2006 Polymer Chemistry in Flow

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HIGHLIGHT

Polymer Chemistry in Flow: New Polymers, Beads,Capsules, and Fibers

JEREMY L. STEINBACHER, D. TYLER MCQUADEDepartment of Chemistry and Chemical Biology, Cornell University, Ithaca,New York 14853

Received 8 June 2006; accepted 15 June 2006DOI: 10.1002/pola.21630Published online in Wiley InterScience (www.interscience.wiley.com).

ABSTRACT: The union be-

tween polymer science and micro-

fluidics is reviewed. Fluids in mi-

croreactors allow the synthesis of a

wide range of polymeric materials

with unique properties. We begin

by discussing the important fluiddynamics that dominate the behav-

ior of fluids on the micrometer

scale. We then progress through a

comprehensive analysis of the poly-

meric materials synthesized to date.

This highlight concludes with an

overview of the methods used to

make microreactors. We enthusias-

tically endorse microreactors as apowerful approach to making mate-

rials with controlled properties, al-

though we have tried to provide a

critical eye to help the nonexpert

enter the field. VVC 2006 Wiley Periodi-

cals, Inc. J Polym Sci Part A: Polym Chem

44: 6505–6533, 2006

Keywords: colloids; microen-capsulation; microfluidics; micro-

particles; particle size distribution

Jeremy L. Steinbacher is currently pursuing a doctorate in the

Department of Chemistry and Chemical Biology at Cornell Univer-

sity (Ithaca, NY) under the tutelage of Professor D. Tyler McQuade.

His research interests include the development of site-isolated cata-

lysts and the production of materials within microfluidic devices. A

native of Pennsylvania, he earned his B.A. in Chemistry from Frank-

lin & Marshall College (Lancaster, PA) in 2003.

D. Tyler McQuade, Assistant Professor of Chemistry and Chemical

Biology at Cornell University, began his faculty position in 2001.J. L. STEINBACHER and D. T. MCQUADE

Correspondence to: D. T. McQuade (E-mail: [email protected])

Journal of Polymer Science: Part A: Polymer Chemistry, Vol. 44, 6505–6533 (2006)

VVC 2006 Wiley Periodicals, Inc.

6505



INTRODUCTION

The continuous synthesis of materials in flow began in

the early 1900s in the fiber industry. Continuous pro-

cessing in flow is a mainstay of oil refining and bulk

chemical manufacturing. For most of the 20th century,

synthesis in flow was relegated to low-margin areas inwhich the benefits of continuous processing were most

strongly felt. The view that flow is only useful for

commodity products has changed over the last 20 years

as two communities have recognized that flow not

only provides low-end assembly-line benefits but also

has value for high-margin products because of the

heat-transfer, mixing, and flow-alignment attributes

conveyed by microreactors. Academic chemists entered

the microreactor area largely through the efforts of

George Whitesides and his use of poly(dimethylsilox-

ane) (PDMS) to create inexpensive microfluidic devi-

ces and through the microreactor community led by

the Institute for Molecular Manufacturing (IMM) inGermany and Yoshida’s microreactor initiatives in

Japan. The area of microreactors and their impact on

chemical and materials synthesis are well reviewed in

a wide variety of contexts.1,2 In this highlight, we

attempt to examine microreactors through the lens of a

polymer scientist describing, by use of examples from

the literature, how microreactors can add value to a

typical polymer scientist’s laboratory.

UNIQUE PROPERTIES OF MICROREACTORS

Mixing

Stirring in classical reactors, such as round-bottom

flasks and larger batch reactors, is limited by inhomo-

geneities in the flow fields created by the stirring bar or impeller, respectively. As a fluid approaches the

stirrer, convection is induced, resulting in turbulence

and chaotic mixing. The shear forces that cause the

convection are significantly dampened away from the

stirrer, and the majority of the round-bottom flask or

reactor experiences little or no mixing. The idle por-

tions of a reaction environment allow time for unpro-

ductive chemistry to take place because of local con-

centration gradients. If unproductive chemistry is not

an issue, longer reaction times may be used to drive

reactions to completion, decreasing efficiency. Rapid

mixing results in faster reaction times and thus cleaner

chemistry, although rapid mixing is difficult to achievein a classic reactor for the reasons outlined previ-

ously.1

On the other hand, continuously flowing micro-

reactors allow rapid and homogeneous mixing because

of their small dimensions. Microreactors can achieve

complete mixing in microseconds, whereas classical

reactors mix on the timescale of seconds.3 Microreac-

tors achieve this rapid mixing using a variety of strat-

He is currently a Dreyfus, 3M, Rohm and Haas, Beckman, and New

York State Office of Science, Technology, and Academic Research

Young Investigator and one of the 2004 Massachusetts Institute of

Technology Tech Review 100. McQuade was born in Atlanta, GA,

and raised in the Santa Cruz Mountains of California. He received a

B.S. in Chemistry and a B.S. in Biology from the University of Cal-ifornia–Irvine and a Ph.D. in Chemistry from the University of Wiscon-

sin–Madison under the guidance of Professor Samuel Gellman. His

education was completed by a National Institutes of Health fellowship

at the Massachusetts Institute of Technology with Professor Timothy

Swager.

The McQuade Group is focused on creating synthetic systems that use

site isolation (via encapsulation) and selectivity (via recognition) to

carry out multistep syntheses with greater efficiency. The multidiscipli-

nary environment of the group, which uses tools from biology, chem-

istry, and materials science, is yielding both polymers and small mole-

cules that will provide the building blocks for the next generation of

reagents for sustainable process chemistry. Many of these early inno-

vations nucleated the Systanix enterprise that won Cornell’s Big RedVentures 2005 Business Idea Competition.

6506 J. POLYM. SCI. PART A: POLYM. CHEM.: VOL. 44 (2006)

Journal of Polymer Science: Part A: Polymer ChemistryDOI 10.1002/pola



egies. Researchers at IMM in Germany and at Battelle

in the United States (Fig. 1) have created devices that

mix fluids using a multilamellar approach in whichlayers of fluids ranging in thickness from 50 to 200 lm

are sandwiched together. The small dimensions allow

rapid diffusional mixing to occur in as little as 100 ls.

Such rapid mixing occurs because these lamellar systems

achieve surface-to-volume ratios of up to 30,000 m2 mÀ3,

in contrast to laboratory beakers and batch reactors,

which typically have surface-to-volume ratios of 100

and 4 m2 mÀ3, respectively. As discussed later, these

surface-to-volume ratios impact thermal and mass

transport. Other strategies that complement the lamellar

design are twisted or undulating tubes, impinging

flows, or static mixers placed in flow.4,5

Thermal Management

Heating and cooling a reaction is an important variable

that, if left uncontrolled, can lead to either very slow

reactions (needing heat) or runaway reactions that can

lead to explosions (needing cooling). Also, reactions

that offer two potential products from either kinetic or

thermodynamic pathways are very sensitive to temper-

ature. Batch reactors often provide broad temperature

profiles that can allow access to multiple pathways

when only one pathway is desired. Figure 2 compares

the temperature distributions in batch and microreac-

tors to the kinetic energy needed to access a byprod-

uct-forming pathway.2 Although the batch reactor’s

broad temperature distribution allows the undesired

side reaction, the narrow temperature distribution in

Figure 1. (A) IMM interdigital microreactors with characteristic lamellar dimensions on the

order of tens of micrometers and mixing times of several hundred milliseconds and (B) sche-

matic of a Velocys stacked microreactor that forces submicrometer droplets of the disperse phase

through a porous membrane into flowing streams of the continuous phase. Reproduced with per-

mission from (A) Institut fur Mikrotechnik Mainz GmbH and from (B) Chemical Engineering

Progress, August 2004.

Figure 2. (left) Comparison of the ideal temperature distributions for a hypothetical reaction

(black) and the actual temperature distributions in a batch reactor (blue) and a microreactor (red)

and (right) schematic comparison of these temperature distributions to two product-forming path-

ways. The batch reactor’s broad temperature distribution allows the production of undesired

product C, but the narrow temperature distribution in the microreactor restricts the reaction to

target product B. Reprinted with permission from Schwalbe, T. et al., Org Process Res. Dev.

2004, 8, 440–454. Copyright 2004, American Chemical Society.

HIGHLIGHT 6507




the microreactor restricts the reaction to the target

product. Microreactors achieve such efficient input or

removal of heat and nearly constant reaction tempera-

tures because of their high surface-to-volume ratios.

Rapid temperature changes6 and heat-exchange coeffi-

cients up to 25 kW mÀ2 KÀ1 are possible, depending

on the materials and heat exchanger used.3

The precise thermal management available in a

microreactor enables efficient, high-temperature reac-

tions, such as the conversion of methane to methanol,

fine control over the reaction selectivity, and the abilityto perform otherwise explosive chemistry. Anyone famil-

iar with Imperial Chemical Industries history of polyeth-

ylene research recognizes that exotherms resulting from

polymerizations can cause explosions.7 A microreactor

can enable highly exothermic polymerizations safely and

with a degree of control that limits side reactions such

as premature chain termination or chain transfer.

Figure 3. A demonstration of laminar flow provided by

flowing two dyed solutions together in a Y-shaped junction.

