products.
Complex particles are also needed in the emerging field of
barcoded-particle technologies
. Existing techniques typically add
new functional groups one-by-one
. A one-step synthesis is highly
desired. Challenges also exist in aligning particles before detection,
and custom shapes may facilitate this.
limitations to continuously synthesize a variety of dierent shapes
using several dierent oligomers and make bifunctional Janus
particles. The method is straightforward to implement using a
standard fluorescence microscope, and can easily be extended
to create particles that have more than two distinct coded (for
example, chemically, fluorescently, magnetically) regions in a
one-step synthesis.
In a representative experiment, an acrylate oligomer
stream (typically poly(ethylene glycol) diacrylate) containing
a photosensitive initiator was passed through a rectangular,
all-PDMS microfluidic device as shown in
Fig. 1a. Particle
arrays of mask-defined shapes (see squares in Fig. 1b) were
formed by exposing the flowing oligomer to controlled pulses
of ultraviolet (UV) light using an inverted microscope and
collected in the device reservoir (Fig. 2). Rapid polymerization
kinetics permitted the particles to form quickly (
<0.1 s), and
oxygen-aided inhibition near the PDMS surfaces allowed for
particle flow within the unpolymerized oligomer stream (see
Supplementary Information, Movie S1). This serendipitous ability
of the particles to flow is because molecular oxygen diusing
through the PDMS surfaces reacts with initiator species to form
chain-terminating peroxide radicals
lubricating layer (see Supplementary Information, Section S2) near
the PDMS walls (inset of Fig. 1a). The phenomenon of oxygen
inhibition at the PDMS walls is applicable to any free-radical
polymerization, rendering our approach suitable for a broad range
of polymer chemistries.
The shape of the particles in the
xy plane (Fig. 1b) is
determined by the shape of the feature used on the transparency
mask (Fig. 1a), whereas the
z-plane projection (shown in Fig. 1c) is
dependent on the height of the channel used and the thickness of
the oxygen inhibition layer. Using our microscope projection setup,
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PDMS layer
PDMS layer
(i) Insert transparency mask with desired particle shape in field-stop slider
(ii) Flow monomer + initiator solution through microchannel
(iii) Polymerize using shuttered UV light from microscope objective
(iv) The particles polymerize quickly and advect through the unpolymerized monomer
PDMS device
PDMS device
Glass slide
Oxygen inhibition layer
Transparency mask
(field-stop plane)
50 μm
40 μm
Figure 1 Experimental setup. a, Schematic depicting the experimental setup used in the study. A mask containing the desired features is inserted in the field-stop plane of
the microscope. The monomer stream flows through the all-PDMS device in the direction of the horizontal arrow. Particles are polymerized, by a mask-defined UV light beam
emanating from the objective, and then advect within the unpolymerized monomer stream. The side-view of the polymerized particles can be seen in the insetshownonthe
right. Also shown is the unpolymerized oxygen inhibition layer that allows the particles to flow easily after being formed. b, A brightfield microscopy image (xy plane) of an
array of cuboids moving through the unpolymerized monomer. c, A cross-sectional view of the cuboids seen in b upon collection in a droplet that has turned most particles on
their sides.
the objective used, rang ing from 7.8 times using a
×20 object ive
to 39 times using a
×100 objective. For example, using the ×20
objective, a 350-
μm-square mask feature was used to synthesize
cuboids (rectangular parallelepiped objects) that had 45-
μm/7.8 = 45 μm) in the xy plane(Fig.1b).Theheightofthe
particles was equal to the height of the channel minus the thickness
of the inhibition layers (see Supplementary Information, Section
S2). Cuboids with a height of 15
μm (Fig. 1c) were synthesized
in a 20-
μm-high channel because of the 2.5-μm-thick oxygen
inhibition layer at both the top and bottom walls of the device.
By designing masks with varied features and selecting channels
of diering heights, we synthesized particles of several distinctive
shapes, sizes and aspect ratios (Figs 2, 3).
We have synthesized various polygonal shap e s such as triangles,
squares and hexagons (Fig. 3a–c); colloidal entities (Fig. 3d);
high-aspect-ratio objects such as posts with circular, triangular
and square cross-sections (Fig. 3e,f); and non-symmetric or curved
objects (Fig . 3g–i). All of the particles showed good fidelity to the
original mask features and had st raight sidewalls.