The streams experience no convection and mix by diffusion

only. Reprinted from Choban, E. R.; Markoski, L. J.; Wieck-

owski, A.; Kenis, P. J. A. J. Power Sources 2004, 128, 54–

60, copyright 2004, with permission from Elsevier.

Figure 4. Cartoon illustrating the effects of the channel di-ameter on the laminar flow. (A) With a large channel, the

fish, representing fluid streamlines, can swim in any direction

without feeling the walls. (B) Shrinking the channel causes

the fish to swim mostly in the same direction, but the channel

is still large enough to turn (or turbulently mix). (C) When

the channel is shrunk further, the fish are now forced to swim

in one direction without turning (laminar flow). [Color figure

can be viewed in the online issue, which is available at

www.interscience.wiley.com.]

Figure 5. Example of the use of laminar flow to pattern

polymeric structures. Here, oppositely charged polyelectro-

lytes precipitate at the interface of two coflowing streams.

Reprinted with permission from Kenis, P. J. A. et al., Science

1999, 285, 83–85. Copyright 1999, AAAS.

Figure 6. Simulations of a flow field in a mixer including

the velocity field and convective diffusion of molecules from

the center stream to the outer, sheath streams. Reprinted with

permission from Santiago, J.G. Stanford Microfluidics Labo-

ratory website. Available at: http://microfluidics.stanford.edu/

micromix.htm. Copyright 2006, Stanford Microfluidics Labo-

ratory. [Color figure can be viewed in the online issue, which

is available at www.interscience.wiley.com.]





Although vastly improved mixing and thermal man-

agement are very useful, these virtues of microreactors

add value by making already tractable problems easier

to manage. The truly revolutionary advantage that

microreactor systems convey for the polymer chemist

is precise control over the fluid behavior and structure.

Fluid Behavior

Most synthetic chemists have no formal training in fluid

dynamics or fluid behavior. Unlike our colleagues in

physics and engineering, we view fluids as media that

we do not consider beyond polarity effects and perhapsviscosity. A fluid in a round-bottom flask represents a

relatively boring variable, yet as fluids are forced into

small volumes, their physical behavior begins to change.

Fluid behavior at the micrometer scale rarely corre-

sponds with our day-to-day intuition. This is nicely illus-

trated by Whitesides’s Science cover 8 in 1999, in which

seven dyed solutions flowed together in a small channel

and Kenis’s two dyed solutions flowing together in a

Y-junction9 (Fig. 3). In this particular case, the small

channel width forced the fluid into a laminar flow re-

gime, and the fluids did not mix convectively. Rather,

the individual streams flowed side by side, mixing only

by diffusion at the interface.

Engineers, being more practical than the average

physical scientist, often reduce basic observations

Figure 7. Long-strand DNA structures in a microchannel: (C) DNA molecules in flow at

10 lL minÀ1 (the actual flow speed at the focus position is ca. 100 lm sÀ1) and (D) a fluores-

cence intensity distribution map of one DNA molecule from part C. In a nonflowing state, these

DNA molecules form a coiled structure. However, in flow, they stretch and undulate as though

swimming and orient in the same direction as the flow. Bright and dark points can be seen

within individual molecules. The presence of these points suggests that well-stretched and non-

stretching parts exist within individual molecules. Reprinted from Analytical Biochemistry, Vol.

332, Yamashita, K., Direct Observation of Long-strand DNA, 274–279 (2004), with permission

from Elsevier.

Figure 9. Demonstration of the effect of Ca on the flow

regime. (b) At low flow rates, surface tension dominates over

viscous forces, and plugs are formed from the combinationof both water phases. (c) At an intermediate Ca value, the

water streams take turns snapping off droplets. (d,e) At the

highest Ca values, viscous forces dominate over surface ten-

sion, and the water phases begin to coflow with the oil con-

tinuous phase. Reprinted with permission from Zheng, B.

et al., Anal. Chem. 2004, 76, 4977–4982. Copyright 2004,

American Chemical Society. [Color figure can be viewed in

the online issue, which is available at www.interscience.

wiley.com.]

Figure 8. Formation of droplets from a jet of fluid by

breakup due to the Rayleigh–Plateau instability. Minimiza-

tion of the surface area drives breakup when the jet experien-

ces perturbations larger than the circumference of the jet.

Reprinted with permission from Anna, S. L. et al., Applied

Physics Letters, 2003, 82, 364–366. Copyright 2004, Ameri-

can Institute of Physics.

HIGHLIGHT 6509




down to dimensionless parameters that are empirically

derived. Many dimensionless parameters exist, but

when we consider reactions in flow, only two, the

Reynolds number ( Re) and Capillary number (Ca),

offer visceral insight. The following discussion is

meant only as a primer on fluid behavior and simplifies

certain issues for the sake of clarity. This primer maybe followed up by a reading of the authoritative review

by Squires and Quake10 on the subject of fluids in

microfluidic devices.

Re

Turbulent mixing and chaotic mixing are the tools of

the average chemist armed with a round-bottom flask.

However, moving to channels with length scales on the

order of nanometers to millimeters prevents turbulent

and chaotic mixing altogether. This transition from tur-

bulent flow to smooth flow occurs when viscous effects

begin to dominate over inertial effects in the fluid. Rep-resenting this ratio of inertial forces to viscous forces,

Re is defined as follows:

Re ¼qvl

gð1Þ

where q is the density, v is the mean velocity, l is a

characteristic length scale (e.g., the diameter of a tube),

and g is the dynamic viscosity. The exact transition

point depends on the given channel geometry, but flu-

ids with Re below *2000 flow laminarly, without tur-

bulence. By thinking of a fluid as a series of fish mov-

ing in a stream, one can get a visceral feel for fluidmovement on different length scales (assuming that the

fluid and its velocity are held constant). Figure 4

shows fish swimming in a large channel in which the

fish can swim in any direction without feeling the

Figure 10. Droplet patterns in rounded channels at different

water and oil pressures (psi noted in the figure) and the corre-

sponding phaselike diagram depicting the relationship between

the oil and water pressure differences and droplet morphology:

() solid water stream, (*) elongated droplets, (~) triple

droplet layer, (~) double droplet layer, (n) jointed droplets,

and (u) separated droplets. Solid lines are used to define ap-

proximate boundaries between the following droplet states (topto bottom): solid water stream, ribbon layer, pearl necklace,

single droplets, and solid oil stream. Reprinted figure with per-

mission from T. Thorsen et al., Phys. Rev. Lett., 2001, 86,

4163–4166. Copyright 2001 by the American Physical Society.

Figure 11. (left) Schematic of a microfluidic device for creating double emulsions and (right)

red and blue aqueous droplets contained in larger organic droplets. Reprinted in part with per-

mission from Okushima, S. et al., Langmuir 2004, 20, 9905–9908. Copyright 2004, American

Chemical Society. [Color figure can be viewed in the online issue, which is available at www.

interscience.wiley.com.]





walls. Shrinking the channel causes the fish to swim in

the same direction, but the channel is still large enough

to turn (or turbulently mix). If we shrink the channel fur-

ther, the fish now swim in one direction without turning

(laminar flow). The fish represent the smallest turbulent

motions available to the fluid based on the values of the

variables in eq 1. Once the channel dimensions are

smaller than this length, the turbulence is damped, and

the fluid moves nonturbulently with parallel streamlines.

Laminar flow provides the polymer chemist with an

opportunity. The interface between fluids offers the op-

portunity to perform polymerization at the interface atwhich the two fluids meet. Figure 5 is an early exam-

ple from the Whitesides laboratory in which a polymer

was deposited at the interface between two fluids to

create a permeable membrane in situ.8 Most micro-

reactors are designed so that the interface of the two flu-

ids contacts the ceiling and floor of the channels, and

when an interfacial polymerization occurs, the polymer

adheres to the walls. This issue can be overcome with

axisymmetric or coaxial systems (discussed later), which

prevent one phase from touching the walls of the device.

The interface between liquids flowing laminarly has

some unique attributes. A fluid jet like the one shown

in Figure 6 creates an extensional flow field in whichlarge macromolecules can be aligned. If two fluids

flowing past each other are moving at different rates, a

shear force develops at the interface that can align

structures. For instance, Maeda et al.11 showed that

DNA can be elongated and aligned at the interface

formed by a fluid jet (Fig. 7).

Depending on the parameters of the system, a liquid

jet can transform from a thin finger of fluid to droplets

(Fig. 8). The process that breaks the stream into droplets

is called a Rayleigh–Plateau instability,12,13 and it arises

when the jet becomes unstable to perturbations longer

than its circumference and breaks up into droplets to min-

imize the surface area. The droplets are typically mono-disperse13 and can be organized downstream into interest-

ing structures. The minimization of the interface is where

Re bows out and turns over responsibility to Ca.

Ca

A surface tension exists at the interface between two

fluids. In a two-phase, flowing system, the balance

between this surface tension and viscous forces within

the fluids dominates the structure of the fluids. Thus,

Ca is defined as follows:

Ca ¼vg

cð2Þ

where v is the mean velocity, g is the dynamic viscos-

ity, and c is the interfacial surface tension. Ismagilov

et al.15 provided one of the nicest examples demon-

strating how variations in Ca impact the geometry that

a fluid adopts in flow. Figure 9 shows an experiment inwhich two channels containing dyed water enter a third

channel containing a fluorinated solvent carrier phase.

In Figure 9(b), Ca is low, meaning that surface ten-

sion dominates the fluid geometry. The aqueous flows

entering the channel from the top and bottom are stiff

because of the surface tension and do not bend under

pressure from the third fluid flowing orthogonally. The

fingers of fluid from top and bottom are so stiff that

they collide with each other before the pressure from

the orthogonal fluid snaps the two fluids as a single

plug. In Figure 9(c), the flow rate has been increased,

and this makes the viscous forces more important.

Now the finger from the bottom flow is no longer stiff enough to resist the pressure from the orthogonal flow

and protrudes from the junction slightly before it snaps

off. Figure 9(d,e) shows cases in which the surface ten-

Figure 12. Microfluidic system for cation-initiated vinyl

ether polymerization. The initiator and monomer mix at M1,

react through microtube reactor R1 submerged in a cooling

bath, and are quenched by the addition of the solvent at

mixer M2. Reprinted with permission from Nagaki, A. et al.,

J. Am. Chem. Soc. 2004, 126, 14702–14703. Copyright

2004, American Chemical Society.

Scheme 1

HIGHLIGHT 6511




sion no longer dominates over viscous forces. We see

that the fingers of fluid are much more flexible and the

fluid thins until smaller droplets snap off far down-

stream. This example shows that with small variations

in the fluid properties and flow rates, one can create a

range of monodisperse emulsions with different sizes.

These emulsions provide an opportunity to create

monodisperse beads or capsules more easily than try-

ing to optimize a batch emulsion polymerization to bemonodisperse.

The full impact of Ca is best viewed from the per-

spective of how the emulsion droplets can be organ-

ized in flow. Quake et al.16 created monodisperse drop-

lets in which water and oil collide using a simple T-

junction shown in Figure 10. By varying the ratio of

the water pressure to the oil pressure and total pres-

sure, they were able to assemble droplets into a wide

array of structures. These structures ranged from single

monodisperse droplets to beautiful patterns of con-

nected droplet strings (Fig. 10). This is a treasure trove

for any polymer scientist trying to create new fibers,

beads, capsules, or particles of novel shapes.Quake et al.’s work has been followed by a wide

range of publications detailing other structures that can

be formed in flow. For example, Nisisako et al.17 formed

monodisperse double emulsions using a tandem T-junc-

tion arrangement (Fig. 11). These two examples are just

the tip of the Ca iceberg. As we discuss instances in

which new materials were produced in microreactors, we

will point out how capillary forces played a role.

SYNTHESIS OF MATERIALS IN FLOW

Now that we have covered some valuable attributes of

microreactors, we will highlight where they have been

applied to create four basic polymeric materials: linear

polymers, beads and other solids, microcapsules, and

finally, fibers.

Linear Polymers

Life without linear polymers would not be as rich,

safe, or hospitable. Despite the infinite value that linear

polymers have provided, polymer chemists continue to

develop means of synthesizing old polymers with

Scheme 2

Figure 13. Microreactor system used in the polymerization

of N e-benzyloxycarbonyl-L-lysine, alanine, leucine, or NCA.

The system consists of a PDMS micromixer and poly(tetra-

fluoroethylene) microtubes. The mixer and reaction region

were kept at 30 8C in a water bath. From T. Honda et al.,

Lab on a Chip 2005, 5, 812–818. Reproduced by permission

of The Royal Society of Chemistry.





greater control over the molecular weight and polydis-

persity index (PDI) as well as discovering and charac-

terizing new linear polymers. Microreactors are emerg-

ing as tools to achieve both better syntheses and the

discovery of new polymers.

Cationic, ring-opening, and free-radical polymeriza-

tions are three types of polymerization mechanisms

that have benefited from the rapid mixing and precise

temperature control found in a microreactor. Yoshida

et al.18 were among the first to show that microreactors

can yield improved polymerizations. They showed that

N -methoxycarbonyl- N -(trimethylsilylmethyl)butyl-

amine decomposes to a cation (2) that is irreversiblyformed and can be collected (Scheme 1). By rapidly

mixing cation 2 with a vinyl ether in an IMM micro-

reactor, they found that the resulting cationic polymeri-

zation provided PDIs superior to those of polymers

prepared in a batch reactor (Fig. 12). The authors dem-

onstrated that rapid mixing controls the PDI by adjust-

ing the flow rates. Mixing in a IMM microreactor

increases with the flow rate, and as Yoshida et al. low-

ered the flow rates, the resulting polymers exhibited

broadened PDIs. Thus, more efficient mixing at a high

flow rate yields the narrowest PDIs.

Iwasaki and Yoshida19 went on to show that micro-

reactors are also useful in radical polymerization,

yielding lower PDIs than those observed in batch reac-

tions. The authors noted that highly exothermic poly-merizations show improved control in the microreactors

relative to the batch because microreactors dissipate

heat much more rapidly.

Not all radical reactions in flow provide significant

improvements in PDI. Jones et al.,20,21 using reversible

addition–fragmentation chain-transfer polymer izati on,

and Cunningham et al.,22 using nitroxide-mediated

radical polymerizations, observed similar or higher PDIs

in tubular reactions than in batch reactors. In both of

these cases, however, mixing was performed before intro-

duction into the microreactor, and the reactions were per-

formed in microemulsions that flowed through the micro-

reactors. Jones et al. suggested that PDI erosion was dueto axial dispersion of the plugs and thus a distribution of

residence times. As the plugs became large, the PDIs

approached the batch values, and this was consistent with

axial dispersion being the problem.

Maeda et al.23 showed that the benefits of micro-

reactors are not limited to cationic and radical poly-

merizations by creating homopolymers of N e-benzyloxy-

carbonyl-L-lysine, alanine, leucine, or glutamic acid

(NCA). Reactions were run in batches and microreac-

tors by combining NCA and triethylamine (Scheme 2).

Instead of an IMM microreactor, a PDMS multilayered

system was used (Fig. 13).24 In all cases, the micro-

reactor provided slightly higher molecular weights andmuch better PDIs. Again, the NCA polymerization was

strongly affected by mixing and potentially by temper-

Figure 15. Schematic of microchannel-confined surface-ini-tiated polymerization (lSIP). The base of the device is a sili-

con wafer coated with a self-assembled monolayer of an ini-

tiator for atom-transfer radical polymerization. A microchan-

nel is formed by the bonding of a molded slab of PDMS to

the substrate. Polymer brushes with a thickness gradient are

formed by the monomer flowing from the inlet, across the

channel, and out the other end. Reprinted with permission

from Xu, C. et al., Macromolecules 2005, 38, 6–8. Copyright

2005, American Chemical Society.

Figure 14. (top) Microfluidic device fabricated with a rapid

prototyping technique based on an optical thiolene resin. The

reagents are introduced on the left, active mixing is induced

with a stir flea, and the reaction proceeds in the wavy chan-

nel. (bottom) Size exclusion chromatograms of polymers syn-

thesized in the microfluidic device at various flow rates.

Increasing the flow rates results in shorter residence times

and lower molecular weight polymers (thin lines). The mo-

lecular weight is further tunable by the reduction of the

amount of the initiator (thick line). Reprinted in part with

permission from Wu, T. et al., J. Am. Chem. Soc. 2004, 126,

9880–9881. Copyright 2004, American Chemical Society.

HIGHLIGHT 6513




ature control, although no experiments directly tested

this hypothesis. The authors noted that their device

could produce *15 g dayÀ1. If the authors numbered

up their system to 1000 microreactors, they could pro-

duce 5 Mg year À1.

Beers et al.25 showed that microreactors are useful

for systematically varying the molecular weight of both

homopolymers and block copolymers. They developed

microfluidic methods to carry out controlled radicalpolymerizations in which variables such as the mono-

mer ratios or monomer/initiator ratio are altered to pro-

duce gradients of molecular weights or monomer ratios

in copolymers. The homopolymer synthesis was

achieved with a two-channel microreactor with the two

channels meeting in a reservoir containing a magnetic

flea stirring bar for active mixing. The mixing chamber

emptied into a much longer microchannel reactor (Fig.

14, top). One inlet channel contained the monomer and

catalyst, and the other contained the initiator. Both

were dissolved in 50:50 water/methanol. The initiator/

monomer ratios were varied by changes in the relative

concentrations, and the polymerization at a fixed initia-tor/monomer ratio was then monitored as a function of

the flow rate. The molecular weight decreased as a

function of the flow rate, which was inversely propor-

tional to the residence time (Fig. 14, bottom). The

PDIs under all conditions were very good, ranging

from 1.19 to 1.32. Using a similar approach, but with

three channels instead of two, Beers et al.26 were able

to create poly(ethylene oxide)-b-poly(2-hydroxypropyl

methacrylate) on-chip with excellent control over the

conversion, PDI, and block ratios.