The fundamental limitations of a projection photolithography
technique, such as ours, are mainly governed by the optical
(see Supplementary Information, Section S3). The resolution of
an objective is the smallest distinguishable feature that can be
discerned, and the depth of field is the length over which the
beam of light emanating from the objective can be considered
to have a constant diameter. In our case, the resolution limits
the size of the smallest particle that can be made, whereas the
straight. Better resolution comes at the cost of decreased depth of
field. Additionally, practical constraints on particle synthesis are
imposed by finite polymerization times and the minimum feature
size currently printable on a transparency mask (
10 μm).
The exposure time required to polymerize particles was
inversely proportional to both the height of the channels used
and the size of the transparency mask feature (see Supplementary
Information, Section S4); particles required longer polymerization
times when either of these two parameters was decreased. The
oxygen inhibition layer thickness is independent of channel height,
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30 μm 30 μm
30 μm 10 μm
Figure 2 Differential interference contrast images of collections of particles. Particles were generated in a high-throughput fashion and collected in a reservoir. a, Rings
formed using a 9.6-μm-high channel and the ×20 objective. b, Triangles formed in a 38-μm-high channel using a triangular mask and the ×20 objective. c, Cylinders
synthesized using circular masks in 38-μm-high channels using the ×20 objective. d, Colloidal cuboids synthesized using a square mask and the ×20 objective in a
9.6-μm-high channel. All of the particles were synthesized using exposure times obtained from the data shown in Section S4 of Supplementary Information.
Figure 3 Scanning electron microscope images of particles. Microparticles formed using a ×20 objective (except d, which was formed using a ×40 objective) were
washed before being observed using SEM. The scale bar in all of the figures is 10 μm. ac, Flat polygonal structures that were formed in a 20-μm-high channel. d,A
colloidal cuboid that was formed in a 9.6-μm-high channel. e,f, High-aspect-ratio structures with different cross-sections that were formed in a 38-μm-high channel.
gi, Curved particles that were all formed in a 20-μm-high channel. The inset in the figure shows the transparency mask feature that was used to make the corresponding
particle. All of the particles were synthesized using exposure times obtained from the data in Section S4 of Supplementary Information.
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50 μm
Figure 4 Synthesis of Janus particles. a, A schematic diagram showing the synthesis of Janus (two-faced) particles. The widths of the streams, L
and L
, can be altered
by changing the flow rates of the streams. b, Two streams containing PEG-DA (grey) and PEG-DA with rhodamine-labelled cross linker (white) are co-flowed through a
channel. A schematic representing the formation of a bar-shaped particle 130 μm in length and 20 μm width is overlaid on the picture. Diffusion-limited mixing seen in
laminar flow is exploited to ensure the streams flow distinctly. c, DIC image of a Janus particle. d, Fluorescence microscopy image of the particle in c. The
rhodamine-labelled portion is seen in red. e, An overlaid image of the entire particle showing both the fluorescently labelled (orange) and the non-labelled (green) sections.
The scalebar in figures ce is 50 μm. f, Multiple Janus particles with the fluorescent portion shown in orange. The scalebar is 100 μm.
leading to more-pronounced eects in low-height channels, where
Supplementary Information, Section S2). Smaller t ransparency
feature sizes require increased polymerization doses as a result
of diraction-induced limitations in the internal microscope
optics (see Supplementary Information, Section S5). Longer
polymerization times lead to constraints on the maximum velocity
of the oligomer stream, to avoid shape deformation of the particles
(see Supplementary Information, Section S6). Although we have
only generated particles greater than 3
μm using continuous flow,
preliminary experiments showed that we could synthesize even
smaller objects (
1 μm) in a stop-polymerize-flow mode. In
addition to controlling particle size and shape, our approach allows
for the selection of various particle chemistries. The oligomer
streams used in this process can incorporate diverse functional
moieties to synthesize particles that are field-responsive
for applications in
self-assembly, rheology, biosensing and drug deliver y.
Entities with multiple chemistries
are proving to
be important in sorting and targeting applications
or in
self-assembly studies
. Using our technique, particles with
two or more functionalities may be easily and controllably
synthesized. Exploiting the diusion-limited mixing seen in
laminar flow (Fig. 4a,b), we synthesized bifunctional Janus particles
(Fig. 4c–e) by polymerizing rectangular particles across the
interface of co-flowing and rhodamine-labelled oligomer streams.