Beers et al.,27 in addition to their fundamental work

with linear polymer synthesis in flow, made surface-

grafted polymer brushes with thickness gradients. Gra-

dients are produced by the monomer flowing slowly over

a surface activated for atom transfer radical polymeriza-tion (Fig. 15). The surface at the inlet receives much

more monomer than that near the outlet, so the brushes

have a linear gradient of heights moving from the inlet

Figure 17. Patterns of droplet formation observed in the T- junction (left) and pocket (right) when the flow rate of the

continuous phase (Qc; aqueous) was varied at a fixed dis-

persed phase (monomer) flow rate of 0.1 mL hÀ1: (a,b) Qc

¼ 0.5 mL hÀ1, (c,d) Qc ¼ 1.0 mL hÀ1, (e,f) Qc ¼ 2.0 mL

hÀ1, (g,h) Qc ¼ 4.0 mL hÀ1, (i,j) Qc ¼ 18.0 mL hÀ1, and

(k,l) Qc ¼ 22.0 mL hÀ1. Reprinted from Chemical Engineer-

ing Journal, Vol. 101, Nisisako, T., ‘‘Novel Microreactors for

Functional Polymer Beads,’’ 23–29, Copyright 2004 with

permission from Elsevier.

Figure 16. (left) Schematics of the emulsification device

made from etched silicon. A monomer solution is forced

through the microchannels into the well area, which contains

the continuous phase. Monodisperse droplets of the monomer

snap off because of interfacial tension. (right) The droplets

are later thermally polymerized to form crosslinked beads.

Particles of different sizes have been prepared from two devi-

ces with smaller (top) or larger (bottom) microchannels.Reprinted with permission from Sugiura, S. et al., Ind. Eng.

Chem. Res. 2002, 41, 4043–4047. Copyright 2002, American

Chemical Society.





end to the outlet end. Within the microchannel, flow is

laminar, and little diffusive mixing occurs on the time-

scale of the polymerization rate. This is an example in

which a specific polymer morphology is achieved within

a microreactor that would be difficult to form otherwise.

Beads, Disks, and Other Solid Materials

Soon after Quake’s seminal microfluidic emulsion

manuscript15 was published, reports describing the for-

mation of solid, monodisperse microspheres began to

appear. The first work that we have identified was

from Nakajima’s laboratory.28,29 He and his coworkers

created divinylbenzene-containing droplets in a novel

microchannel emulsification device (Fig. 16, left) using

a continuous phase of aqueous poly(vinyl alcohol).The droplets were then thermally polymerized to yield

highly crosslinked beads (Fig. 16, right). Nakajima’s

approach of forming monomer droplets first and poly-

merizing them later ensured that the emulsion appara-

tus did not get clogged by the solid material. Particle

sizes were several to tens of micrometers with diame-

ter coefficients of variation (CVs) of less than 5%. The

approach is noteworthy for its novelty, but the droplet

Figure 18. Microchannel geometry used to create plugs and disks: (a) a schematic of a channel

with plug and disk creation zones marked, (b) an optical micrograph of polymerized plugs in the

200-lm section of the channel (38-lm height), and (c) an optical micrograph of polymerized disks

in the 200-lm section of the channel (16-lm height). Reprinted with permission from Dendukuri,

D. et al., Langmuir 2005, 21, 2113–2116. Copyright 2005, American Chemical Society.

Figure 19. (a) Schematic of the flow-focusing geometry used

in the microfluidic droplet generator. The two immiscible liquids,

A and B, are forced into the narrow orifice, in which the inner

liquid core breaks to release monodisperse droplets in the outlet

channel. (b,c) Schematics of devices used for producing photo-chemically and thermally solidified particles. The channels used

for photochemical crosslinking are elongated to allow longer dura-

tions of exposure of the droplets to UV light. (d–f) Representations

of the shapes of droplets in the microfluidic channels. If the volume

of the droplet exceeds that of the largest sphere that can be accom-

modated in the channel, the droplet is deformed into (e) a disk or

(f) a rod. From S. Xu et al., Angew Chem Int Ed Engl 2005, 44,

724–728;' 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Wein-

heim, reproduced by permission.

HIGHLIGHT 6515




size depends only very weakly on the applied pressure,

determined instead by the interfacial tension and the

size of the channel. Thus, to change the final particle

size, one must adjust the surface tension of the contin-

uous phase, which may be inconvenient or impossible,

or fabricate a new device, which requires lengthy li-

thography and silicon etching.

A few years after Nakajima’s report, Nisisako lead

a series of publications creating polymer beads in

flow. Unlike Nakajima, Nisisako30 used a T-junction

approach to droplet formation. As shown in Figure 17,

two fluids collided at a T-junction, just like Quake’s

experiment, and the resulting droplets were subse-

quently photopolymerized downstream. The monomer

was 1,6-hexanediol diacrylate and was initiated with

Darocur 1173. Nisisako showed that the flow rate

could be used to tune the droplet sizes (30–120 lm)

and thus the final bead size after polymerization. The

method produced beads with diameter CVs less than

2%, although micrometer-sized satellite droplets were

also produced at the T-junction. Nisisako17 also made

a device with sequential T-junctions to make double

emulsions, although these emulsions were not later

used to template solid particles.

Doyle et al.,31 using the same T-junction approach

as Nisisako, created solid disk and plug-shaped par-

ticles. As shown in Figure 18, snap-off at the junc-

tion yielded plugs containing Norland optical adhe-

sive (NOA) 60, a photopolymerizable resin. When

an ultraviolet (UV) beam was shone on the plug in

the narrow channel, a plug structure was captured,

but if the plug was allowed to expand laterally and

then polymerized, a disk was formed. Because of the

small dimensions of the plugs and disks, the photo-

polymerization occurred in less than 1 ls, using only

3 J cmÀ2 of energy.

A few weeks before Doyle et al.’s work,31 the team

of Whitesides and Kumacheva32 reported a flow-focus-

ing method to make a variety of shapes out of photo-

polymerized tripropylene glycol diacrylate (TPGDA),

dimethacrylate oxypropyldimethylsiloxane, divinylben-

zene, ethylene glycol diacrylate, and pentaerythritol tri-

acrylate. Figure 19 shows a schematic of the flow-

focusing device and the various shapes realized with

channels of different geometries. Figure 19(b) also

illustrates the wavy channel used to increase the resi-

dence time while the droplets and other structures are

photopolymerized.

Figure 20. Microscopy images of poly(TPGDA) particles produced with photoinitiated polym-

erization, including (a) microspheres, (b) a crystal of microspheres, (c) rods, (d) disks, and (e)

ellipsoids, and optical microscopy images of (f) agarose disks and (g) bismuth alloy ellipsoids

produced with thermal solidification. From S. Xu et al., Angew Chem Int Ed Engl 2005, 44, 724–

728; ' 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, reproduced by permission.

Figure 21. Optical microscopy images of a lattice of dimethacrylate oxypropyldimethylsiloxane

disks (a) before and (b) after in situ photopolymerization and (c) typical SEM image of the sol-

idified disks. The scale bar is 200 lm. Reprinted with permission from Seo, M. et al., Langmuir

2005, 21, 4773–4775. Copyright 2005, American Chemical Society.





The combination of flow focusing and alteration of

channel dimensions allowed the capture of microspheres,

rods, disks, and ellipsoids (Fig. 20). Channel clogging

was prevented because the continuous phase of aqueous2 wt % sodium dodecyl sulfate (SDS) prevented the

droplets from contacting the walls. The authors men-

tioned that up to 250 particles could be formed per

second and 5–10% shrinkage was observed after poly-

merization. Also, the authors were able to control the

size by changing the flow rate and observed diameter

CVs smaller than 1.5%. In addition to the excellent

range of structures, the team of Whitesides and Kuma-

cheva32 was able to incorporate dyes, quantum dots, and

liquid crystals into the microparticles.

Using essentially the same type of flow-focusing

approach, Kumacheva et al.33 organized discoid drop-

lets of silicone oil or dimethacrylate oxypropyldime-thylsiloxane into two-dimensional lattices [Fig. 21(a)].

The lattices were then polymerized by a photoinitiated

radical polymerization. As shown in Figure 21(b), the

polymerized disks shrink by 7%. The shrinkage is im-

portant because if the discs increased in size, the chan-

nels would clog. Figure 21(c) shows a scanning elec-

tron microscopy (SEM) image of the monodisperse

discs after polymerization.

Kumacheva et al.34 followed up this work by creat-

ing a microfluidic device that flow-focused three fluids

to create droplet-in-droplet structures. In this system,

three immiscible liquids are used: aqueous SDS (liquid

C), monomers (liquid B), and silicon oil (liquid A;

Fig. 22). After the photopolymerization of the two

Figure 22. (a) Schematic of the production of droplets in a

microfluidic flow-focusing device by a laminar coflow of (A)

silicone oil, (B) monomer, and (C) aqueous phases. The ori-

fice has a rectangular shape with a width and height of 60

and 200 lm, respectively. (b) Schematic of the wavy channel

used for the photopolymerization of the monomer in the

core–shell droplets. (c) Optical microscopy image of core–

shell droplets flowing in the wavy channel used for in situ

photopolymerization. The scale bar is 200 lm. (d) Photo-

graph of a polyurethane microfluidic system. Reprinted with

permission from Nie, Z. H. et al., J. Am. Chem. Soc. 2005,

127, 8058–8063. Copyright 2005, American Chemical Soci-

ety. [Color figure can be viewed in the online issue, which is

available at www.interscience.wiley.com.]

Figure 23. Ternary phase-like diagram of the hydrody-

namic conditions used in the production of droplets with var-

ious morphologies. The axes of the diagram correspond tothe flow rates of the water (Qw), monomer (Qm), and oil

phases (Qo), normalized to the total flow rate. The letters cor-

respond to droplet shapes subsequently polymerized to the

microparticles shown in Figure 24. Reprinted with permission

from Nie, Z. H. et al., J. Am. Chem. Soc. 2005, 127, 8058–

8063. Copyright 2005, American Chemical Society.

Figure 24. (a–e) SEM images of polymer microparticles

obtained by the polymerization of TPGDA in droplets

obtained in regimes A–D in Figure 23 after the removal of

the silicone oil cores and (f) cross section of a polyTPGDA

particle with three cores obtained by the polymerization

of core–shell droplets with three cores. All scale bars are

40 lm. Reprinted with permission from Nie, Z. H. et al., J.

Am. Chem. Soc. 2005, 127, 8058–8063. Copyright 2005,

American Chemical Society.

HIGHLIGHT 6517




monomers, TPGDA or ethylene glycol dimethacrylate,

the droplet-in-droplet structures were captured, yieldingnovel bead structures.

Subtle changes in the ratios of the three solution

flow rates allowed Kumacheva et al.34 to precisely

control the fascinating structures produced in their

device. They mapped out a ternary phase-like dia-

gram in which the axes reflected the effect of the

flow rates of the aqueous, monomer, and oil phases

on the structure of the formed particle (Fig. 23).

The letters in the pseudo-phase diagram correspond

to the letters in Figure 24, which shows SEMimages of the various microcapsule morphologies.

Also, in a separate report, Kumacheva et al.35 dem-

onstrated the creation of TPGDA-co-acrylic acid

copolymer beads.

Seong et al.,36 using a flow-focusing device (Fig.

25), created hydrogel beads impregnated with glucose

oxidase and horseradish peroxidase. They formed the

beads by flow-focusing a solution of the enzymes to-

Figure 25. Schematic illustration of the process for fabricating the apparatus used to manufac-

ture microparticles: (A) fixing the acryl anchor, bonding the glass pipette onto the anchor, pour-

ing the PDMS prepolymer, and curing on the hot plate; (B) taking out the cured PDMS and cut-

ting; (C) pulling out the micropipette; (D) puncturing the hole for sheath flow; (E) exposing to

oxygen plasma and bonding the pulled micropipette; and (F) inserting and bonding the outlet

pipette and shielding. An expanded illustration of the microfluidic nozzle and reagents used to

fabricate the microparticles is shown on the bottom. Reprinted in part with permission from

Jeong, W. J. et al., Langmuir 2005, 21, 3738–3741. Copyright 2005, American Chemical Soci-

ety. [Color figure can be viewed in the online issue, which is available at www.interscience.

wiley.com.]





gether with 85 wt % 4-hydroxybutyl acrylate, 11 wt %

acrylic acid, 3 wt % 2,2-dimethyoxy-2-phenyl-aceto-

phenone (the initiator), and 1 wt % ethylene glycol di-

methyl acrylate. The monomer/initiator/enzyme drop-

lets were then polymerized via a photoinitiated radical

polymerization (Fig. 26). The device produced mono-

disperse beads at rates up to 2600 per minute with a

1 lL minÀ1 disperse phase flow rate. The enzyme–

hydrogel beads were then packed into a nozzle and

reagents, which yielded a fluorescent product after the

sequential action of the two enzymes, were passed

through the packed beads. A fluorescent product was

observed, indicating that both encapsulated enzymeswere active, although the activity of the enzymes was

not quantified. To the best of our knowledge, this

report represents the first instance of active enzyme-

encapsulated beads formed in flow.

Using a flow-focusing device, De Smedt et al.37 syn-

thesized biodegradable microgels by forming dextran

hydroxyethyl methacrylate/Irgacure 2959 droplets and

initiating subsequent polymerization by passing the drop-

lets over a UV beam. Monodisperse beads were formed

with a diameter of *10 6 0.3 lm. Also, the authors

explored the use of enzyme-containing beads in con-trolled-release experiments.

In two separate reports,30,38 Nisisako and coworkers

pushed complex bead creation forward by creating

biphasic, Janus-faced droplets and solid beads. Figure

27 illustrates the formation of Janus droplets by two

solutions flowing laminarly into a flow-focusing de-

vice.30 The bicolored droplets contain either carbon

black or titanium dioxide to provide black and white

hemispheres, respectively. The droplets contain a pho-

toinitiator and 1,6-hexanediol diacrylate or isobornyl

acrylate to effect polymerization. After photocuring the

droplets into beads, Nisisako et al.38 then used these

Janus beads as the active elements in electroactive,switchable surfaces. The switching is due to the differ-

ent charging properties exhibited by carbon black and

titanium dioxide. Figure 28 shows beads on top of a

display panel. Depending on the bias of the surface,

the Janus-faced particles display their white or black

sides. Figure 28(a) portrays the display panel with a

given bias and also 0.5 s after the bias was reversed,

whereas Figure 28(b) is a blowup of the black and

Figure 26. SEM micrograph of microparticles polymerized

from droplets formed at a monomer flow rate of 1 lL minÀ1

and a continuous phase flow rate of 225 lL minÀ1. These

particles have diameters of 90 lm with CVs less than 2%.

Reprinted in part with permission from Jeong, W. J. et al.,

Langmuir 2005, 21, 3738–3741. Copyright 2005, American

Chemical Society.

Figure 27. Formation of a bicolored droplet at the sheath

flow junction. To capture clear images of the color edge,

white pigments were not used in this case. Reprinted from

Chemical Engineering Journal, Vol. 101, Nisisako, T.,

‘‘Novel Microreactors for Functional Polymer Beads,’’ 23–

29. Copyright 2004 with permission from Elsevier.

Figure 28. Electrical actuation of biphasic, electrically ani-

sotropic spheres: (a) color switching test using prepared par-

ticles [a voltage of 100 V was applied between the 0.4-mm

gap of two electrode panels (40 mm Â 40 mm) at a switch-

ing frequency of 1 Hz] and (b) magnified top view of the dis-

play panel in part a. From T. Nisisako et al., Adv. Mater.

2006, 18, 1152–1156; ' 2006 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim, reproduced by permission. [Color fig-

ure can be viewed in the online issue, which is available at

www.interscience.wiley. com.]

HIGHLIGHT 6519




white portions of the panel. The size control and low

dispersity of these beads could make this type of chro-

mic display sharper than displays made with other

methods. The authors also demonstrated a new device

design for making large quantities (tons per year) of

these beads.

Very recently, Doyle et al.39

introduced a revolu-tionary technique for fabricating irregularly shaped

microparticles in a flow device. The authors employed

microscope projection photolithography to photopoly-

merize oligomeric diacrylate monomers flowing in a

PDMS microfluidic device (Fig. 29). Because the po-

lymerization is faster than 100 ms, the particles do not

move appreciably during the patterning, minimizing

the distortion of the shapes. Doyle et al. were able to

create a variety of shapes, including triangles, cuboids,

cylinders, and various irregular forms, with a spatial

resolution of around 3 lm (Fig. 30). The key to the

technique lies in an oxygen-rich zone near the PDMS

walls, formed as O2 diffuses from the elastomer into

the monomer stream. The oxygen in this zone, roughly

2.5 lm thick, inhibits polymerization and ensures thatno polymer forms in contact with the channel. In addi-

tion to novel microparticle shapes, the authors created

chemically biphasic particles by using coflowing lami-

nar streams of monomer, one of which contained a

rhodamine-labeled crosslinker, and forming particles

across this interface. The method presented by Doyle

et al. promises to yield many exciting applications in

the future.

Figure 29. (a) Schematic depicting the experimental setup used in the study. A mask contain-

ing 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 advected

within the unpolymerized monomer stream. The side view of the polymerized particles can be

seen in the inset shown on the right. Also shown is the unpolymerized oxygen inhibition layer that allows the particles to flow easily after being formed. (b) Bright-field microscopy image

( x – y plane) of an array of cuboids moving through the unpolymerized monomer. (c) Cross-sec-

tional view of the cuboids seen in part b upon collection in a droplet that has turned most par-

ticles on their sides. Reprinted with permission from Macmillan Publishers, Ltd: Nature Materi-

als, 5, 365–369, 2006.





Capsules

The transition from creating solid beads to hollow cap-

sules requires changing from a polymerization withinthe droplet to either the polymerization of double

emulsions or an interfacial polymerization. This change

sounds relatively simple, but most devices would rap-

idly clog if an interfacial polymerization were per-

formed within them. Two almost simultaneous reports

from the Weitz and Whitesides groups describe the

use of radially symmetric flow-focusing devices to

create microcapsules in flow. These devices create

droplets that are protected from the device walls by a

coaxial sheath of fluid, unlike device schemes such as

T-junctions or planar flow-focusing devices.

Weitz’s device40 (Fig. 31) consists of nested glass

capillaries, allowing two coaxial fluids to collide, anda third, outer fluid provides the flow focusing. All three

are then forced into a small orifice leading to an exit

tube. This device creates double emulsions with a great

deal of control over the size and number of internal

droplets. To create capsules, the Weitz group uses a

70:30 mixture of NOA and acetone as the outer layer

of the double emulsion (i.e., the middle layer of the

originally focused phases). The double emulsion passes

through a UV beam, forming a shell of crosslinked

NOA [Fig. 32(B,C)]. The authors noted that droplet pro-

duction is up to an astounding 5000 per second. Weitz

et al.41 also formed polymerosomes by using water-in-oil-in-water emulsions with a diblock copolymer,

poly(n-butyl acrylate)-b-poly(acrylic acid), dissolved in

the middle organic phase. Upon drying, a flexible, per-

meable polymer shell remains [Fig. 32(D–F)].