By controlling the location of the interface using the flow rates of
the streams or the location of the projected light by moving the
microscope stage, we can synthesize particles that contain variable
proportions of dierent chemistries. By simply flowi ng multiple,
concurrent, laminar streams through a microfluidic device and
polymerizing particles across these streams, our approach may be
used to generate particles with several adjacent chemistr ies. The
ability to tune the proportion of so many chemistries allows for
great flexibility in the design of barcoded particles.
We have demonstrated a photolithography-based microfluidic
technique that can be used to continuously synthesize polymeric
particles of varied complex shapes and multiple chemistries.
The advantage over traditional lithography techniques
is the
continuous nature of the process, permitting the high-throughput
(400,000 particles h
) generation of polymeric particles. In a
next-generation device, we could increase the area of the light
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source and parallelize the technology to achieve much higher
throughput. The morphology and the chemistry of the particles
can be independently chosen to form large numbers of uniquely
shaped, functionalized particles for applications including drug
delivery, biosensors, microactuators and fundamental studies on
self-assembly and rheology. Greater control of particle morphology
could potentially be achieved using grey-scale photomasks,
multiphoton illumination or multiple-beam lithography
technique presents an opportunity for the high-throughput
synthesis of morphologically or chemically unique particles for
various applications.
All of the particles shown in this work were made using 5% (v/v) solutions of
Darocur 1173 (Sigma Aldrich) initiator in poly(ethylene glycol)(400) diacrylate
(PEG-DA, Polysciences). The viscosity of the PEG-DA is reported by the
supplier to be 57 cP at 25
C. We also made particles composed of
trimethylpropane triacrylate, 1,6-hexanediol diacrylate and tri(propylene
glycol) diacrylate (all from Polysciences). All of these materials belong to the
class of multifunctional acrylate molecules that are known to be highly reactive
and form tightly cross linked networks upon radical-induced polymerization.
The method should work for other radical-induced polymerizations because
they are, in general, inhibited by oxygen
. Solutions, 0.005 wt%, of the
fluorescent methacryloxyethyl thiocarbamoyl rhodamine B (Polysciences) in
PEG-DA were used to fluorescently label the polymer.
Devices were fabricated by pouring polydimethylsiloxane (PDMS, Sylgard 184,
Dow Corning) on a silicon wafer containing positive-relief channels patterned
in SU-8 photoresist (Microchem). The devices were rectangular channels of
varying widths (200, 600 or 1,000
μm) and heights (9.6, 20 or 38 μm). These
devices were placed on glass slides spin-coated with PDMS to ensure that the
oligomer was only exposed to the PDMS surfaces. The devices were mounted
on an inverted microscope (Axiovert 200, Zeiss), and the formation of the
microparticles was visualized using a charge-coupled-device camera (KPM1A,
Hitachi). Images were captured and processed using NIH Image software.
Photomasks were designed in AUTOCAD 2005 and printed using a
high-resolution printer at CAD Art Services (Poway, California). The mask was
then inserted into the field-stop of the microscope. A 100 W HBO mercury
lamp served as the source of UV light. A filter set that allowed wide UV
excitation (11000v2: UV, Chroma) was used to select light of the desired
wavelength and a VS25 shutter system (Uniblitz) driven by a
computer-controlled VMM-D1 shutter driver provided specified pulses of UV
light. Oligomer solutions were driven through the microfluidic device using a
KDS 100 syringe pump (KD Scientific).
The particles were collected, washed and then re-suspended three times in
ethanol to dissolve the unpolymerized PEG-DA. They were then washed three
times in water, and finally suspended in water. The particle size distribution
and extent of polymerization were quantified using standard methods (see
Supplementary Information, Section S7).
Received 26 October 2005; accepted 22 February 2006; published 9 April 2006.
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We gratefully acknowledge the support of NSF NIRT Grant No. CTS-0304128 for this project. We
thank Y. Hu for assistance with fluorescence microscopy, as well as K. Krogman and J. Lutkenhaus for
assistance with FTIR measurements.
Correspondence and requests for materials should be addressed to P.S.D.
Supplementary Information accompanies this paper on
Competing financial interests
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Reprints and permission information is available online at
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