The Whitesides device42 also accomplishes droplet

formation by focusing a coaxial flow through a small

orifice (Fig. 33). The Whitesides design uses an insu-

lated optical fiber cut with a scalpel as a template (Fig.

34). The fiber is exposed by the insulation being pulled

back slightly, and a large segment of the fiber, in-

cluding the exposed fiber section, is encased in PDMS.

Once the PDMS is fully cured, all the fiber compo-

nents are removed from the PDMS. Tubes are placedin the voids left by the insulated portions. The small

orifice in the center of the device shown in Figure 33

was formed by the exposed portion of the optical fiber.

The Whitesides group created nylon-6,6 capsules by

using aqueous 1,6-diaminohexane as the disperse phase

and introducing adipoyl chloride through a third inlet,

as shown in Scheme 3). Presumably, they started the

interfacial polymerization downstream of where the

Figure 30. SEM images of particles produced using microscope projection photolithography.

The scale bar in all cases is 10 lm. (a–c) Flat, polygonal structures that were formed in a 20-

lm-high channel, (d) colloidal cuboid that was formed in a 9.6-lm-high channel, (e,f) high-as-

pect-ratio structures with different cross sections that were formed in a 38-lm-high channel, and

(g–i) curved particles that were all formed in a 20-lm-high channel. The inset in each panel

shows the transparency mask feature that was used to make the corresponding particles.

Reprinted with permission from Macmillan Publishers, Ltd: Nature Materials, 5, 365–369, 2006.

HIGHLIGHT 6521




droplets form, rather than including the acid chloride

directly in the continuous phase, to prevent clogging at

the narrow orifice. The axisymmetric device yieldedcapsules with monodisperse diameter CVs and allowed

the formation of capsules with interesting features such

as encapsulated magnetic particles (Fig. 35).

At the same time that the Weitz and Whitesides

publications appeared, Ganan-Calvo et al.43 introduced

a flow-focusing device that his group calls an atomizer.

The device, as shown in Figure 36, relies on an outer

fluid to focus one or two coaxial phases as the three

fluids leave the device. In some cases, the focusing

fluid was actually air. With the compound atomizer,

poly(D,L-lactic acid-co-glycolic acid) (PLGA) micro-

capsules containing encapsulated gentamycin, an anti-

biotic, were formed. The process started with PLGAdissolved in an organic solvent (outside layer of the

coaxial fluids) and gentamycin in an aqueous solution

(core of the coaxial flow). After breakup, the organic

solvent evaporated, leaving a PLGA shell surrounding

the gentamycin solution. Besides evaporative coacerva-

tions, Ganan-Calvo used three immiscible fluids to cre-

ate multicored capsules out of the photopolymer SK9

(Fig. 37). The same authors recently published a report

using the same device to create monodisperse polysty-

rene microcapsules and dye-labeled microcapsules,

although both of these results were mentioned in theoriginal report.44

A few months after the reports by Weitz, White-

sides, and Ganan-Calvo, we introduced a very simple

microfluidic device45 consisting of laboratory tubing

and small-gauge needles that form T-junctions in the

middle of the tube channel. As shown in Figure 38, a

continuous phase is pumped through 1/16-in. poly(vi-

nyl chloride) (PVC) tubing, and a 154-lm-i.d. needle

introduces a disperse phase to the continuous flow.

Polyamide capsules are formed by the inclusion of poly

(ethylene imine) in the continuous phase and by the

addition of sebacoyl chloride and 1,3,5-benzene tricar-

boxylic acid chloride in a chloroform/cyclohexane dis-perse phase. The interfacial polymerization begins im-

mediately as the two phases meet, yielding capsules

with diameter CVs ranging from 3.3 to 8.6%. As in the

flow-focusing cases, the capsule sizes can be easily var-

ied from 865 to 313 lm by the alteration of the flow

rate (Fig. 39).

The McQuade system is very easy to set up and op-

erate, providing the opportunity to create many differ-

Figure 31. Microcapillary geometry for generating double emulsions from coaxial jets. Part A

is a schematic of the microcapillary fluidic device. The geometry requires the outer fluid to beimmiscible with the middle fluid and the middle fluid to be in turn immiscible with the inner

fluid. The typical inner dimension of the square tube is 1 mm; this matches the outer diameter of

the untapered regions of the collection tube and the injection tube. Typical inner diameters of

the tapered end of the injection tube and the orifice of the collection tube are 10–50 and 50–500

lm, respectively. The thickness of the coating fluid on each drop can vary from extremely thin

(<3 lm), as in part B, to significantly thicker. Parts F and G show double emulsions containing

many internal drops with different size and number distributions. Part H shows double emulsion

drops, each containing a single internal droplet, flowing in the collection tube. From Utada, A.

S. et al., SCIENCE 308: 537–541 (2005). Reprinted with permission from AAAS.





ent materials in flow. As an example to underscore thisfact, the McQuade group46 created hierarchical capsules

composed of oligomeric and crystalline diphenylsilane-

diol. We formed these spiny capsules by using a con-

tinuous phase of 70% aqueous glycerol and snapping

off monodisperse droplets of dichlorodiphenylsilane.

The chlorosilane quickly hydrolyzed to diphenylsilane-

diol, which then oligomerized and crystallized. The

oligomers formed the amorphous shell, and the crystals

were the spines (Fig. 40).

Fibers

All the previous examples of preparing solid materialsin flow used the droplet pseudophase to template the

final materials. Yet, as discussed previously, coflowing

laminar streams are also attainable within a microflui-

dic device, and a number of groups have created mate-

rials shaped by these extended boundaries to form

elongated membranes and fibers. The first synthesis of

such a structure in flow was provided by the White-

sides laboratory.8 The filament formation is shown in

Figure 41, in which a solution of polystyrene sulfonateand hexadimethrine bromide are collided under laminar

flow conditions. The two oppositely charged polymers

precipitate at the interface to yield a fiber. Because the

Figure 32. Core–shell structures fabricated from double emulsions generated in the microca-pillary device. (A) Optical photomicrograph of the water-in-oil-in-water double emulsion pre-

cursor to solid spheres. The oil consists of 70% NOA and 30% acetone. (B) Optical photomi-

crograph of rigid shells made by the crosslinking of the NOA by exposure to UV light. (C)

SEM image of the shells shown in part B after they have been mechanically crushed. The

scale bar in part C also applies to parts A and B. (D) Bright-field photomicrograph of the

water-in-oil-in-water double emulsion precursor to a polymer vesicle. The oil phase consists

of a mixture of toluene and tetrahydrofuran (70/30 v/v) with dissolved diblock copolymer

(poly(butyl acrylate)-b-poly(acrylic acid)) at 2% (w/v). (E) Phase-contrast image of the diblock

copolymer vesicle after evaporation of the organic solvents. (F) Phase-contrast image of the

deflated vesicle after osmotic stress is applied through the addition of 0.1 M sucrose to the

outer fluid. The scale bar in part F also applies to parts D and E. From Utada, A. S. et al.,

SCIENCE 308: 537–541 (2005). Reprinted with permission from AAAS.

Figure 33. Three-dimensional, axisymmetric flow-focusing

channel. The channel is composed of a cylindrical tube with

a narrow cross section halfway down its length. The narrow

region serves as the orifice in which fluid is focused and

breaks into aqueous droplets. In this geometry, wetting prob-

lems are avoided because the aqueous phase does not make

contact with the walls. From S. Takeuchi et al., Adv Mater

2005, 17, 1067–1072; ' 2005 Wiley-VCH Verlag GmbH &

Co. KGaA, Weinheim, reproduced by permission.

HIGHLIGHT 6523




ribbon is trapped within the device, no further charac-

terization or discussion is provided.

Beebe et al.47 recognized the value of depositing a

film within a microfluidic device and reported the for-

mation of a nylon membrane by colliding two fluids at

a cross-junction. The authors designed their cross-junc-

tion so that the aqueous phase entering from the northwould run along a path to the west by coating thenorth inlet and west outlet with a hydrophilic surface(Fig. 42). Conversely, the south inlet and east outlet

were coated with a hydrophobic surface to direct anorganic phase. By putting 1,6-diaminohexane into theaqueous phase and adipoyl chloride into the organicphase, they deposited a nylon membrane at the inter-face at which the two fluids met on their respectivewetting pathways. The membrane was determined tohave a pore size smaller than 200 nm. This exampleand the Whitesides example are interesting and provideuseful membranes, but they suffer from the limitation

that the polymeric material formed in the channels isstuck there permanently.

Beebe, with Lee and others,48 continued to createmicrofibers and hollow tubes in flow by using acoaxial microfluidic device. A coaxial setup ensuresthat no part of the fiber touches the device wall; other-

wise, the polymerized material adheres to the walls,causing the device to clog. They achieved efficient

fiber formation by using the same flow-focusing device

that Beebe developed with Seong and Lee to make

enzyme-impregnated microgels. Figure 43(a) illustrates

the device in which a sample fluid flows through a

capillary surrounded by a sheath fluid. This approach

provides a thin sample stream whose diameter can be

varied by changes in the sheath flow rate. By filling

the sample stream with a photopolymerizable cocktail

[4-hydroxybutyl acrylate (85%), acrylic acid (11%),

ethylene glycol diacrylate (1%), and 2,20-dimethyoxy-

2-phenyl-acetonephenone (3%)], they could cure the

thin stream by a UV beam downstream [Fig. 43(a)]. Inthe same publication, the authors created hollow

microtubes by increasing the complexity of their sys-

tem. They introduced a second core phase, as shown in

Figure 43(b). Using an inert inner core solution and

the same photocurable outer core solution, they created

hollow fibers. In addition to characterizing the fibers

and tubes, the authors impregnated the tubes with

enzymes, created biphasic fibers, and wove the fibers

into a responsive swatch.

CONCLUSIONS

The use of microreactors and microfluidic devices for

the production of polymers with controlled properties

and morphologies appears to have a bright future. The

small dimensions of these microdevices provide benefits

Figure 34. (a) Schematic depicting the fabrication process

of the flow-focusing device. The insulation surrounding an

optical fiber was cut with a scalpel, and the ends were pulled

to expose the fiber. The fiber was embedded in a block of

PDMS. After the PDMS had cured, the fiber was removed by

being pulled through the end of the PDMS block. Two glass

capillaries were inserted as an inlet and outlet. (b) Image of

the final device. From S. Takeuchi et al., Adv Mater 2005,

17, 1067–1072; ' 2005 Wiley-VCH Verlag GmbH & Co.

KGaA, Weinheim, reproduced by permission.

Scheme 3. From S. Takeuchi et al., Adv Mater 2005, 17,

1067–1072; ' 2005 Wiley-VCH Verlag GmbH & Co.






Figure 35. (a) Collection of nylon-6,6-coated aqueous droplets, (b) coated droplet containing 50-nm-di-

ameter magnetic particles in an applied magnetic field (the particles are aligned with respect to the magnetic

field), and (c,d) distributions of the diameter of the droplets before and after polymerization, respectively.

From S. Takeuchi et al., Adv Mater 2005, 17, 1067–1072; ' 2005 Wiley-VCH Verlag GmbH & Co.


Figure 36. Flow-focusing atomizer: (a) a simple jet with (1) a focusing fluid, (2) a focused

fluid, and (3) a meniscus and (b) a compound atomizer with two concentric needles with (1) a

focusing fluid, (2) focused fluids (core fluid and shell fluid), and (3) a compound meniscus. From

L. Martin-Banderas et al., Small 2005, 1, 688–692. ' 2005 Wiley-VCH Verlag GmbH & Co.


HIGHLIGHT 6525




in thermal and mass transport as well as unique control

over the fluid structure. Enhanced transport characteris-

tics allow more precise synthesis of soluble polymers

that can also be produced in traditional batch reactors.

Perhaps more importantly, the interesting and unique

fluid morphologies available within microfluidic devices

open the door to particle shapes not accessible through

other means. Solid, hollow, and multicored, asymmetric,

and irregularly shaped polymer microparticles as well as

membranes and fibers can all be produced with micro-

fluidic devices. These particles are generally monodis-

perse, and the sizes may be tuned from a few micro-

meters to hundreds of micrometers, depending on the

specific device geometry and flow parameters. Novel

microparticles may have applications as functional col-

loids, in photonics, and in the encapsulation of materials

for catalysis and controlled delivery. The process of

rapid prototyping and the emergence of simple, home-

made devices that take only minutes or hours to con-

struct have enabled many groups to explore this exciting

field. Indeed, the field is currently limited only by the

imagination of those seeking to push the bounds of poly-

mer chemistry and particle synthesis.

BRIEF OVERVIEW OF MICROREACTORFABRICATION

To a polymer chemist accustomed to the world of

stirred reaction vessels, the vast array of microfluidic

device geometries and materials may seem daunting.

To help would-be microreactor users, we are providing

a brief overview of device fabrication. From hard litho-

graphic techniques to soft lithography and in-house-

built devices, a concise description is given, and readers

may follow the appropriate citations for more details.

The foundations of microfluidic fabrication techni-ques lie in the well-established field of semiconductor

microelectronics. For instance, the microfabrication

tools of lithography, resist layers, and wet and dry

etching have been instrumental in the fabrication of

many microfluidic systems. These methods have been

used to create microfluidic systems in both direct and

indirect ways. In the direct method, the microfabricated

component is used directly as a channel in a device.

Figure 37. (left) In-flight photograph of the breakup of a

coaxial jet of blue ink surrounded by a photopolymer (SK9)

and (right) optical microscopy image of the multicored

microcapsules produced after UV curing. From L. Martin-

Banderas et al., Small 2005, 1, 688–692. ' 2005 Wiley-

VCH Verlag GmbH & Co. KGaA, Weinheim, reproduced bypermission. [Color figure can be viewed in the online issue,

which is available at www. interscience.wiley.com.]

Figure 38. Schematic of the simplified microfluidic device.

The continuous phase flows through PVC tubing, and a dis-

perse phase is introduced through small-gauge needles. Both

phases are driven by syringe pumps. Reprinted with permis-

sion from Quevedo, E. et al., J. Am. Chem. Soc. 2005, 127,

10498–10499. Copyright 2005, American Chemical Society.

[Color figure can be viewed in the online issue, which is

available at www.interscience.wiley.com.]

Figure 39. Light microscopy images of polyamide capsules

formed with a constant organic flow rate and an increasing

aqueous flow rate: (A) 2.00, (B) 11.0, (C) 13, and (D) 25 mL

minÀ1. Reprinted with permission from Quevedo, E. et al., J.

Am. Chem. Soc. 2005, 127, 10498–10499. Copyright 2005,






Direct methods have the disadvantage that each com-

pleted fabrication yields only one device. However, if

the fabrication is fast, this can allow for rapid prototyp-

ing of many designs. On the other hand, indirect meth-

ods use the microfabricated component as a master to

transfer the design to a secondary material in a replica-

tion step. This molded material is then used in the final

device. Indirect methods have the advantage of needing

only one master to create many (up to hundreds) of

final devices.

Master Production

Most device fabrication strategies begin with a lithog-

raphy step. Lithography is the process of using a mask

that contains a desired pattern to expose specified areasof a photosensitive material to X-ray or UV radia-

tion.49 The mask pattern is thereby transferred to the

underlying material (Fig. 44). Usually, the photosensi-

tive material is a polymeric resist layer coated as a thin

film on a substrate. After exposure, the resist is then

developed, and a washing step removes either the

exposed portion (positive tone) or the unexposed por-

tion (negative tone). At this point, various etching

techniques may be employed to remove substrate mate-

rial that is no longer shielded by the resist, reproducing

the original mask pattern (or its negative) in the sub-

strate.

The most common substrate for microfluidic master

production is elemental silicon. Silicon may be

removed by two general methods, wet or dry etching.

Wet etching,50 by far the more widely used and less ex-

pensive, is further divided into isotropic or anisotropic

methods. In isotropic etching, aqueous strong acids such

as HF and HNO3 remove material without preference to

any crystallographic direction. Thus, rounded channels

are produced, and mask undercutting may be a concern

(Fig. 45, left). On the other hand, alkaline anisotropic

etching conditions lead to the removal of certain crystal-

lographic planes over others, etching at an angle of

54.78 from the (100) direction in silicon. In this case,

trapezoidal features are formed, and they limit the depth

Figure 40. SEM images of organosilane microcapsules produced in a microfluidic device: (A)

a population of typical, spheroidal microcapsules; (B) a higher magnification image of the spiny

surface, and (C) a microcapsule fragment showing the inner, amorphous shell and the outer,

spiny layer. Reprinted with permission from Steinbacher, J. L. et al., J. Am. Chem. Soc. 2006 in

press. Copyright 2006, American Chemical Society.

Figure 41. Schematic and optical micrograph of a poly-

meric structure deposited on glass at the laminar flow inter-

face of 0.005% aqueous solutions of poly (sodium 4-styrene-

sulfonate) and hexadimethrine bromide. Reprinted with

permission from Kenis, P. J. A. et al., SCIENCE 1999,

285, 83–85. Copyright 1999, AAAS.

Figure 42. Fabrication of a semipermeable polyamide

membrane: (a) a schematic illustration of the surface-pat-

terned channel and (b) a schematic illustration of the polymer

membrane fabricated inside the channel by interfacial poly-

merization. Reprinted in part with permission from Zhao, B.

et al., J. Am. Chem. Soc. 2002, 124, 5284–5285. Copyright,

2002 American Chemical Society. [Color figure can be viewed

in the online issue, which is available at www.interscience.

wiley.com.]

HIGHLIGHT 6527




and aspect ratio of features that may be fabricated

(Fig. 45, middle). Conversely, dry etching techniques51

employ low-temperature plasmas to chemically and

physically etch materials. Reactive-ion etching (RIE)

employs reactive gasses, such as SF6, which form mo-

lecular ions and radicals in the plasma, which then react

with substrate silicon to form volatile species. Alterna-tively, ion-beam etching (IBE) uses inert gasses, result-

ing in physical etching. When proper inhibitors are used,

dry etching processes result in large aspect ratios with

vertical features (Fig. 45, right).

For certain applications, the disadvantages of sili-

con, namely its brittleness and potentially poor release

properties,52 may preclude its use as a master. Thus, a

patterned silicon substrate may be electroplated with a

metal, often nickel or a nickel alloy.53 After the sub-

strate is removed, the metal electroform may be used

as a master in later replication steps instead of the sili-

con master. A prominent method that avoids the use of

silicon altogether is the so-called LIGA [lithographie (li-

thography) galvanoformung (electroplating) abformung

(molding)] process.54 In the LIGA process, a polymericsubstrate, usually poly(methyl methacrylate) (PMMA),

is ablated with either X-rays or UV lasers through a

patterned mask (Fig. 46). High aspect ratios and very

low surface roughness are achieved. After patterning,

the resulting structures are electroplated with a metal,

the polymeric substrate is removed, and the metalized

master is used in subsequent replication steps.

A simpler method of producing masters is rapid

prototyping, introduced by Whitesides et al.55 in the

mid-1990s. With high-resolution laser printers, patterns

Figure 43. (a) Schematic of the basic apparatus for fabri-

cating microfibers. (b) By the addition of an additional stage,

the apparatus is capable of producing microtubes. From T.

Honda et al., Lab on a Chip 2005, 5, 812–818. Reproduced

by permission of The Royal Society of Chemistry.

Figure 44. Schematic of the lithography process. A mask

containing the desired pattern is placed between a UV or X-

ray beam and a photosensitive resist layer spun on top of the

substrate. After exposure, the resist is developed, and a wash-

ing step removes either the exposed portion (positive tone,

right) or the unexposed portion (negative tone, left). An etch-

ing step removes substrate material no longer shielded by the

resist, which is removed, reproducing the original mask pattern

(or its negative) in the substrate.





are printed directly on transparencies with black ink

and used as photolithographic masks with resolutions

of roughly 20 lm. Although this resolution is not as

fine as those of traditional lithographic masks, which

are less than 1 lm, the cost is roughly $1 per squareinch versus roughly $1500 per square inch for chro-

mium-on-glass masks. In addition to the obvious cost

advantage, patterns can be designed and printed in

house rather than contracting custom fabricators, who

may require weeks to months. Once the mask has been

printed, a master is made via lithography of negative

tone resists such as Microposit 1813 or SU-8, which

are durable polymer resists. These rapidly prototyped,

polymeric masters are then used as masters in further

replication techniques.

Indirect Fabrication

Once a suitable master has been produced, the replica-

tion of the pattern into the device material is achieved

by one of several methods. Similarly to its ubiquitoususe for creating macroscopic objects, injection molding

has been used to create microchannels. Injection mold-

ing is the process of forcing a polymer above its melt-

ing temperature (T m) into a mold under high pressure

and then cooling it below the T m and releasing the

mold. McCormick et al.56 used a silicon master to cre-

ate nickel electroforms that templated channels into

injection-molded acrylic, whereas Arnold et al.57 used

laser-ablated masters to create injection-molded

PMMA channels and gratings. More commonly, im-

printing methods are used in which structures on a

master are pushed under pressure into a polymer

substrate, transferring the pattern to the polymer

(Fig. 47).58 Xu et al.59 performed the room-temperature

imprinting of PMMA, copolyester, polycarbonate, and

polystyrene using silicon masters, creating channels

Figure 45. Schematic of etching processes. Isotropic etching, using acidic media, produces

rounded channels and possibly undercut masks. Alkaline anisotropic etching yields straight but

trapezoidal channels. Dry etching techniques, such as RIE and IBE, produce vertical walls with

high aspect ratios. [Color figure can be viewed in the online issue, which is available at www.

interscience.wiley.com.]

Figure 46. UV laser micromachining process. A UV exci-

mer laser pulse rapidly breaks chemical bonds within a re-

stricted volume to cause a miniexplosion and ejection of

ablated material. Reprinted with permission from Roberts, M.

A. et al., Anal. Chem. 1997, 69, 2035–2042. Copyright 1997,


Figure 47. Schematic of the embossing process. A silicon

or metal template is pushed under pressure into a slab of a

polymer. The pattern on the template is transferred to the

polymer, which constitutes the final channel material after

sealing to an appropriate base. [Color figure can be viewed

in the online issue, which is available at www.interscience.

wiley.com.]

HIGHLIGHT 6529




90 lm wide and 30–40 lm deep (Fig. 48). Imprinting

may also be performed above the glass-transition tem-perature of the polymer, in which case it is called hot

embossing. Ueno et al.60 created 100-lm-wide chan-

nels in polystyrene by imprinting with a silicon master

at 108 8C, whereas Chou et al.61 created 60-nm-wide

channels using PMMA hot-embossed at 200 8C.

An indirect duplication method that has gained wide-

spread use in the academic world is soft lithography,62 a

collective set of methods that uses patterned elastomers

as masks, stamps, or molds. Soft lithography is often

paired with masters fabricated with rapid prototyping, as

described previously. To create microfluidic devices, a

liquid prepolymer mixture, often PDMS, is poured onto

a patterned master and then cured at a mildly elevatedtemperature (Fig. 49).63 The solid elastomeric stamp is

then peeled off the master, and the channels are sealed

by the bonding of the stamp to a wide variety of materi-

als, including silicon, silica, silicon nitride, glass, poly-

styrene, and polyethylene.53 PDMS is an ideal material

for many microfluidic applications because of its optical

transparency down to 300 nm, the opportunities for sur-

face functionalization, and its compatibility with biologi-

cal samples, although it swells in many organic sol-

vents.64

Direct Fabrication

Direct fabrication methods do not rely on master pat-

terns created in prior steps; instead, the patterned mate-rial is used directly in the final device. Microfluidic

devices may be fabricated directly from the photosensi-

tive glass FOTURAN65 or polymer materials66 patterned

via lithography steps similar to those described previ-

ously for mask preparation. The polymer resist SU-8 is

an especially versatile material for microelectromechani-

cal systems67,68 and microfluidic channels,69 supporting

aspect ratios as high as 10:1 and displaying exceptional

Figure 48. (A) SEM image and (B) profilometer cross sec-

tion of an embossed PMMA device. Reprinted with permission

from Xu, J. D. et al., Anal. Chem. 2000, 72, 1930–1933. Copy-

right 2000, American Chemical Society.

Figure 49. Scheme describing replica molding of microflui-dic devices in the soft lithography methodology: (A) a master

is fabricated by rapid prototyping; (B) posts are placed on

the master to define reservoirs; (C) the prepolymer is cast on

the master and cured; (D) the PDMS replica is removed from

the master; and (E) exposing the replica and an appropriate

material to an air plasma and placing the two surfaces in

conformal contact make a tight, irreversible seal. Reprinted

with permission from Duffy, D. C. et al., Anal. Chem. 1998,

70, 4974–4984. Copyright 1998, American Chemical Society.





mechanical durability (Fig. 50). Moreover, LIGA, dis-

cussed previously, may be employed to directly fabri-

cate microfluidic devices. For instance, Roberts et al.70

used an excimer laser operating at 193 nm to ablate

channels into a variety of polymers, including polysty-

rene, polycarbonate, cellulose acetate, and poly(ethylene

terephthalate). Pethig et al.71 used an excimer laser operating at 248 nm in a multistep process to create a

prototype cell-handling device. Even higher energy li-

thography has employed X-ray72,73 and synchrotron74

radiation to directly pattern microfluidic channels into

PMMA. Although the resolution and aspect ratio are

excellent, access to suitable equipment has limited the

use of such procedures in the academic community.

Microfluidic devices may also be fabricated directly

by milling techniques, which obviate the need for li-

thography altogether. Vasile et al.75 used focused ion

beams to create smooth, deep channels in PMMA. In

the same publication, they employed ion beams to cre-

ate steel micromilling tools that were then used to millchannels in PMMA with a mechanical, high-precision

milling machine.76 Other researchers have used me-

chanical micromilling techniques to create structures in

steel and brass with 50-lm resolution77 and micro-

grooves and microchannels in stainless steel, alumi-num, titanium, silver, and other metals with 8-lm reso-

lution (Fig. 51).78 A recently introduced technique uses

commercially available cutting plotters, traditionally

used by the graphics arts industry, to cut patterns into

a variety of polymeric materials.79 Termed xurography,

it has been used to realize a variety of shapes and two-

and three-dimensional microfluidic channel geometries

with a resolution of roughly 35 lm.

A trend in the last several years has been the crea-

tion of microfluidic devices by unconventional, in-

house techniques that do not require the use of photoli-

thography or complex instrumentation. We have dis-

cussed these devices previously, but they bear mention-ing again. Jeong et al.36 invented a technique that uses

a small glass capillary to template a channel in a

PDMS slab. The capillary is later removed, and pulled

pipettes are then inserted, forming core annular flow

and layered channels.48 Similarly, Takeuchi et al.42

used a cut optical fiber as a template for a flow-focus-

ing device in PDMS. Utada et al.40 used pulled pip-

ettes nested into square capillaries to achieve coaxial

alignment of a flow-focusing device. Finally, we devel-

oped a simple microfluidic device consisting of labora-

tory tubing and small-gauge needles that requires only

minutes to construct.45

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2006 Polymer Chemistry in Flow